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. 2017 Aug 16;12(8):e0182307.
doi: 10.1371/journal.pone.0182307. eCollection 2017.

Epidemiology of Clostridium difficile in infants in Oxfordshire, UK: Risk factors for colonization and carriage, and genetic overlap with regional C. difficile infection strains

Nicole Stoesser  1   2 , David W Eyre  1   2 , T Phuong Quan  1   2 , Heather Godwin  1 , Gemma Pill  1 , Emily Mbuvi  1 , Alison Vaughan  1   2 , David Griffiths  1   2 , Jessica Martin  3 , Warren Fawley  4 , Kate E Dingle  1   2 , Sarah Oakley  5 , Kazimierz Wanelik  1 , John M Finney  1   2 , Melina Kachrimanidou  6 , Catrin E Moore  1 , Sherwood Gorbach  7 , Thomas V Riley  8 , Derrick W Crook  1   2 , Tim E A Peto  1   2 , Mark H Wilcox  3 , A Sarah Walker  1   2 ; Modernising Medical Microbiology Informatics Group (MMMIG)
Affiliations

Epidemiology of Clostridium difficile in infants in Oxfordshire, UK: Risk factors for colonization and carriage, and genetic overlap with regional C. difficile infection strains

Nicole Stoesser et al. PLoS One. .

Abstract

Background: Approximately 30-40% of children <1 year of age are Clostridium difficile colonized, and may represent a reservoir for adult C. difficile infections (CDI). Risk factors for colonization with toxigenic versus non-toxigenic C. difficile strains and longitudinal acquisition dynamics in infants remain incompletely characterized.

Methods: Predominantly healthy infants (≤2 years) were recruited in Oxfordshire, UK, and provided ≥1 fecal samples. Independent risk factors for toxigenic/non-toxigenic C. difficile colonization and acquisition were identified using multivariable regression. Infant C. difficile isolates were whole-genome sequenced to assay genetic diversity and prevalence of toxin-associated genes, and compared with sequenced strains from Oxfordshire CDI cases.

Results: 338/365 enrolled infants provided 1332 fecal samples, representing 158 C. difficile colonization or carriage episodes (107[68%] toxigenic). Initial colonization was associated with age, and reduced with breastfeeding but increased with pet dogs. Acquisition was associated with older age, Caesarean delivery, and diarrhea. Breastfeeding and pre-existing C. difficile colonization reduced acquisition risk. Overall 13% of CDI C. difficile strains were genetically related to infant strains. 29(18%) infant C. difficile sequences were consistent with recent direct/indirect transmission to/from Oxfordshire CDI cases (≤2 single nucleotide variants [SNVs]); 79(50%) shared a common origin with an Oxfordshire CDI case within the last ~5 years (0-10 SNVs). The hypervirulent, epidemic ST1/ribotype 027 remained notably absent in infants in this large study, as did other lineages such as STs 10/44 (ribotype 015); the most common strain in infants was ST2 (ribotype 020/014)(22%).

Conclusions: In predominantly healthy infants without significant healthcare exposure C. difficile colonization and acquisition reflect environmental exposures, with pet dogs identified as a novel risk factor. Genetic overlap between some infant strains and those isolated from CDI cases suggest common community reservoirs of these C. difficile lineages, contrasting with those lineages found only in CDI cases, and therefore more consistent with healthcare-associated spread.

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Conflict of interest statement

Competing Interests: The institution of DWC and TEAP received per-case funding from Optimer Pharmaceuticals to support fidaxomicin trial patient expenses. DWC and TEAP also received honoraria from Optimer Pharmaceuticals for participation in additional meetings related to investigative planning for fidaxomicin. MHW has received honoraria for consultancy work, financial support to attend meetings and research funding from bioMerieux, Optimer, Novacta, Pfizer, Summit, The Medicines Company and Viropharma. No other author has a conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Participant disposition.
a The total numbers of individuals screened for recruitment was not recorded.
Fig 2
Fig 2. Clostridium difficile ST prevalence in Oxfordshire infants and symptomatic patients.
ST15, ST26 and a subset of ST3 are non-toxigenic and hence were only identified in symptomatic Oxfordshire patients between December 2010 to September 2011, and from April 2012 to September 2013. Only three infant samples were obtained prior to January 2011, therefore STs from symptomatic patients are shown separately for January 2011 to September 2013 to provide a comparison of the strains circulating during the study. Circle size represents the proportion of strains per ST within an isolate collection.
Fig 3
Fig 3. Clusters of infant isolates related within two SNVs.
Each isolate is shown as a circle colored according to the infant’s home location on the map. SNVs between isolates are labeled on the connecting lines. Where indistinguishable sequences were obtained from more than one infant, the size of the circle is increased and the circle labeled with each isolate’s collection date. *ST 26 and ST15 are non-toxigenic, all other STs shown are toxigenic.
Fig 4
Fig 4. Comparison of the number of SNVs and elapsed time between C. difficile isolates (toxigenic and non-toxigenic) related within ten SNVs in Oxfordshire.
Panel A compares samples from infants to all prior isolates from infants i.e. whether infants might plausibly be transmitting to other infants; the most closely related prior sequence is plotted. Panel B compares infants with prior symptomatic patients, i.e. shows whether symptomatic patients might plausibly be a source of infant carriage or colonization. Panel C compares infants with subsequent symptomatic patient sequences, i.e. shows where infant carriage is a potential source of subsequent symptomatic infection. Compatibility with transmission from source to recipient (either direct or via one or more intermediates) is determined by evolutionary rates (x-axis scales differ); the 95% prediction interval for compatibility with transmission is represented by the shaded blue areas.
See this image and copyright information in PMC

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