TY - JOUR
T1 - Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children
T2 - a reanalysis of the GEMS case-control study
AU - Liu, Jie
AU - Platts-Mills, James A.
AU - Juma, Jane
AU - Kabir, Furqan
AU - Nkeze, Joseph
AU - Okoi, Catherine
AU - Operario, Darwin J.
AU - Uddin, Jashim
AU - Ahmed, Shahnawaz
AU - Alonso, Pedro L.
AU - Antonio, Martin
AU - Becker, Stephen M.
AU - Blackwelder, William C.
AU - Breiman, Robert F.
AU - Faruque, Abu S.G.
AU - Fields, Barry
AU - Gratz, Jean
AU - Haque, Rashidul
AU - Hossain, Anowar
AU - Hossain, M. Jahangir
AU - Jarju, Sheikh
AU - Qamar, Farah
AU - Iqbal, Najeeha Talat
AU - Kwambana, Brenda
AU - Mandomando, Inacio
AU - McMurry, Timothy L.
AU - Ochieng, Caroline
AU - Ochieng, John B.
AU - Ochieng, Melvin
AU - Onyango, Clayton
AU - Panchalingam, Sandra
AU - Kalam, Adil
AU - Aziz, Fatima
AU - Qureshi, Shahida
AU - Ramamurthy, Thandavarayan
AU - Roberts, James H.
AU - Saha, Debasish
AU - Sow, Samba O.
AU - Stroup, Suzanne E.
AU - Sur, Dipika
AU - Tamboura, Boubou
AU - Taniuchi, Mami
AU - Tennant, Sharon M.
AU - Toema, Deanna
AU - Wu, Yukun
AU - Zaidi, Anita
AU - Nataro, James P.
AU - Kotloff, Karen L.
AU - Levine, Myron M.
AU - Houpt, Eric R.
N1 - Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/9/24
Y1 - 2016/9/24
N2 - Background Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). Methods GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. Findings We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2–96·0) at the population level, compared with 51·5% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. Interpretation A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Funding Bill & Melinda Gates Foundation.
AB - Background Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). Methods GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. Findings We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2–96·0) at the population level, compared with 51·5% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. Interpretation A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Funding Bill & Melinda Gates Foundation.
UR - http://www.scopus.com/inward/record.url?scp=84991294564&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(16)31529-X
DO - 10.1016/S0140-6736(16)31529-X
M3 - Article
C2 - 27673470
AN - SCOPUS:84991294564
SN - 0140-6736
VL - 388
SP - 1291
EP - 1301
JO - The Lancet
JF - The Lancet
IS - 10051
ER -
