Pediatric Clostridium difficile: A Phantom Menace or Clinical Reality?

Clostridiumdifficile is the leading cause of nosocomial gastrointestinal illness in adult patients in hospitals. Even though C. difficile disease in adults has been well studied, research on pediatric C. difficile disease is still in its infancy. For many years it has been believed that C. difficile was a disease that affected only adults and was not a problem for children. This erroneous belief arose from the observation that neonates acquire C. difficile quickly (within 48 hours of birth) but show no intestinal symptoms (1–4). More recent evidence has been documented in case reports of pediatric C. difficile and outbreaks of C. difficile disease in pediatric populations (5–7). Pediatric C. difficile disease has also been associated with the occurrence of severe complications and high mortality rates (8–10). The cascade of events in the pathogenesis of C. difficile disease is similar in children and adults. Normal intestinal microflora are disrupted by antibiotic exposure, medications, or surgery. If the child is then exposed to C. difficile (or its spores), colonization may occur, with production of toxins A and B. These toxins act on enterocytes, causing an inflammatory response and morphologic changes that lead to diarrhea or colitis. Host factors (age, diet, immune response) play an important role in determining whether C. difficile develops into asymptomatic carriage or active disease. Treatment for pediatric C. difficile disease usually relies on metronidazole or vancomycin, but clinical guidelines have not been defined for the pediatric population (11). As in adults, recurrent C. difficile disease that does not respond to conventional therapy develops in a proportion of children treated with antibiotic therapy. EPIDEMIOLOGY Acquisition of Clostridium difficile During the first few weeks of life, as many as 67% of infants become colonized with C. difficile if they are delivered in the hospital (1,4,12,13). Older children and adults are protected from colonization by C. difficile by the ability of the normal intestinal microflora to inhibit the overgrowth of pathogenic organisms by a phenomenon called colonization resistance (14,15). C. difficile disease does not usually occur in adults unless antibiotics or other factors disrupt this colonization resistance (16,17). However, because the neonatal intestine is immature and does not have the protective milieu of normal microflora established in adults, the neonate is susceptible to bacterial colonization and overgrowth. The source of the C. difficile is usually not the mother, but rather exposure to C. difficile spores in the hospital nursery (1,18,19). Delmee et al. (2) found that 60% of neonates in a hospital nursery had C. difficile colonization, and 50% of the environmental surfaces were positive for C. difficile spores. Prevalence and Incidence The frequency of pediatric C. difficile is dependent on the age of the children (Table 1). Neonates (birth through 1 month of age) have high frequencies (up to 64%) of C. difficile colonization, but are usually asymptomatic carriers (3,4,13). In infants (<2 years of age), the prevalence ranges from 3% to 62%, but more infants with colonization have symptomatic disease (Fig. 1). In older children (3–18 years of age), the prevalence is similar to adult frequencies (5–8%), with similar distributions of symptomatic and asymptomatic carriers.TABLE 1: Frequency of pediatric Clostridium difficile disease from different patient populationsFIG. 1.: Pathophysiology of toxin A and B–mediated Clostridium difficile disease. Toxins cause fluid secretion, inflammation, increased permeability, and activation of neuroimmune cells through several pathways. Data compiled from references 94–97.Outbreaks Several outbreaks of pediatric C. difficile have been described in the literature (1,5,20,21). Delmee et al. (2) prospectively observed children admitted to one neonatal ward at a Belgian hospital for 6 months and found that 76 (67%) of 114 of the neonates acquired C. difficile(2). Once the isolates were identified, 83% of the strains were in one of two serogroup types and 85% of the environmental isolates were also of these two serotypes (2). No significant association was found between acquisition of C. difficile and the development of intestinal symptoms in this neonatal population, because of a high frequency of asymptomatic carriers. However, there were two cases of severe neonatal necrotizing enterocolitis in these neonates. Ferroni et al. (5) described an outbreak of nosocomial diarrhea that occurred in a pediatric orthopedic service in France. Of the 37 children with nosocomial diarrhea, 6 had documented nosocomial C. difficile. These children were aged from 8 months to 18 years, with a mean age of 9.1 ± 7.9 years and five of six (83%) were boys. All C. difficile isolates belonged to serogroup C. The only significant risk factor was lincomycin, and when this antibiotic was discontinued and increased infection control measures were begun, the outbreak ceased. Larson et al. (1) prospectively observed 451 newborn infants in five postnatal wards in the United Kingdom. The acquisition of C. difficile ranged from 6% to 52%, depending on the ward location. In total, 65 (14.4%) of 451 of the neonates were positive for C. difficile. A cluster of 32 infants on one ward was found, with 52% of the infants positive. The common source of C. difficile was identified to be the nursery's infant bath. In this study, the isolates were not identified. None of the vaginal cultures from the mothers were positive for C. difficile. Frequency of diarrhea was not reported in this study. Small outbreaks of C. difficile diarrhea have also been reported in pediatric oncology wards. Cartwright et al. (6) reported an outbreak involving six patients in which five of the six were infected with the same strain as identified by polymerase chain reaction (PCR) ribotyping. Pediatric outbreaks have occurred in day-care centers. Kim et al. (7) reported five outbreaks of diarrhea in three day-care centers that involved 65 children aged more than 2 years (7). Of the 65 children, 13 had C. difficile diarrhea and 4 had asymptomatic carriage. When children in one day-care center were prospectively observed for 13 weeks and cultures obtained, 50% acquired C. difficile disease. Thus, as in adults, outbreaks of pediatric C. difficile disease have been well documented. CLINICAL PRESENTATION The result of colonization by C. difficile may be separated into four categories: 1) asymptomatic carriage, 2) acute and protracted diarrhea, 3) colitis (pseudomembranous colitis [PMC], fulminant colitis, toxic megacolon, and non-PMC colitis), and 4) recurrent infections. Although there is a high carriage rate in neonates, symptomatic disease is uncommon (21,22). There are several theories to explain why neonates do not exhibit symptoms, despite high colonization rates. C. difficile produces two toxins, A and B, that cause cytokine release, changes in enterocyte morphology, and the activation of the enteric nervous system, which may result in diarrhea (Fig. 1). Receptor sites for the two toxins are located on the epithelial surfaces of the intestine. Several researchers have shown that it is not the absence of receptor sites per se that accounts for the failure of the disease to develop in neonates; receptor sites for C. difficile toxins have been detected (2,18,23–26). The absence of disease may be related to the immaturity in neonates of the toxin receptor sites, which are not able to bind the toxins (22). In addition, a neutralizing effect of maternal antibodies may play a role (22,26). The absence of an inflammatory response may also be caused by the immaturity of the neonatal immune system itself (22). Diet may also play an important role, although this area has not been well studied. Specific dietary substrates may be needed for full expression of the toxins and production of disease. Mahe et al. (27) found that mice fed a complex commercial diet died in response to a challenge with C. difficile, whereas those mice fed a simplified semisynthetic diet survived after C. difficile exposure. That there are no complex substrates in neonatal diets may be one explanation for the absence of symptoms in neonates, even though C. difficile is frequently present. Pediatric C. difficile diarrhea occurs at highest frequencies when the intestinal microflora is becoming established and changes in dietary sources are made. A change from a maternal milk diet to semisolid food was associated with a change in strain types of C. difficile carried by an 11-month-old infant, but the child remained asymptomatic (19). Acute and protracted diarrhea in children may be similar to the symptoms seen in adults, in that diarrhea is observed, and the duration usually ranges from 2 to 9 days (5). Most pediatric patients become symptomatic a few days to weeks after antibiotic exposure, if antibiotics have been administered. Mitchell et al. (28) studied 76 children who were receiving amoxicillin-clavulanate for otitis media, and diarrhea developed in 15 (68%) of the 22 children within 2 days of antibiotic initiation but all 22 developed diarrhea within 7 days. However, many occurrences of pediatric C. difficile disease are not associated with antibiotics (see Risk Factor section), and the incubation period is therefore unclear. C. difficile has also been reported to cause chronic diarrhea, repeated attacks of colic, and other intestinal symptoms in children. Buts et al. (29) reported, in a series of infants with C. difficile 15 had diarrhea, and 4 had evidence of failure to and symptoms in these children recurrent and repeated In in children infected with C. difficile between the of 7 weeks and 7 years, were for from 7 weeks to months et al. observed children with C. difficile and found that the diarrhea for an of months it was the diarrhea in children is to C. difficile or to to is unclear. In diarrhea is not the of pediatric C. difficile disease. et al. reported four children with C. difficile and disease that with of of pediatric colitis may colitis toxic megacolon, and non-PMC colitis. of colitis may diarrhea, and from and The age for children who have is The disease has been reported in children aged days to years cases of fulminant have been reported in neonates, associated with The of is usually or at the of the antibiotic The antibiotics are similar to those in adult patients or In children with the may be et al. found of pediatric patients with 9 et al. also described cases involving in children aged 13 days to C. difficile disease in children has been reported in the and rates have been reported from to after antibiotic et al. reported two pediatric patients with C. difficile diarrhea in chronic diarrhea but patients had several after the was et al. studied cases of C. difficile in pediatric oncology patients and found patients with a reported of Of the symptomatic patients who were then with three 9 had do not which may be because there was no or because of a in the study. In a series of four children with C. difficile diarrhea all four to metronidazole for and no were a of the rate of of pediatric C. difficile disease is in the literature and is usually only reported as a recurrent C. difficile disease in children is as a clinical problem as it is in adults is not of pediatric C. difficile disease are described in the literature but not in with increased of have been found in asymptomatic infants with C. is a for enteric and even infants with no diarrhea may cause clinical complications that have been reported chronic caused by C. difficile in a patient with reported in a infant with intestinal and necrotizing enterocolitis with are at risk for C. difficile because of the of In it is that 50% of children with C. This colonization only in disease in these although four cases of fulminant colitis have been reported As in adults, risk factors for pediatric C. difficile disease may be into several factors that the normal factors (age, immune and or of the Normal Pediatric of C. difficile disease that have been associated with antibiotics occur from 4 to 18 days after the first antibiotic (5). of was found to be associated with a pediatric of C. difficile disease (5). et al. studied pediatric patients with diarrhea for were to the clinical for C. difficile and found 18 were positive. The patients receiving antibiotics had of toxin than those who not antibiotics However, in this no into the or duration of antibiotic was documented. The types of antibiotics that be of C. difficile disease are shown in Most of these reports are from hospital populations of children and in children are associated with Clostridium difficile in adults with C. difficile antibiotic exposure does not to be a for disease development in children. In a of pediatric of those with C. difficile disease had not been exposed to antibiotics in the month There have been several case reports of children with C. difficile disease who have had no exposure to antibiotics the of symptoms Delmee et al. (2) in a of one neonatal ward in no association between antibiotic exposure and C. difficile In neonates who were in the ward for at 1 only had been exposed to antibiotics (2). may have been for normal as in one patient with an that C. difficile disease Host The frequency of symptomatic C. difficile disease depending on the age of the children and to at from 6 months to 2 years (Fig. Neonates acquire C. difficile in neonatal In one study, et al. that were colonized with C. difficile, and 52% were infected with Neonates with toxin had more days of diarrhea ± those with toxin ± Neonates with toxin were and with hospital Thus, this the that no from C. difficile in the neonatal et al. studied children in and reported of the children than months of age had C. difficile The frequency was found to if the children were older for months and for et al. observed pediatric patients in a hospital in and found no of C. difficile disease in children to 6 months of an occurrence in of the children aged 7 to and no occurrence the older children et al. observed receiving antibiotic therapy for otitis media, and C. difficile diarrhea developed in of the children than 1 of whereas it developed in only 3% of the infants 1 to 6 years of A association with age because the development of the intestinal does not the seen in adults the of of occurrence of Clostridium difficile in children. Data are from literature the age of is not of prevalence or because of asymptomatic carriers are usually not were from neonate to 2 years of age and the were not from references of the high frequency of asymptomatic carriage to adults with C. age may not as a risk factor if from children of different are and frequencies of diarrhea and asymptomatic carriage are For et al. studied pediatric aged from 2 weeks to years and reported that the mean age not in children with C. difficile diarrhea with the mean age of control diarrhea months et al. from infants and found C. difficile toxin in of the control diarrhea and in only of the infants with of C. difficile as in than 2 or which may the in C. difficile disease rates in neonates, and older children. In to the effect by the normal intestinal the and of the may be associated with more asymptomatic carriage by The has been shown to be protective C. in cases of pediatric C. difficile disease have been associated with Diet age may be associated with an increased risk of C. difficile disease caused by in infants have C. difficile colonization frequently than et al. found that more infants were C. difficile positive at 6 months of age than infants at 6 and that of those C. difficile at 6 had occurs in neonates and infants (<2 as the immune system of the children full et al. that children with recurrent C. difficile disease have of than do children with no disease. In this of children with C. difficile had and had The children with were of age than children with normal with had a frequency of C. difficile with children with normal The ability of the immune system to protective of C. difficile toxin A has been shown to be important in adults, but has not been documented in children The immaturity of the neonatal immune system may also result in of C. et al. found that to C. difficile toxin was in only of children than 2 years of age though the prevalence of C. difficile in that age is In of children more than 2 years of age and adults had antibodies to C. difficile although the carriage rate is usually or C. difficile disease has been reported in patients in pediatric oncology for the two et al. studied from symptomatic pediatric and from asymptomatic patients admitted as oncology to the for in of the children with diarrhea had C. difficile and of the asymptomatic patients were found to be carriers of C. difficile. No association was found with the of antibiotics or and C. difficile. The only risk factors associated with C. difficile disease with asymptomatic carriers were age months and a hospital days et al. that C. difficile disease was not a disease in this However, several have also reported C. difficile disease in pediatric oncology wards In one of cases of three were associated with or disease et al. described a case involving a with disease who had with development of C. difficile had also been treated with antibiotics and the or was associated with C. difficile disease is C. difficile disease has been reported in pediatric patients who et al. studied pediatric patients who at the of The common bacterial infection in these who were than years of was C. difficile. In the first 2 weeks after C. difficile diarrhea developed in 13 of of the children than 2 years of age and in of children from 2 to years of When patients were observed for 1 to 6 months after the C. difficile remained the common infection in children than 2 years of age and in children aged 2 to years has been reported in infants with who In that of the infants than 2 years of age and of those aged 2 to years were receiving None of the children more than years of age had and the rate of C. difficile diarrhea in these children was risk factors in pediatric patients who may the of and environmental by hospital with C. difficile disease also have been reported to have intestinal or Several of C. difficile have been reported in children with disease of the cases of pediatric C. difficile have been reported with and is and case reports are but with other that occur with C. difficile have been et al. found that 18 of 32 pediatric patients with C. difficile disease had no other enteric but had other bacterial and In of children aged to years, of the children with C. difficile diarrhea carried other reports no association of C. difficile with The of C. difficile disease in pediatric patients is not as as in adults with the disease. with C. difficile disease are defined by a recent of of diarrhea than three per for at 2 of C. difficile or toxin A or and of other of diarrhea (11). As not all children with C. difficile disease have been exposed to and many have of Pediatric The of diarrhea in pediatric patients with C. difficile disease in the literature from more than two per hours (28) to more than four per hours Pediatric diarrhea may also be defined as a fluid of in of per do not a for diarrhea but to with If the diarrhea for more than then it may be protracted or of Clostridium difficile may be by several types of toxin for toxins A B, or a of of the different for C. difficile have not been well documented in the pediatric In adults, have shown that with or have the highest and (Table cultures that C. difficile of C. difficile in the The is the for C. difficile and toxin as as These two and have the of high but the may not be for to and the may not be at all or ranges of and for for Clostridium an to these have been Although and are not as high (Table the are within and are However, in a recent study, et al. all to the in a period and found that toxin A or may not be in pediatric Of from children, were positive for at one C. difficile Of the positive were positive for only toxin were positive for only toxin B, and were positive for toxins A and B. The frequency of toxin was in older children, but not in et al. that for toxin A only of the C. difficile infections. for toxin of the C. difficile infections. The of this is that it is to for toxins, that toxin A positive or toxin positive (or be and that toxins not be positive C. difficile is A of the of C. difficile of the its toxin is not by be on the of C. difficile and the clinical of the disease. If the clinical C. difficile, but the is from at three more be C. difficile is If C. difficile, but the clinical does not asymptomatic carriage is present. of of in adults with C. difficile the of other of diarrhea is not as in pediatric because children have gastrointestinal or of or are usually for children or for disease that C. difficile is for all of and therefore if are found, the is colitis has (Fig. 3) that are 2 to in (11). As shown in have been to C. difficile in children, but the were than and clinical and on does not with clinical The in children with C. difficile disease and of colitis caused by Clostridium difficile. to in are and with of of a child with Clostridium difficile disease. The and are with of of of the The in adults is to the antibiotic that is the C. difficile disease. Although a is in children, it be that pediatric C. difficile disease is not associated with antibiotics In adults, the first of C. difficile is usually treated with metronidazole or is from the intestine although high are in are found in the intestine. metronidazole has been found to be as as in adults with C. difficile disease and is 50% is associated with a frequency of and per has also been for infants and children is not to a after and is in the C. difficile in the However, in adults may from to depending on the of the patient the of and the frequency of have its For adults with recurrent C. difficile a of with a in or days of full by one days for have been (11). In infants and children, there are no is usually per in only severe occurrences of or recurrent colitis, or in children has been to children in from to per for to days (5). of C. difficile have been in several with the frequency from to after is discontinued C. difficile disease from the of the intestinal with or has been This is because these intestinal and have on the of the normal than Several types of show for pediatric C. difficile disease. Buts et al. (29) studied pediatric patients 8 who had chronic diarrhea than 15 and C. difficile toxin identified as the for the was for 15 with to the age of the child if of if years, and 1 if No antibiotics or were the of the 1 symptoms in 18 of the children. of the toxin was observed within 15 days in of of the No were the study. patients had of which after a with No other of in pediatric patients with C. difficile have been children with a of recurrent of C. difficile were treated with strain was for 2 weeks at of No antibiotics or were the of the but all patients were treated with antibiotics in the period of In all four children the disease within to 7 and they were asymptomatic by the of the No were the study. of the children had within 2 months after was No other have been of in pediatric patients with C. difficile. Treatment has been shown that or are in adults with C. difficile disease than in asymptomatic carriers. patients with recurrent C. difficile have also been shown to have of to toxin A with disease have been treated with therapy with immune but have not been reported et al. studied six children with C. difficile colitis 7 who were treated at in These six children were found to have A with children, who had a of of the six symptomatic children were treated with No antibiotics were the first weeks of the study. The children significant to after in but not A to after All five children clinical of the diarrhea, but one child had of disease after have not been and reported two children with recurrent C. difficile who had been treated with which was were by a of and In the child asymptomatic within days of therapy and remained the of and 48 The that may active C. difficile, toxins, or spores from the and may be as an therapy. There have been no reports of this has been in a few children but the are and have not been also vancomycin, and therefore these two not be There is of the role of in pediatric infections. C. difficile disease in pediatric patients is as an cause of from diarrhea to colitis. However, a of the of the asymptomatic colonization of and the it is not to for in an case of C. diarrhea in this age the has not been identified, and although it that metronidazole is the on its and as well as on the frequency of are not the role of also to be a but is that this clinical to the many that