Similar Proportions of Stool Specimens From Hospitalized Children With and Without Diarrhea Test Positive for Clostridium difficile

Leibowitz, Jill; Soma, Vijaya L; Rosen, Lisa; Ginocchio, Christine C.; Rubin, Lorry G.

doi:10.1097/inf.0000000000000556

Cited by 43 publications

(41 citation statements)

References 29 publications

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“…While the detection of toxigenic organisms may be appropriate for determining the need for infection control measures (45), it is not necessarily optimal for deciding whether or not toxigenic C. difficile is the cause of a patient's symptoms (16). Notably, multiple studies have reported NAAT-positive individuals who clinically did not have CDI (12,(15)(16)(17)(18). Until now, no highly sensitive assay existed that could rapidly detect and quantify both toxins A and B in stool samples at the time of diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…Despite arguments that the detection of toxin in stool has highest clinical specificity and predictive value (2,11,12,14), nucleic acid amplification testing (NAAT) for ultrasensitive detection of toxigenic organisms is increasingly employed for diagnosis. However, studies have repeatedly reported on NAAT-positive individuals who clinically would not be diagnosed with CDI (12,[15][16][17][18]. Thus, by detecting C. difficile organisms, rather than toxins A and B, NAAT may lack specificity for clinical disease (2).…”

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confidence: 99%

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Development and Validation of Digital Enzyme-Linked Immunosorbent Assays for Ultrasensitive Detection and Quantification of Clostridium difficile Toxins in Stool

et al. 2015

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The currently available diagnostics for Clostridium difficile infection (CDI) have major limitations. Despite mounting evidence that toxin detection is paramount for diagnosis, conventional toxin immunoassays are insufficiently sensitive and cytotoxicity assays too complex; assays that detect toxigenic organisms (toxigenic culture [TC] and nucleic acid amplification testing [NAAT]) are confounded by asymptomatic colonization by toxigenic C. difficile. We developed ultrasensitive digital enzymelinked immunosorbent assays (ELISAs) for toxins A and B using single-molecule array technology and validated the assays using (i) culture filtrates from a panel of clinical C. difficile isolates and (ii) 149 adult stool specimens already tested routinely by NAAT. The digital ELISAs detected toxins A and B in stool with limits of detection of 0.45 and 1.5 pg/ml, respectively, quantified toxins across a 4-log range, and detected toxins from all clinical strains studied. Using specimens that were negative by cytotoxicity assay/TC/NAAT, clinical cutoffs were set at 29.4 pg/ml (toxin A) and 23.3 pg/ml (toxin B); the resulting clinical specificities were 96% and 98%, respectively. The toxin B digital ELISA was 100% sensitive versus cytotoxicity assay. Twenty-five percent and 22% of the samples positive by NAAT and TC, respectively, were negative by the toxin B digital ELISA, consistent with the presence of organism but minimal or no toxin. The mean toxin levels by digital ELISA were 1.5-to 1.7-fold higher in five patients with CDI-attributable severe outcomes, versus 68 patients without, but this difference was not statistically significant. Ultrasensitive digital ELISAs for the detection and quantification of toxins A and B in stool can provide a rapid and simple tool for the diagnosis of CDI with both high analytical sensitivity and high clinical specificity.T he recent increases in the global incidence and severity of Clostridium difficile infection (CDI) (1-3) are of major concern, and CDI now consumes substantial resources for diagnosis, treatment, and infection control (2, 4). A recent U.S. prevalence survey of health care-associated infections (HAI) (5) found that C. difficile was the most commonly reported pathogen, causing 12.1% of HAI. Despite available therapies, treatment failure and recurrence are common (1, 2, 6). The emergence of epidemic strains capable of toxin hyperproduction and increased disease severity/mortality (2, 7, 8) has further increased the urgency to improve methods for diagnosis and treatment. Accurate diagnosis remains the cornerstone of effective management.Disease caused by C. difficile infection is due to the effects of two large protein exotoxins, toxins A and B (9, 10). While the presence of toxin is necessary to cause disease, the optimal method for diagnosing CDI remains controversial. Appropriate patient selection can improve diagnostic accuracy for all assays (2, 11). The classic gold standard stool assay, toxigenic culture (TC), is complex, lengthy, and unstandardized; furthermore, it is...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Development and Validation of Digital Enzyme-Linked Immunosorbent Assays for Ultrasensitive Detection and Quantification of Clostridium difficile Toxins in Stool

et al. 2015

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“…Using PCR for C. difficile detection in hospitalized patients with and without diarrhea, Leibowitz et al found that there was no statistically significant difference between the positivity rates of asymptomatic and symptomatic children (24% versus 19% of samples, respectively) (20). Pediatric oncology patients may also be colonized or have prolonged shedding following or in conjunction with diarrhea (21).…”

mentioning

confidence: 99%

Diagnosis of Clostridium difficile Infections in Children

Antonara

Leber

2016

J Clin Microbiol

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The detection and diagnosis of Clostridium difficile infection in pediatric populations have some unique considerations in comparison to testing in adults. The testing methodologies, including toxigenic culture, cell cytotoxicity, antigen detection, and, more recently, molecular testing, are the same in all age groups. However, limited data exist on the specific performance characteristics in children. In this review, we focus on the challenges of testing in pediatric populations and assess the available data on test performance in these populations. Additionally, a review of the existing guidance for testing is provided.

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“…Asymptomatic colonization in the community is lower than in the health-care setting and is in the range of 2-4%. Several studies report high carriage rates (25-35%) in children in the first year; the rate drops (to 15%) for ages 1-8 years [182][183][184] . This variation is probably associated with the unstable intestinal microbiota in the first 2-3 years of life, which enables C. difficile to remain established in the intestinal tract 185 .…”

Section: Asymptomatic Carriagementioning

confidence: 99%

Clostridium difficile Infection

Wilcox¹,

Vehreschild²,

Nord³

2015

Annual Update in Intensive Care and Emergency Medicine

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Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis -the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota. Competing interests statement W.K.S. has performed research for Cubist. D.L. has performed research for Immuron and Adenium Biotech. D.B.L. has performed research for MedImmune and Merck. M.H.W. has received consulting fees from Abbott, Actelion Pharmaceuticals, Astellas, AstraZeneca, Bayer, Cerexa, Cubist, Durata, The European Tissue Symposium, The Medicines Company, MedImmune, Merck, Motif Biosciences, Nabriva, Optimer, Paratek, Pfizer, Roche, Sanofi Pasteur, Seres Therapeutics, Summit Pharmaceuticals, and Synthetic Biologics. M.H.W. has also received lecture fees from Abbott, Alere, Astellas, AstraZeneca, Pfizer and Hoffmann La Roche, and received grant support from Abbott, Actelion, Astellas, bioMérieux, Cubist, Da Volterra, The European Tissue Symposium, Merck and Summit Pharmaceuticals. E.J.K. has performed research for Cubist, Novartis and Qiagen, and has participated in advisory forums of Astellas, Optimer, Actelion, Pfizer, Sanofi Pasteur and Seres Therapeutics. These companies had no role in the writing of this Primer. HHS Public AccessAuthor manuscript Nat Rev Dis Primers. Author manuscript; available in PMC 2017 June 01. Published in final edited form as:Nat Rev Dis Primers. ; 2: 16020. doi:10.1038/nrdp.2016.20. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptClostridium difficile is a Gram-positive obligate anaerobic bacterium that was originally identified as part of the flora of healthy infants in 1935, described as an "actively motile, heavy-bodied rod with elongated subterminal or nearly terminal spores" (REF. 1) (FIG. 1). At that time, the strain was named Bacillus difficilis to reflect the difficulty experienced in isolating and culturing it. De...

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Similar Proportions of Stool Specimens From Hospitalized Children With and Without Diarrhea Test Positive for Clostridium difficile

Cited by 43 publications

References 29 publications

Development and Validation of Digital Enzyme-Linked Immunosorbent Assays for Ultrasensitive Detection and Quantification of Clostridium difficile Toxins in Stool

Development and Validation of Digital Enzyme-Linked Immunosorbent Assays for Ultrasensitive Detection and Quantification of Clostridium difficile Toxins in Stool

Diagnosis of Clostridium difficile Infections in Children

Clostridium difficile Infection

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