Epidemiology, Diagnosis, and Treatment of Clostridioides difficile Infection in Immunocompromised Children

Abstract

Clostridioides difficile infection is very common in immunocompromised children. Management is confounded by frequent asymptomatic colonization, multiple alternative etiologies for gastrointestinal symptoms, and high rates of relapse. Important considerations include indications for testing, appropriate choice of diagnostic tests, antibiotic therapy for initial and subsequent episodes, and primary and secondary prevention.

Immunocompromised children are at much higher risk of Clostridioides difficile infection (CDI) than otherwise healthy children [1–7]. Children with cancer appear to be at especially high risk—one large study suggested that the risk is 15 times higher than in children without cancer, with an overall rate of about 2% of all admissions, and around 10%-30% of children with cancer develop health care-associated CDI [1–3, 6]. And, although the intensity of chemotherapy does not strongly predict CDI development, patients with hematologic malignancies are at highest risk (OR 3) compared to those with solid tumors [1, 8]. Rates of CDI are also high in pediatric hematopoietic cell transplantation (HCT; incidence of 18.2%), solid organ transplantation (SOT; incidence of 7.3%-12%) recipients, and children with inflammatory bowel disease (IBD; OR 11.42, incidence of 7.7%) [4, 5, 7, 9–11]. These estimates are all confounded by a very high risk of asymptomatic colonization with C. difficile. The overall severity of CDI typically appears to be similar to children without immunocompromise [12, 13], but the rate of recurrence is high, around 30% in pediatric HCT and up to twice that in SOT [4, 7, 14]. Because of these factors, and because of a frequent need for broad-spectrum antibiotics, the diagnosis, treatment, and prevention of CDI in immunocompromised children is challenging and specialized.

RISK FACTORS AND EPIDEMIOLOGY

Development of CDI occurs at the intersection of colonization with toxigenic C. difficile and disruption of a healthy gut microbiota or immune system. Exposure to medications that disrupt microbiota, including antibiotics or acid suppressing agents, are important and potentially modifiable risk factors. Hospitalization is also a risk factor that reflects not only risk of nosocomial exposure to toxigenic strains but also underlying medical illness and corresponding immunodeficiencies. In the general pediatric population, antibiotic use (OR 1.7), acid-suppressive therapy (OR 1.8 and 7.7), and immunosuppression (OR 2.5) have all been found to be CDI risk factors [15–17].

Not all antibiotics are associated with CDI risk to the same degree. Late generation cephalosporins, carbapenems, and clindamycin are most commonly implicated in adults [18, 19]. Children with cancer are at particular risk from exposure to late generation (third and fourth, including antipseudomonal) cephalosporins or prolonged broad-spectrum antibiotics [3, 20]. The increase in risk of CDI with late-generation cephalosporins is similar for children with cancer (HR 2.4), HCT (OR 2.4), and SOT (OR 3.9) [4, 18]. Notably, although fluoroquinolones have been implicated in adults and pediatrics, they appear protective in the pediatric oncology and transplant populations when used for neutropenia prophylaxis during periods of intensive immunosuppression (eg, acute lymphoblastic leukemia [ALL] induction and acute myeloid leukemia [AML]). Although the exact reason for this apparent paradoxical finding is unknown, it is postulated to be a result of reduced exposure to other broad-spectrum antibiotics during these periods, but may be limited to settings with low levels of fluoroquinolone resistance in C. difficile isolates from pediatric patients [4, 18, 21–23].

Proton pump inhibitors (PPI) and histamine-2 receptor antagonists (H2-RA) might increase the risk of CDI but the association is unclear. In some studies of immunocompromised children, PPIs and H2-RA were associated with CDI, whereas others found a protective or no effect [1, 4, 9, 20, 24].

In specific pediatric populations, the use of immunosuppressive medications may increase CDI risks. The risk of CDI was increased in SOT patients receiving calcineurin inhibitors (OR 2.4), and patients with IBD receiving corticosteroid (aHR 4.4) and antitumor necrosis factor agents (aHR 3.3) [11, 25]. For SOT and IBD, these agents are cornerstones of therapy, making dose or regimen adjustments a problematic target for CDI risk mitigation.

DIAGNOSIS OF CDI IN CHILDREN WITH CANCER OR IMMUNOCOMPROMISE

Clinical Presentation

The diagnosis of CDI in immunocompromised children can be confounded by alternative etiologies for diarrhea and the high frequency of colonization. Almost all patients with CDI present with diarrhea, fever, abdominal pain, nausea, and vomiting are also common [26]. Because it is a colonic infection, the vomiting noted in up to 1 in 4 immunocompromised children with CDI might be a nonspecific response to the illness or might represent a concomitant illness [24]. Severe abdominal distension, ileus, bloody stools, and direct complications such as intraabdominal abscess, bacteremia, or septic arthritis are all rare in this population [24, 26]. The odor of the stool may be characteristic but is not sensitive or specific [27]. The clinical syndrome of CDI in immunocompromised children can overlap with other important problems, such as exacerbation of IBD, graft-vs-host disease in HCT recipients, neutropenic enterocolitis, intestinal infection with CMV, adenovirus, Cryptosporidium parvum, and many others.

Importance of Asymptomatic Colonization

The main difficulty with diagnosis of CDI in immunocompromised children is the high rate of asymptomatic colonization [28–31]. Multiple studies have shown that around 19%-33% of immunocompromised children of any age, especially those with cancer, are colonized with C. difficile in the absence of symptoms, and that colonization can persist well after successful treatment for CDI [28–32]. Therefore, the presence of toxigenic C. difficile in stool does not prove that it is the cause of the symptoms. This is especially important in infants <2 years of age in whom colonization is extremely common, and CDI is rare [32].

Diagnostic Tests

Diagnosis of CDI requires detection of toxigenic C. difficile in stool during a compatible clinical syndrome. Routinely used approaches to C. difficile detection are identification of the toxin B gene by nucleic acid amplification tests (NAAT; eg, PCR) or direct demonstration of toxin by enzyme immunoassay (EIA).

Toxin B gene PCR is rapid, relatively inexpensive, and sensitive. The main criticism of NAAT testing is that it demonstrates only the potential for toxin production, rather than the presence of the actual toxin itself. This might be especially important in the pediatric immunocompromised population in whom asymptomatic colonization with toxigenic C. difficile is so common [32].

In contrast, detection of toxin A or B by EIA does demonstrate the presence of the toxin in stool and is similarly inexpensive and rapid. It is tempting to propose that toxin EIA might better discriminate between C. difficile colonization and infection in immunocompromised children [33]. If true, this approach could markedly reduce overdiagnosis of CDI because EIA is negative in about half of PCR-positive samples. However, in 88 children with a positive toxin B PCR from either formed (asymptomatic) or unformed (symptomatic) stool, EIA was commonly positive in asymptomatic (26%) and negative in symptomatic (56%) individuals, suggesting it does not discriminate well between colonization and infection [34]. Around 40% of these patients had cancer or IBD, so the results are likely applicable to the immunocompromised host population. Toxin EIA sensitivity is improved by a 2-stage test using initial detection of C. difficile glutamate dehydrogenase followed by confirmatory toxin EIA, with PCR for discrepant cases.

On the basis of these data, the optimal strategy for diagnosis of CDI in immunocompromised children is not well defined. It is therefore reasonable to use either a glutamate dehydrogenase assay followed by confirmatory toxin EIA (with NAAT for discrepant cases) or a single-step NAAT-based approach for diagnosis of CDI in immunocompromised children. Clinical evaluation prior to sending the test is essential to ensure optimal care. Confirm the presence of diarrhea and consider alternative etiologies, such as recent laxatives, before sending stool for C. difficile testing, because false-positive results may lead to inappropriate treatment and postpone the correct diagnosis.

Imaging

Imaging tests can provide information about severity and extent of CDI by demonstrating bowel wall-thickening, pneumatosis intestinalis, or perforation, but is most often normal [3]. Use of imaging should be restricted to patients with signs or symptoms suggesting peritonitis, colitis, or other complications. In patients with neutropenia, abdominal ultrasound may identify small or large bowel wall-thickening that can indicate neutropenic enterocolitis, however, it is unclear whether this contributes to management in this population since broader antibiotic therapy is frequently used as discussed below [35].

Disease Severity Stratification

Once the diagnosis of CDI is made, treatment approaches may be tailored to disease severity (non-severe vs severe) [36]. However, severity stratification in immunocompromised hosts is complicated by the frequent suppression of white blood cells which is traditionally utilized to diagnose severe CDI on immunocompetent populations, and the absence of data to support the clinical significance of stratification models [36]. One practical approach to stratification is to use requirement of critical care or the presence of hemodynamic instability, ileus, toxic megacolon, or pseudomembranous colitis to guide therapy [36].

TREATMENT OF C. DIFFICILE IN CHILDREN WITH CANCER OR IMMUNOCOMPROMISE

Recommendations for CDI treatment in immunocompromised children are mostly extrapolated from data for adults and immunocompetent children. Antibiotic therapy targeting C. difficile and restoration of the microbiome are the mainstays of treatment success (Table 1). Systemic antibiotics should be discontinued whenever possible, and if discontinuation is not appropriate, consideration should be given to narrowing the spectrum of antimicrobial activity (ie, de-escalation).

Table 1.

Options for Treatment of C. difficile Infection in Immunocompromised Children

Clinical Setting	Recommended Treatment	Dosage, Frequency, and Duration	Maximum Dose and Notes
All cases	1. Discontinue all other antibiotics if safe to do so 2. Narrow spectrum of antibiotics if unable to discontinue
Initial episode; non-severe	Vancomycin, or	10 mg/kg/dose PO qid × 10 days	125 mg per dose
	Metronidazole, or	7.5 mg/kg/dose PO tid or qid × 10 days	500 mg per dose
	Fidaxomicin	16 mg/kg/dose PO bid × 10 days	200 mg per dose
Initial episode; severe or fulminant	Vancomycin	10 mg/kg/dose PO qid × 10 days Same dosing if rectal administration indicated	500 mg per dose Final volumes for rectal administration should be individualized to age/body size; caution with rectal administration in neutropenic hosts
	Consider addition of Metronidazole	10 mg/kg/dose IV tid × 10 days	500 mg per dose
Subsequent episodes; non-severe	Vancomycin, or	10 mg/kg/dose PO qid × 10-14 days	125 mg per dose
	Fidaxomicin, or	16 mg/kg/dose PO bid × 10 days	200 mg per dose
	Vancomycin	10 mg/kg/dose PO qid × 10-14 days Followed by vancomycin taper: 10 mg/kg/dose PO bid × 1 week 10 mg/kg/dose PO once daily × 1 week 10 mg/kg/dose PO every 2-3 days × 2-8 weeks	125 mg per dose
Multiple recurrent episodes	As above and consider: • Fecal microbiome transplantation • Vancomycin prophylaxis during high-risk periods(eg, 10 mg/kg (max 125 mg) PO once daily while receiving and for 5 days after systemic antibiotics)

Treatment of Non-Severe CDI

Common treatments for non-severe CDI in immunocompromised children include metronidazole, oral vancomycin, and oral fidaxomicin. Although a recent analysis of 2 prospective randomized trials of adults with CDI found that initial treatment success was higher for vancomycin than metronidazole (81% vs 73%; P = .02), with a smaller difference for non-severe disease (82% vs 76%) [37], children were not included in this study and the proportion of patients with immunocompromise diagnosis was not reported [37].

A randomized trial of oral fidaxomicin vs vancomycin in children with non-severe CDI found that clinical improvement was similar between groups (77.6% vs 70.5%) and that fidaxomicin was associated with a lower rate of recurrence (11.8% vs 29%), so fidaxomicin was associated with a significantly higher chance of cure at 30 days after completion of therapy (68.4% vs 50%, respectively; adjusted treatment difference of 18.8%, 95% CI 1.5% to 35.3%) [21]. In this study, 45% of participants were immunocompromised, and a post hoc analysis suggested a similar, though non-statistically significant reduction in recurrence in this subgroup (7.1% fidaxomicin vs 25% vancomycin). This finding is consistent with data from adult patients with cancer in which a cure without recurrence (ie, global cure) was enhanced with fidaxomicin compared to vancomycin (73.6% vs 52.1%, respectively; P = .003) [38].

These data suggest that clinicians have options when treating non-severe CDI in immunocompromised children. Metronidazole is acceptable for a first episode and recommended in published guidelines as cure rates are high [3, 12, 36, 39, 40]. More recently, some pediatric clinicians appear to prefer vancomycin, perhaps extrapolating that the benefit over metronidazole seen in adults translates to children [39, 40]. Likewise, first recurrences could be treated with either vancomycin or fidaxomicin for similar reasons. The use of fidaxomicin is hampered by higher acquisition costs, although this could be offset by a lower rate of recurrent infection and a more limited disruption to the microbiome in this vulnerable population [41]. Combination therapy with oral vancomycin and metronidazole is not uncommonly seen, but since this practice is not supported by published data, it is an opportunity for antimicrobial stewardship programs to optimize care [3, 12]. For the first recurrent episode of CDI, treatment with vancomycin or fidaxomicin is appropriate, in addition to secondary prevention measures discussed below.

Treatment of Severe or Fulminant CDI

Evidence for classification and treatment of severe CDI in immunocompromised children is even more limited. Oral vancomycin (with or without metronidazole) remains the recommended drug of choice. This is based partly on data suggesting greater superiority of vancomycin over metronidazole in adult patients with severe CDI (78.5% vs 66.3%; P = .06) [37]. In patients with severe CDI receiving vancomycin, higher doses (>500 mg per day), prolonged courses (≥10 days), and ICU-level care are associated with some risk of systemic vancomycin absorption which can lead to acute kidney injury [42]. If enteral administration is not feasible (eg, ileus), intravenous metronidazole combined with rectal instillation of vancomycin may be utilized, but caution is advised with rectal administration of drugs in neutropenic patients [43].

Fidaxomicin has not been directly compared to either metronidazole or vancomycin for severe CDI in a prospective manner. Retrospective evidence suggests comparable outcomes between fidaxomicin and oral vancomycin in adults and that it likely is superior to metronidazole though the number of patients studied is small [44, 45]. The study of fidaxomicin for CDI in children excluded severe CDI, so further investigation in this area is needed.

Treatment of Concomitant Clinical Syndromes

Although treatment of CDI ideally involves reducing exposure to other antibiotics, competing priorities in immunocompromised children may require continuing, or even initiating, broad-spectrum concurrent antibiotic therapy. For example, many patients with febrile neutropenia are at high risk of bacterial infection if treated with only antibiotics directed at CDI, and patients with neutropenic enterocolitis may have translocation of gram-negative and aerobic gram-positive organisms from the gut that can lead to serious illness if left untreated [46].

PRIMARY PREVENTION OF C. DIFFICILE INFECTION

Although children with immunocompromise have high rates of CDI and may have multiple risk factors for infection, modifying antibiotic use, preventing cross-contamination, and other interventions may reduce the risk.

Modification of Antibiotic Exposure

The primary risk factor for CDI is recent antibiotic exposure, so modification of antibiotic exposure is essential for prevention. Avoiding unnecessary and high-risk antibiotic exposure is the most important tool for CDI prevention. However, common infectious syndromes such as febrile neutropenia, bacteremia, and neutropenic enterocolitis (ie, typhlitis) are often accompanied by CDI and require broad-spectrum antibacterial coverage initially. Institution-specific, risk-stratified syndromic treatment guidelines should be implemented, and encourage (whenever possible): limiting broad-spectrum or combination antibiotics to those patients at highest risk of serious infection or poor outcomes, narrowing therapy once life-threatening or antibiotic-resistant infection has been excluded (eg, stopping adjunctive aminoglycoside or vancomycin in patients with sepsis or febrile neutropenia), step-down therapy (eg, from an antipseudomonal cephalosporin to a broad-spectrum fluoroquinolone in low-risk febrile neutropenia), and discontinuing antibiotic therapy after the appropriate course for the syndrome [47]. Antimicrobial stewardship interventions are effective in improving antibiotic use in these settings [48]. Antibacterial prophylaxis with levofloxacin in appropriate populations (eg, children with AML or ALL undergoing higher risk induction therapy) may also reduce the risk of CDI, but should not be extended to lower risk populations because of other consequences such as tendinopathy and antibiotic resistance [21, 23].

Infection Control and Prevention

Conventional infection-prevention mechanisms for reducing the risk of CDI are somewhat controversial, because colonization may already exist at admission in patients who develop CDI during hospitalization [31]. However, evidence of higher CDI risk in children with cancer residing in hospital with another patient who has CDI, and of CDI outbreaks occurring on units treating immunocompromised children, suggest that reducing cross-contamination is important [1]. Glove and gown use by staff and visitors, strict handwashing, room cleaning with techniques that kill C. difficile spores (eg, bleach, peroxide-based cleaners, and ultraviolet light) should typically be used in all patients with suspected or documented CDI to protect others [39, 49].

Other Interventions to Prevent CDI

The safety and efficacy of probiotics, prebiotics, and other interventions to directly support microbiome colonization resistance for primary prevention of CDI in immunocompromised children are not supported by high-quality evidence, and there is some evidence for harm. A special concern in immunocompromised hosts is the possibility of invasive infection with a probiotic agent, which has been described [36]. In our experience, there is a significant risk of infection from probiotics in profoundly immunocompromised children, and we do not recommend routine use.

Another potential intervention to prevent CDI is reduction in the use of acid suppression agents. Because the effect of this intervention in CDI is unknown, there insufficient information to recommend avoidance of acid suppression for prevention of CDI, especially in immunocompromised hosts who may have multiple risk factors for gastritis or ulceration.

SECONDARY PREVENTION OF C. DIFFICILE INFECTION

After treatment of an initial episode of CDI, recurrence remains a challenge, affecting up to one-third of immunocompromised patients. In addition to attention to the factors described above for primary prevention of CDI, options to prevent recurrence include treatment with a different drug than the initial episode, the use of vancomycin tapers or secondary prophylaxis, extended-pulse fidaxomicin, bezlotoxumab, and fecal microbiota transplantation (FMT).

Fidaxomicin is a reasonable treatment option for recurrent CDI. However, it is important to note that the study that reported a reduction in recurrent disease in children had only short-term follow-up (30 days) and did not stratify analysis by first or recurrent infection at enrollment, so there may not be an equivalent benefit for the treatment of recurrent infection [21, 36]. Fidaxomicin has also been studied as an “extended-pulsed” regimen: In an open-label randomized controlled trial in adults, this approach was superior to a 10-day course of vancomycin alone (70% vs 59%, respectively; P = .03), but it is unclear whether the regimen is superior to a standard 10-day course of fidaxomicin [50].

Bezlotoxumab, a humanized monoclonal antibody that binds to and neutralizes C. difficile toxin B, given as an intravenous infusion with standard CDI therapy, reduces the rate of CDI recurrence in adults, including immunocompromised patients [51]. However, it has not been evaluated in pediatric patients and a clinical trial is currently underway.

In adults at high risk of CDI recurrence, prophylactic vancomycin during high-risk periods reduced recurrence in an open-label randomized controlled trial [52]. This study had limited power (n = 50 per group), a short follow-up period, and limited evaluation of resistance development. There is not yet high-quality evidence for secondary prophylaxis against CDI with oral vancomycin in immunocompromised children, but it may be considered in unusually high-risk situations, for example, patients with multiple past recurrences who now need broad-spectrum antibiotic therapy. However, there are significant risks to this approach, including the possibility of further reducing C. difficile colonization resistance, leading to further increases in risk for future episodes [53]. Metronidazole should not be used for prophylaxis because of peripheral neuropathy associated with prolonged and repeated exposure [54].

Finally, FMT might ameliorate dysbiosis and prevent recurrent CDI. Although encouraging outcomes have been reported in small case series, data remain limited [55, 56]. FMT is generally considered only for patients with multiple CDI recurrences and extreme caution should be taken when utilized in immunocompromised hosts. Indeed, the FDA has published a safety alert after the transmission of extended-spectrum β-lactamase-producing E. coli occurred in 2 immunocompromised adults leading to invasive infection in both and death in 1 recipient [57, 58]. The alert highlights the need for careful donor screening measures, including pretransplant stool testing, to minimize the risk of transmitting multidrug-resistant organisms to patients.

We typically use a standard course of vancomycin for first recurrences and a tapered vancomycin regimen for second or subsequent recurrences. Fidaxomicin is also a reasonable treatment for recurrent CDI in this population.

Conclusions

Management of CDI in immunocompromised children is confounded by frequent asymptomatic colonization, multiple alternative etiologies for gastrointestinal symptoms, and high rates of relapse. Important considerations include indications for testing, appropriate choice of diagnostic tests, antibiotic therapy for initial and subsequent episodes, and primary and secondary prevention.

Notes

Financial support. This work is supported, in part, by the National Cancer Institute Cancer Center Support (CORE) grant P30 CA021765 and the American Lebanese Syrian Associated Charities (ALSAC).

Supplement sponsorship. This supplement was sponsored by Pfizer, Merck, and Azurity.

Conflict of Interest. J.W. reports his institution receiving compensation from Astellas Inc. for participation in industry-sponsored research. S.C. is a clinical consultant for Lexicomp^® (Wolters Kluwer). All authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.