Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study
Authors: Elizabeth T Rogawski, Jie Liu, James A Platts-Mills, Furqan Kabir, Paphavee Lertsethtakarn, Mery Siguas, Shaila S Khan, Ira Praharaj, Arinao Murei, Rosemary Nshama, Buliga Mujaga, Alexandre Havt, Irene A Maciel, Darwin J Operario, Mami Taniuchi, Jean Gratz, Suzanne E Stroup, James H Roberts, Adil Kalam, Fatima Aziz, Shahida Qureshi, M Ohedul Islam, Pimmada Sakpaisal, Sasikorn Silapong, Pablo P Yori, Revathi Rajendiran, Blossom Benny, Monica McGrath, Jessica C Seidman, Dennis Lang, Michael Gottlieb, Richard L Guerrant, Aldo A M Lima, Jose Paulo Leite, Amidou Samie, Pascal O Bessong, Nicola Page, Ladaporn Bodhidatta, Carl Mason, Sanjaya Shrestha, Ireen Kiwelu, Estomih R Mduma, Najeeha T Iqbal, Zulfiqar A Bhutta, Tahmeed Ahmed, Rashidul Haque, Gagandeep Kang, Margaret N Kosek, Eric R Houpt, Angel Mendez Acosta, Rosa Rios de Burga, Cesar Banda Chavez, Julian Torres Flores, Maribel Paredes Olotegui, Silvia Rengifo Pinedo, Dixner Rengifo Trigoso, Angel Orbe Vasquez, Imran Ahmed, Didar Alam, Asad Ali, Muneera Rasheed, Sajid Soofi, Ali Turab, Aisha Yousafzai, Anita KM Zaidi, Binob Shrestha, Bishnu Bahadur Rayamajhi, Tor Strand, Geetha Ammu, Sudhir Babji, Anuradha Bose, Ajila T George, Dinesh Hariraju, M. Steffi Jennifer, Sushil John, Shiny Kaki, Priyadarshani Karunakaran, Beena Koshy, Robin P Lazarus, Jayaprakash Muliyil, Preethi Ragasudha, Mohan Venkata Raghava, Sophy Raju, Anup Ramachandran, Rakhi Ramadas, Karthikeyan Ramanujam, Anuradha Rose, Reeba Roshan, Srujan L Sharma, Shanmuga Sundaram, Rahul J Thomas, William K Pan, Ramya Ambikapathi, J Daniel Carreon, Viyada Doan, Christel Hoest, Stacey Knobler, Mark A Miller, Stephanie Psaki, Zeba Rasmussen, Stephanie A Richard, Karen H Tountas, Erling Svensen, Caroline Amour, Eliwaza Bayyo, Regisiana Mvungi, John Pascal, Ladislaus Yarrot, Leah Barrett, Rebecca Dillingham, William A Petri, Rebecca Scharf, AM Shamsir Ahmed, Md Ashraful Alam, Umma Haque, Md Iqbal Hossain, Munirul Islam, Mustafa Mahfuz, Dinesh Mondal, Baitun Nahar, Fahmida Tofail, Ram Krishna Chandyo, Prakash Sunder Shrestha, Rita Shrestha, Manjeswori Ulak, Aubrey Bauck, Robert Black, Laura Caulfield, William Checkley, Gwenyth Lee, Kerry Schulze, Samuel Scott, Laura E Murray-Kolb, A Catharine Ross, Barbara Schaefer, Suzanne Simons, Laura Pendergast, Cláudia B Abreu, Hilda Costa, Alessandra Di Moura, José Quirino Filho, Álvaro M Leite, Noélia L Lima, Ila F Lima, Bruna LL Maciel, Pedro HQS Medeiros, Milena Moraes, Francisco S Mota, Reinaldo B Oriá, Josiane Quetz, Alberto M Soares, Rosa MS Mota, Crystal L Patil, Cloupas Mahopo, Angelina Maphula, Emanuel Nyathi
Journal: The Lancet Global Health (2018)

BackgroundEnteropathogen infections in early childhood not only cause diarrhoea but contribute to poor growth. We used molecular diagnostics to assess whether particular enteropathogens were associated with linear growth across seven low-resource settings.MethodsWe used quantitative PCR to detect 29 enteropathogens in diarrhoeal and non-diarrhoeal stools collected from children in the first 2 years of life obtained during the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite cohort study. Length was measured monthly. We estimated associations between aetiology-specific diarrhoea and subclinical enteropathogen infection and quantity and attained length in 3 month intervals, at age 2 and 5 years, and used a longitudinal model to account for temporality and time-dependent confounding.FindingsAmong 1469 children who completed 2 year follow-up, 35 622 stool samples were tested and yielded valid results. Diarrhoeal episodes attributed to bacteria and parasites, but not viruses, were associated with small decreases in length after 3 months and at age 2 years. Substantial decrements in length at 2 years were associated with subclinical, non-diarrhoeal, infection with Shigella (length-for-age Z score [LAZ] reduction −0·14, 95% CI −0·27 to −0·01), enteroaggregative Escherichia coli (−0·21, −0·37 to −0·05), Campylobacter (−0·17, −0·32 to −0·01), and Giardia (−0·17, −0·30 to −0·05). Norovirus, Cryptosporidium, typical enteropathogenic E coli, and Enterocytozoon bieneusi were also associated with small decrements in LAZ. Shigella and E bieneusi were associated with the largest decreases in LAZ per log increase in quantity per g of stool (−0·13 LAZ, 95% CI −0·22 to −0·03 for Shigella; −0·14, −0·26 to −0·02 for E bieneusi). Based on these models, interventions that successfully decrease exposure to Shigella, enteroaggregative E coli, Campylobacter, and Giardia could increase mean length of children by 0·12–0·37 LAZ (0·4–1·2 cm) at the MAL-ED sites.InterpretationSubclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting.FundingBill & Melinda Gates Foundation.