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Stool Toxin Concentration Does Not Distinguish Clostridioides difficile Infection from Colonization in Children Less Than 3 Years of Age.

ABSTRACT: In a prospective cohort study, stools from children <3 years with and without diarrhea who were Clostridioides difficile nucleic acid amplification test-positive underwent ultrasensitive and quantitative toxin measurement. Among 37 cases and 46 controls, toxin concentration distributions overlapped substantially. Toxin concentration alone does not distinguish C. difficile infection from colonization in young children.

SUBMITTER: Sandora TJ

PROVIDER: S-EPMC9595052 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Stool Toxin Concentration Does Not Distinguish Clostridioides difficile Infection from Colonization in Children Less Than 3 Years of Age.

Sandora Thomas J TJ Williams David N DN Daugherty Kaitlyn K Geer Christine C Cuddemi Christine C Kociolek Larry K LK Chen Xinhua X Xu Hua H Savage Timothy J TJ Banz Alice A Garey Kevin W KW Gonzales-Luna Anne J AJ Kelly Ciarán P CP Pollock Nira R NR

Journal of the Pediatric Infectious Diseases Society 20221001 10

In a prospective cohort study, stools from children <3 years with and without diarrhea who were Clostridioides difficile nucleic acid amplification test-positive underwent ultrasensitive and quantitative toxin measurement. Among 37 cases and 46 controls, toxin concentration distributions overlapped substantially. Toxin concentration alone does not distinguish C. difficile infection from colonization in young children. ...[more]

PMID: 35801632

Similar Datasets

Baseline stool toxin concentration is associated with risk of recurrence in children with Clostridioides difficile infection.

Project description:BackgroundIn adults with Clostridioides difficile infection (CDI), higher stool concentrations of toxins A and B are associated with severe baseline disease, CDI-attributable severe outcomes, and recurrence. We evaluated whether toxin concentration predicts these presentations in children with CDI.MethodsWe conducted a prospective cohort study of inpatients aged 2-17 years with CDI who received treatment. Patients were followed for 40 days after diagnosis for severe outcomes (intensive care unit admission, colectomy, or death, categorized as CDI primarily attributable, CDI contributed, or CDI not contributing) and recurrence. Baseline stool toxin A and B concentrations were measured using ultrasensitive single-molecule array assay, and 12 plasma cytokines were measured when blood was available.ResultsWe enrolled 187 pediatric patients (median age, 9.6 years). Patients with severe baseline disease by IDSA-SHEA criteria (n = 34) had nonsignificantly higher median stool toxin A+B concentration than those without severe disease (n = 122; 3,217.2 vs 473.3 pg/mL; P = .08). Median toxin A+B concentration was nonsignificantly higher in children with a primarily attributed severe outcome (n = 4) versus no severe outcome (n = 148; 19,472.6 vs 429.1 pg/mL; P = .301). Recurrence occurred in 17 (9.4%) of 180 patients. Baseline toxin A+B concentration was significantly higher in patients with versus without recurrence: 4,398.8 versus 280.8 pg/mL (P = .024). Plasma granulocyte colony-stimulating factor concentration was significantly higher in CDI patients versus non-CDI diarrhea controls: 165.5 versus 28.5 pg/mL (P < .001).ConclusionsHigher baseline stool toxin concentrations are present in children with CDI recurrence. Toxin quantification should be included in CDI treatment trials to evaluate its use in severity assessment and outcome prediction.

| S-EPMC10330943 | biostudies-literature

Clostridioides difficile Toxin B PCR Cycle Threshold as a Predictor of Toxin Testing in Stool Specimens from Hospitalized Adults.

Project description:Rapid, accurate detection of Clostridioides difficile toxin may potentially be predicted by toxin B PCR cycle threshold (tcdB Ct). We investigated the validity of this approach in an inpatient adult population. Patients who tested positive by C. difficile PCR (Cepheid GeneXpert) from December 2016 to October 2020 (n = 368) at a tertiary medical center were included. All stool samples were further tested by rapid glutamate dehydrogenase (GDH)/toxin B EIA and cell cytotoxin neutralization assay (CCNA). Receiver operating characteristic curves were analyzed. The area under the curve for tcdB Ct predicting toxin result by EIA was 0.795 (95% confidence interval (CI) 0.747-0.843) and by CCNA was 0.771 (95% CI 0.720-0.822). The Youden Ct cutoff for CCNA was ≤27.8 cycles (sensitivity 65.0%, specificity 77.2%). For specimens with Ct ≤ 25.0 cycles (n = 115), CCNA toxin was positive in >90%. The negative predictive value of tcdB Ct for CCNA was no greater than 80% regardless of cutoff chosen. In summary, very low Ct values (≤25.0) could have limited value as a rapid indicator of positive toxin status by CCNA in our patient population. A broad distribution of Ct values for toxin-negative and toxin-positive specimens precluded more robust prediction. Additional data are needed before broader application of Ct values from qualitatively designed assays to clinical laboratory reporting.

| S-EPMC9137712 | biostudies-literature

Transmission of Clostridioides difficile infection (CDI) from patients less than 3 years of age in a pediatric oncology setting.

Project description:Clostridioides difficile infection (CDI) is prevalent in pediatric oncology patients, but the transmission risk to peers is unknown. In 224 children with CDI, multilocus sequence typing (MLST) identified only 7 alleged transmission events (18%) originating from children <3 years old. None of these events were corroborated by WGS.

| S-EPMC7673106 | biostudies-literature

Consortium of Probiotics Attenuates Colonization of Clostridioides difficile.

Project description:Clostridioides difficile infection (CDI) is increasing morbidity and mortality rates globally. Fecal microbiota transplantation (FMT), an effective therapy for eliminating Clostridioides difficile (C. difficile), cannot be used extensive due to a range of challenges. Probiotics thus constitutes a promising alternative therapy. In our study, we evaluated the effect of consortium of probiotics including five Lactobacilli strains and two Bifidobacterium strains on the colonization of toxigenic BI/NAP1/027 C. difficile in a mouse model. The results of 16S rRNA sequencing and targeted metabolomics showed the consortium of probiotics effectively decreased the colonization of C. difficile, changed the α- and β-diversity of the gut microbiota, decreased the primary bile acids, and increased the secondary bile acids. Spearman's correlation showed that some of the OTUs such as Akkermansia, Bacteroides, Blautia et al. were positively correlated with C. difficile numbers and the primary bile acids, and negatively correlated with the secondary bile acids. However, some of the OTUs, such as Butyricicoccus, Ruminococcus, and Rikenellaceae, were negatively correlated with C. difficile copies and the primary bile acids, and positively correlated with the secondary bile acids. In summary, the consortium of probiotics effectively decreases the colonization of C. difficile, probably via alteration of gut microbiota and bile acids. Our probiotics mixture thus offers a promising FMT alternative.

| S-EPMC6920126 | biostudies-literature

Natural Clostridioides difficile Toxin Immunization in Colonized Infants.

Project description:BackgroundClostridioides (Clostridium) difficile colonization is common among infants. Serological sequelae of infant C. difficile colonization are poorly understood.MethodsIn this prospective cohort study of healthy infants, stools serially collected between ages 1-2 and 9-12 months were tested for non-toxigenic and toxigenic C. difficile (TCD). Cultured isolates underwent whole-genome sequencing. Serum collected at 9-12 months underwent measurement of IgA, IgG, and IgM against TCD toxins A and B and neutralizing antibody (NAb) titers against toxin B. For comparison, antitoxin IgG and NAb were measured in cord blood from 50 mothers unrelated to study infants.ResultsAmong 32 infants, 16 (50%) were colonized with TCD; 12 were first colonized >1 month before serology measurements. A variety of sequence types were identified, and there was evidence of putative in-home (enrolled siblings) and outpatient clinic transmission. Infants first colonized with TCD >1 month prior had significantly greater serum antitoxin IgA and IgG against toxins A (P = .02 for both) and B (P = .009 and .008, respectively) compared with non-TCD-colonized infants, and greater IgG compared with unrelated cord blood (P = .005). Five of 12 (42%) colonized infants had detectable NAb titers compared with zero non-TCD-colonized infants (P = .02). Breastfeeding was not associated with differences in serological measurements.ConclusionsTCD colonization is associated with a humoral immune response against toxins A and B, with evidence of toxin B neutralization in vitro. The extent and duration of protection against CDI later in life afforded by natural C. difficile immunization events require further investigation.

| S-EPMC7201415 | biostudies-literature

Spores of Clostridioides difficile are toxin delivery vehicles.

Project description:Clostridioides difficile causes a wide range of intestinal diseases through the action of two main cytotoxins, TcdA and TcdB. Ingested spores germinate in the intestine establishing a population of cells that produce toxins and spores. The pathogenicity locus, PaLoc, comprises several genes, including those coding for TcdA/B, for the holin-like TcdE protein, and for TcdR, an auto-regulatory RNA polymerase sigma factor essential for tcdA/B and tcdE expression. Here we show that tcdR, tcdA, tcdB and tcdE are expressed in a fraction of the sporulating cells, in either the whole sporangium or in the forespore. The whole sporangium pattern is due to protracted expression initiated in vegetative cells by σD, which primes the TcdR auto-regulatory loop. In contrast, the forespore-specific regulatory proteins σG and SpoVT control TcdR production and tcdA/tcdB and tcdE expression in this cell. We detected TcdA at the spore surface, and we show that wild type and ΔtcdA or ΔtcdB spores but not ΔtcdR or ΔtcdA/ΔtcdB spores are cytopathic against HT29 and Vero cells, indicating that spores may serve as toxin-delivery vehicles. Since the addition of TcdA and TcdB enhance binding of spores to epithelial cells, this effect may occur independently of toxin production by vegetative cells.

| S-EPMC11237016 | biostudies-literature

Comparison of Clostridioides difficile Stool Toxin Concentrations in Adults With Symptomatic Infection and Asymptomatic Carriage Using an Ultrasensitive Quantitative Immunoassay.

Project description:BackgroundWe used an ultrasensitive, quantitative single molecule array (Simoa) immunoassay to test whether concentrations of Clostridioides (formerly Clostridium) difficile toxins A and/or B in the stool of adult inpatients with C. difficile infection (CDI) were higher than in asymptomatic carriers of toxinogenic C. difficile.MethodsPatients enrolled as CDI-NAAT had clinically significant diarrhea and a positive nucleic acid amplification test (NAAT), per US guidelines, and received CDI treatment. Potential carriers had recently received antibiotics and did not have diarrhea; positive NAAT confirmed carriage. Baseline stool samples were tested by Simoa for toxin A and B.ResultsStool toxin concentrations in both CDI-NAAT (n = 122) and carrier-NAAT (n = 44) cohorts spanned 5 logs (0 pg/mL to >100000 pg/mL). Seventy-nine of 122 (65%) CDI-NAAT and 34 of 44 (77%) carrier-NAAT had toxin A + B concentration ≥20 pg/mL (clinical cutoff). Median toxin A, toxin B, toxin A + B, and NAAT cycle threshold (Ct) values in CDI-NAAT and carrier-NAAT cohorts were similar (toxin A, 50.6 vs 60.0 pg/mL, P = .958; toxin B, 89.5 vs 42.3 pg/mL, P = .788; toxin A + B, 197.2 vs 137.3 pg/mL, P = .766; Ct, 28.1 vs 28.6, P = .354). However, when CDI/carrier cohorts were limited to those with detectable toxin, respective medians were significantly different (A: 874.0 vs 129.7, P = .021; B: 1317.0 vs 81.7, P = .003, A + B, 4180.7 vs 349.6, P = .004; Ct, 25.8 vs 27.7, P = .015).ConclusionsToxin concentration did not differentiate an individual with CDI from one with asymptomatic carriage. Median stool toxin concentrations in groups with CDI vs carriage differed, but only when groups were defined by detectable stool toxin (vs positive NAAT).

| S-EPMC6293008 | biostudies-literature

Clinical evaluation of a non-purified direct molecular assay for the detection of Clostridioides difficile toxin genes in stool specimens.

Project description:Recently, a new rapid assay for the detection of tcdB gene of Clostridioides difficile was developed using the GENECUBE. The assay can directly detect the tcdB gene from stool samples without a purification in approximately 35 minutes with a few minutes of preparation process. We performed a prospective comparative study of the performance of the assay at eight institutions in Japan. Fresh residual stool samples (Bristol stool scale ≥5) were used and comparisons were performed with the BD MAX Cdiff assay and toxigenic cultures. For the evaluation of 383 stool samples compared with the BD MAX Cdiff assay, the sensitivity, and specificity of the two assays was 99.0% (379/383), 98.1% (52/53), 99.1% (327/330), respectively. In the comparison with toxigenic culture, the total, sensitivity, and specificity were 96.6% (370/383), 85.0% (51/60), and 98.8% (319/323), respectively. The current investigation indicated the GENECUBE Clostridioides difficile assay has equivalent performance with the BD MAX Cdiff assay for the detection of tcdB gene of C. difficile.

| S-EPMC7269250 | biostudies-literature

Host Immune Markers Distinguish Clostridioides difficile Infection From Asymptomatic Carriage and Non-C. difficile Diarrhea.

Project description:BackgroundRecent data indicate that Clostridioides difficile toxin concentrations in stool do not differentiate between C. difficile infection (CDI) and asymptomatic carriage. Thus, we lack a method to distinguish a symptomatic patient with CDI from a colonized patient with diarrhea from another cause. To address this, we evaluated markers of innate and adaptive immunity in adult inpatients with CDI (diagnosed per US guidelines), asymptomatic carriage, or non-CDI diarrhea.MethodsCDI-NAAT patients had clinically significant diarrhea and positive nucleic acid amplification testing (NAAT) and received CDI treatment. Carrier-NAAT patients had positive stool NAAT but no diarrhea. NAAT-negative patients (with and without diarrhea) were also enrolled. A panel of cytokines and anti-toxin A and B immunoglobulin (Ig) were measured in serum; calprotectin and anti-toxin B Ig A/G were measured in stool. NAAT-positive stool samples were tested by an ultrasensitive toxin assay (clinical cutoff, 20 pg/mL).ResultsMedian values for interleukin (IL)-4, IL-6, IL-8, IL-10, IL-15, granulocyte colony-stimulating factor (GCSF), MCP-1, tumor necrosis factor α (TNF-α), and IgG anti-toxin A in blood and IgA/G anti-toxin B in stool were significantly higher in CDI patients compared with all other groups (P < .05). Concentration distributions for IL-6, GCSF, TNF-α, and IgG anti-toxin A in blood, as well as IgA and IgG anti-toxin B in stool, separated CDI patients from all other groups.ConclusionsSpecific markers of innate and adaptive immunity distinguish CDI from all other groups, suggesting potential clinical utility for identifying which NAAT- and toxin-positive patients with diarrhea truly have CDI.

| S-EPMC8204484 | biostudies-literature

Non-Toxin-Based Clostridioides difficile Vaccination Approaches.

Project description:Clostridioides difficile (CD) is a Gram-positive, anaerobic bacterium that infects mainly hospitalized and elderly people who have been treated with long-term antibiotic therapy leading to dysbiosis. The deteriorating demographic structure and the increase in the number of antibiotics used indicate that the problem of CD infections (CDI) will continue to increase. Thus far, there is no vaccine against CD on the market. Unfortunately, clinical trials conducted using the CD toxin-based antigens did not show sufficiently high efficacy, because they did not prevent colonization and transmission between patients. It seems that the vaccine should also include antigens found in the bacterium itself or its spores in order not only to fight the effects of toxins but also to prevent the colonization of the patient. This literature review summarizes the latest advances in research into vaccine antigens that do not contain CD toxins.

| S-EPMC9966970 | biostudies-literature

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