What s New in Number Two?: An update on pediatric acute gastroenteritis. David Goldfarb BC Children s Hospital/UBC March 2 nd, 2017
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1 What s New in Number Two?: An update on pediatric acute gastroenteritis David Goldfarb BC Children s Hospital/UBC March 2 nd, 2017 Tropical and Geographic Medicine Intensive Short Course 2015
2 Disclosure Faculty: Dr. David Goldfarb Relationships with commercial interests: Nothing to disclose Research funding from the Public Health Agency of Canada, CIHR, Grand Challenges Canada, CDC Foundation, Bill and Melinda Gates Foundation, IDRC, ArcticNet, and investigator initiated grant from biomerieux
3 Outline Global Burden of childhood enteric infections New insights from enhanced diagnostic studies Examples of efforts to address childhood diarrheal disease
4 Outline Global burden of childhood enteric infections New insights from enhanced diagnostic studies Examples of efforts to address childhood diarrheal disease
5 Burden of diarrheal diseases Diarrhea kills 2,195 children every day more than AIDS, malaria, and measles combined 2 nd leading cause of child death Liu L et al, Lancet. 2012;379(9832):
6 Burden Diarrheal Disease (cont d) What about the children that make it through these frequent episodes of diarrhea in childhood?
7
8 Mata L et al. 1971
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10 Global burden of enteric infections synergy between malnutrition and infection Brown K H, J. Nutr. 2003
11 Global burden of enteric infections early childhood diarrhea leads to stunting (HAZ <-2) Checkley W et al. Int J Epi, 2008
12 Global burden of enteric infections early childhood diarrhea leads to stunting Checkley W et al. Int J Epi, 2008
13 But does being a little shorter really matter?
14 Global burden of enteric infections brain development is greatest before age 2 Thompson RA, Nelson CA. Am Psychol. 2001;56:5 15
15 Global burden of enteric infections stunting and cognitive outcomes Grantham-McGregor S et al. Lancet. 2007;369:61.
16 From: Guerrant R, Ped Acad Soc Mtg, April
17 Global burden of enteric infections overall infections and cognitive development Eppig C et al. Proc Biol Sci, 2010 Image from The Economist July1, 2010
18
19
20 Outline Global burden of childhood enteric infections New insights from enhanced diagnostic studies Examples of efforts to address childhood diarrheal disease
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22 xtag GPP Assay Used in Prospective Clinical Studies in Europe Netherlands 19% detection Germany 31% detection No pathogen One target Two targets Three targets No Pathogen One targets Two targets Wessels E et al. Clin Micro Inf 2013 Malecki M et al. ESCV 2011
23 Benefits of Syndromic approach GPP Number of Pathogens detected Clinician ordered testing Number of Pathogens detected Wessels E et al. Clin Microbiol Infect 2014; 20: O182 O187
24 Pediatric Oncology Population J Mol Diagn Nov;17(6):715-21
25
26
27 Chapin K et al. Clin Viro Symp April 2016
28 Nunavut a high burden setting
29 Harper et al., 2015
30 Enteric panels for public health surveillance As part of National Enteric Surveillance Program (NESP) in 2012 Nunavut had only reported 2 Campylobacter 8 Salmonella 1 E. coli O157 OpenArray Source:
31 PCR Detection of Enteric Pathogens clinical samples submitted to Iqaluit hospital (QGH) Clinical Testing Real time PCR Bacteria Bacteria No Pathogen Virus Parasite No Pathogen Goldfarb DM et al; Int J Circumpolar Health. 2013;72:19903.
32 Novel Diagnostics - Public Health old specimens, new tools Goldfarb et al; Int J Circumpolar Health. 2013;72:19903.
33 Shirley DT et al., Curr Opin Infect Dis 2012, 25: How common is Cryptosporidium in Iqaluit compared to rest of world? QGH prevalence
34 Cryptosporidium discovery new kid on the map Spring 2013: Crypto retrospectively found to be leading stool pathogen July 2013: first observed Crypto outbreak in Arctic July 2014: new cases on Ungava coast Slide courtesy Dr. Cedric Yansouni McGill University
35 Cryptosporidium is a big problem in the Arctic! Cryptosporidiosis Rates/100, Canada (2011) 1 Qikiqtaaluk (2010/11) 2 3 Nunavik (2013/14) 1. Canadian Notifiable Disease Surveillance System (CNDSS) Goldfarb DM et al; Int J Circumpolar Health. 2013;72: Thivierge K et al.; PLoS Negl Trop Dis Apr 8;10(4):e
36 What about other high burden settings? Diarrheal Deaths
37 Two Large Multi-centre Studies of childhood diarrheal disease Global Enteric Multicentre Study (GEMS) The Interactions of Malnutrition & Enteric Infections: Consequences for Child Health and Development (MAL ED)
38 Global burden of enteric infections etiologic spectrum and impact Kotloff KL et al. Lancet 2013; 382:
39 Global Enteric Multicenter Study M. Levine, Ped Acad Soc Mtg, Boston, 2012
40 GEMS case control design Cases of mod to severe diarrhea = 9439 Community controls =
41 Global Enteric Multicenter Study M. Levine, Ped. Acad. Soc., Boston, 2012
42 Attributable Fraction Kotloff KL et al. Lancet 2013; 382:
43 Lindsay B et al. J. Clin. Microbiol. 2013, 51(6):1740. Culture estimated to have missed ~50% of Shigella cases in GEMS Receiver operating characteristic (ROC) curves
44 Newer More Sensitive Techniques Enteropathogen Yield with Conventional Testing in Botswana 1 Bacterial Parasitic Mixed None Detected Enteropathogen Yield with Multiplex Molecular Detection in Botswana 2 Bacterial Parasitic Viral Mixed None Detected 1.Rowe J, et al. PLoS One June 2;5(6):e Goldfarb DM et al. PAS. Boston 2012.
45 32 Pathogen Gene targets (Luminex) Taniuchi M et al. J Inf Dis. 2013;208:
46 Conventional testing vs. Multiplex molecular testing Liu J et al., J. Clin. Microbiol. 2013, 51(2):472.
47 qpcr re-analysis of GEMS samples Liu J et al. Lancet 2016
48 qpcr re-analysis changed a lot! Liu J et al. Lancet 2016
49 Outline Global burden of childhood enteric infections New insights from enhanced diagnostic studies Examples of efforts to address childhood diarrheal disease
50
51 Rotavirus vaccination Americas and Europe 2006 Africa and Asia
52 Scale-up of rotavirus vaccine Introduction-Map-EN _blank.jpg
53 Vaccine efficacy and GDP Nelson et al., Lancet, 2010
54 Botswana RV Vaccine Impact Study Botswana among first African countries to introduce RV vaccine in 2012 High in hospital gastroenteritis mortality Pediatr Infect Dis J May;32(5):570-2
55 No. of diarrhea deaths Rotavirus season deaths % 43% mo Baseline rotavirus season 2013 Rotavirus season 2014 Rotavirus season Rotavirus season = May to October Clin Infect Dis. (2016) 62 (suppl 2): S168-S174.
56 Deaths
57 Deaths
58 Deaths
59 Hospital Acquired GE in Botswana Pathogens Detected 4/32 (12%) in-hospital mortality at one site Rotavirus 2 nd leading 19% 33% 22% 26% 19% Norovirus Rotavirus Other pathogen Negative Welch H et al. Ped Acad Soc Mtg Vancouver 2014
60
61 Nicole Has kwashiokor (edematous malnutrition) and admitted with acute diarrhea Has a ~ 1/4 chance of dying 1 during this admission Photos used with permission 1. Pernica JM et al., JPIDS, 2016
62 Nicole What can we do to ensure that she has the best outcome possible? Survival Long-term growth and development
63 Botswana n=671 children admitted to hospital with gastroenteritis median age 8.3 months, 11% severe acute malnutrition 26 deaths (case-fatality rate 3.9%) Pernica JM et al. J Pediatr Infect Dis Soc 2016
64 Measuring Impact of Diarrheal Diagnostics Immediate sample collection BioFire - rapid pathogen detection Point of Care Diagnostics for Diarrheal Disease
65 Study design experimental arms: 1. rapid testing + treatment (if indicated) + probiotic 2. rapid testing + treatment (if indicated) + placebo 3. delayed testing + probiotic 4. delayed testing + placebo probiotic: Lactobacillus reuteri 5x10 8 cfu/ml daily x 60 days
66 Results Pilot Study (n=73) group Delayed testing + placebo OR of recurrence of diarrhoea by 60 days (95% CI) (ref) p Rapid testing + placebo 0.45 (0.12 to 1.79) 0.26 Delayed testing + L. reuteri 0.10 (0.01 to 0.93) 0.04 Rapid testing + L. reuteri 0.07 (0.01 to 0.61) 0.02 Pernica JM et al. under review
67 Results Pilot Study (n=73) group Delayed testing + placebo difference in 60 d adjusted for baseline (95% CI) (ref) p Rapid testing + placebo (-0.24 to 0.89) NS Delayed testing + L. reuteri (-0.08 to 1.11) NS Rapid testing + L. reuteri (0.09 to 1.13) 0.02 Pernica JM et al. under review
68 Can we improve growth/development? ETEC Shigella
69 Can we improve growth/development? Shigella ETEC
70 Nicole in follow up with her mother
71 Acknowledgements University of Botswana - Dr. Loeto Mazhani - Margaret Mokomane - Dr. Isaac Quaye (now U of Nam.) - Moses Vuriya - Dr. B.A. Gashe - Dr. I. Kasvosve McMaster University - Dr. Marek Smieja - Dr. Jeffrey Pernica - Dr. James Mahony - Sylvia Chong - Kathy Luinstra Botswana-UPenn Partnership - Dr. Andrew Steenhoff - Dr. Harvey Friedman - Banno Moorad - Kwana Lechiile Nunavut Dept of Health - Dr. Maureen Baikie - Dr. Amber Miners CDC - Dr. Umesh Parashar - Dr. Paul Gastanaduy - Dr. J. Tate Funding:
72 Thank you!
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