Establishing a case definition of thiamine responsive disorders among infants and young children in Lao PDR: protocol for a prospective cohort study

Sonja Y Hess, Taryn J Smith, Philip R Fischer, Indi Trehan, Laurent Hiffler, Charles D Arnold, Dalaphone Sitthideth, Daniel J Tancredi, Michael A Schick, Jay Yeh, Rebecca Stein-Wexler, Christine N McBeth, Xiuping Tan, Kouyang Nhiacha, Sengchanh Kounnavong, Sonja Y Hess, Taryn J Smith, Philip R Fischer, Indi Trehan, Laurent Hiffler, Charles D Arnold, Dalaphone Sitthideth, Daniel J Tancredi, Michael A Schick, Jay Yeh, Rebecca Stein-Wexler, Christine N McBeth, Xiuping Tan, Kouyang Nhiacha, Sengchanh Kounnavong

Abstract

Introduction: Diagnosis of infantile thiamine deficiency disorders (TDD) is challenging due to the non-specific, highly variable clinical presentation, often leading to misdiagnosis. Our primary objective is to develop a case definition for thiamine responsive disorders (TRD) to determine among hospitalised infants and young children, which clinical features and risk factors identify those who respond positively to thiamine administration.

Methods and analysis: This prospective study will enrol 662 children (aged 21 days to <18 months) seeking treatment for TDD symptoms. Children will be treated with intravenous or intramuscular thiamine (100 mg daily for a minimum of 3 days) alongside other interventions deemed appropriate. Baseline assessments, prior to thiamine administration, include a physical examination, echocardiogram and venous blood draw for the determination of thiamine biomarkers. Follow-up assessments include physical examinations (after 4, 8, 12, 24, 36, 48 and 72 hours), echocardiogram (after 24 and 48 hours) and one cranial ultrasound. During the hospital stay, maternal blood and breast-milk samples and diet, health, anthropometric and socio-demographic information will be collected for mother-child pairs. Using these data, a panel of expert paediatricians will determine TRD status for use as the dependent variable in logistic regression models. Models identifying predictors of TRD will be developed and validated for various scenarios. Clinical prediction model performance will be quantified by empirical area under the receiver operating characteristic curve, using resampling cross validation. A frequency-matched community-based cohort of mother-child pairs (n=265) will serve as comparison group for evaluation of potential risk factors for TRD.

Ethics and dissemination: Ethical approval has been obtained from The National Ethics Committee for Health Research, Ministry of Health, Lao PDR and the Institutional Review Board of the University of California Davis. The results will be disseminated via scientific articles, presentations and workshops with representatives of the Ministry of Health.

Trial registration number: NCT03626337.

Keywords: echocardiography; neuroradiology; nutrition & dietetics; paediatrics.

Conflict of interest statement

Competing interests: SYH has completed a consultancy for the Bill & Melinda Gates Foundation and her spouse previously worked for the Bill & Melinda Gates Foundation.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Study design overview of hospitalised and community cohort in the Lao Thiamine Study. At the onset of the Lao Thiamine Study, the eligibility age was 21 days to

Figure 2

Flow chart of data collection…

Figure 2

Flow chart of data collection timing among hospitalised infants and young children in…

Figure 2
Flow chart of data collection timing among hospitalised infants and young children in the Lao Thiamine Study.
Figure 2
Figure 2
Flow chart of data collection timing among hospitalised infants and young children in the Lao Thiamine Study.

References

    1. Johnson CR, Fischer PR, Thacher TD, et al. . Thiamin deficiency in low- and middle-income countries: disorders, prevalences, previous interventions and current recommendations. Nutr Health 2019;25:127–51. 10.1177/0260106019830847
    1. Whitfield KC, Bourassa MW, Adamolekun B, et al. . Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci 2018;1430:3–43. 10.1111/nyas.13919
    1. Barennes H, Sengkhamyong K, René JP, et al. . Beriberi (thiamine deficiency) and high infant mortality in northern Laos. PLoS Negl Trop Dis 2015;9:e0003581 10.1371/journal.pntd.0003581
    1. Khounnorath S, Chamberlain K, Taylor AM, et al. . Clinically unapparent infantile thiamin deficiency in Vientiane, Laos. PLoS Negl Trop Dis 2011;5:e969 10.1371/journal.pntd.0000969
    1. Soukaloun D, Lee SJ, Chamberlain K, et al. . Erythrocyte transketolase activity, markers of cardiac dysfunction and the diagnosis of infantile beriberi. PLoS Negl Trop Dis 2011;5:e971 10.1371/journal.pntd.0000971
    1. Barennes H, Simmala C, Odermatt P, et al. . Postpartum traditions and nutrition practices among urban Lao women and their infants in Vientiane, Lao PDR. Eur J Clin Nutr 2009;63:323–31. 10.1038/sj.ejcn.1602928
    1. Holmes W, Hoy D, Lockley A, et al. . Influences on maternal and child nutrition in the highlands of the northern Lao PDR. Asia Pac J Clin Nutr 2007;16:537–45.
    1. Soukaloun D, Kounnavong S, Pengdy B, et al. . Dietary and socio-economic factors associated with beriberi in breastfed Lao infants. Ann Trop Paediatr 2003;23:181–6. 10.1179/027249303322296493
    1. Allen LH. B vitamins in breast milk: relative importance of maternal status and intake, and effects on infant status and function. Adv Nutr 2012;3:362–9. 10.3945/an.111.001172
    1. World Health Organization Thiamine deficiency and its prevention and control in major emergencies. Geneva: World Health Organization, 1999.
    1. Hiffler L, Rakotoambinina B, Lafferty N, et al. . Thiamine deficiency in tropical pediatrics: new insights into a neglected but vital metabolic challenge. Front Nutr 2016;3:16 10.3389/fnut.2016.00016
    1. Wani NA, Qureshi UA, Ahmad K, et al. . Cranial ultrasonography in infantile encephalitic beriberi: a useful first-line imaging tool for screening and diagnosis in suspected cases. AJNR Am J Neuroradiol 2016;37:1535–40. 10.3174/ajnr.A4756
    1. Carreras I, Martinesz Garcia D, Indi EP, et al. . Thiamine deficiency in neurological acute disorders in resource-limited settings: case reports. 3rd World Congress on Controversies in Pediatrics, Barcelona, Spain, 2016.
    1. Duce M, Escriba J, Masuet C, et al. . Suspected thiamine deficiency in Angola. Field Exch 2003;20:26–8.
    1. Ogunlesi TA. Thiamine deficiency: a cause of childhood ataxia not to be ignored. Ann Trop Paediatr 2004;24:357–60. 10.1179/146532804X10835
    1. Keating EM, Nget P, Kea S, et al. . Thiamine deficiency in tachypnoeic Cambodian infants. Paediatr Int Child Health 2015;35:312–8. 10.1080/20469047.2015.1109226
    1. Coats D, Shelton-Dodge K, Ou K, et al. . Thiamine deficiency in Cambodian infants with and without beriberi. J Pediatr 2012;161:843–7. 10.1016/j.jpeds.2012.05.006
    1. Lima LFPde, Leite HP, Taddei JAdeAC. Low blood thiamine concentrations in children upon admission to the intensive care unit: risk factors and prognostic significance. Am J Clin Nutr 2011;93:57–61. 10.3945/ajcn.2009.29078
    1. Gibson RS. Principles of nutritional assessment. 2nd ed New York: Oxford University Press, 2005.
    1. Talwar D, Davidson H, Cooney J, et al. . Vitamin B1 status assessed by direct measurement of thiamin pyrophosphate in erythrocytes or whole blood by HPLC: comparison with erythrocyte transketolase activation assay. Clin Chem 2000;46:704–10. 10.1093/clinchem/46.5.704
    1. Herve C, Beyne P, Lettéron P, et al. . Comparison of erythrocyte transketolase activity with thiamine and thiamine phosphate ester levels in chronic alcoholic patients. Clinica Chimica Acta 1995;234:91–100. 10.1016/0009-8981(94)05980-7
    1. World Health Organization Western Pacific Region Pocket book of hospital care for children : Guidelines for the management of common childhood illnesses. 4 ed Manila, The Philippines: World Health Organization Western Pacific Region, 2017.
    1. Frank LL. Thiamin in clinical practice. JPEN J Parenter Enteral Nutr 2015;39:503–20. 10.1177/0148607114565245
    1. Crook MA, Sriram K. Thiamine deficiency: the importance of recognition and prompt management. Nutrition 2014;30:953–4. 10.1016/j.nut.2014.03.003
    1. McCandless D. Thiamine deficiency and associated clinical disorders. Humana Press, 2009.
    1. Park SW, Yi YY, Han JW, et al. . Wernicke's encephalopathy in a child with high dose thiamine therapy. Korean J Pediatr 2014;57:496–9. 10.3345/kjp.2014.57.11.496
    1. WHO Multicentre Growth Reference Study Group WHO child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization, 2006.
    1. Hampel D, Shahab-Ferdows S, Islam MM, et al. . Vitamin concentrations in human milk vary with time within feed, circadian rhythm, and single-dose supplementation. J Nutr 2017;147:603–11. 10.3945/jn.116.242941
    1. Lu J, Frank EL. Rapid HPLC measurement of thiamine and its phosphate esters in whole blood. Clin Chem 2008;54:901–6. 10.1373/clinchem.2007.099077
    1. Hampel D, York ER, Allen LH. Ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) for the rapid, simultaneous analysis of thiamin, riboflavin, flavin adenine dinucleotide, nicotinamide and pyridoxal in human milk. J Chromatogr B Analyt Technol Biomed Life Sci 2012;903:7–13. 10.1016/j.jchromb.2012.06.024
    1. Lopez L, Colan SD, Frommelt PC, et al. . Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the pediatric measurements writing group of the American Society of echocardiography pediatric and congenital heart disease Council. J Am Soc Echocardiogr 2010;23:465–95. quiz 576-7 10.1016/j.echo.2010.03.019
    1. Cashin K, Oot L. Guide to anthropometry: a practical tool for program planners, managers, and implementers. 360 Washington DC: Food and Nutrition Technical Assistance III Project (FANTA)/ FHI, 2018.
    1. de Onis M, Onyango AW, Van den Broeck J, et al. . Measurement and standardization protocols for anthropometry used in the construction of a new international growth reference. Food Nutr Bull 2004;25:S27–36. 10.1177/15648265040251S105
    1. World Health Organization Recommendations for data collection, analysis and reporting on anthropometric indicators in children under 5 years old. Geneva, Switzerland: World Health Organization and United Nations Children's Fund, 2019.
    1. Wessells KR, Brown KH, Kounnavong S, et al. . Comparison of two forms of daily preventive zinc supplementation versus therapeutic zinc supplementation for diarrhea on young children’s physical growth and risk of infection: study design and rationale for a randomized controlled trial. BMC Nutrition 2018;4:39 10.1186/s40795-018-0247-6
    1. Coates J, Swindale A, Bilinsky P. Household Food Insecurity Access Scale (HFIAS) for measurement of food access: indicator guide. Washington, DC: USAID, 2007.
    1. Crowne DP, Marlowe D. A new scale of social desirability independent of psychopathology. J Consult Psychol 1960;24:349–54. 10.1037/h0047358
    1. Menon P, Nguyen PH, Saha KK, et al. . Combining intensive counseling by frontline workers with a nationwide mass media campaign has large differential impacts on complementary feeding practices but not on child growth: results of a cluster-randomized program evaluation in Bangladesh. J Nutr 2016;146:2075–84. 10.3945/jn.116.232314
    1. Hess SY, Smith TJ, Arnold CD. Lao thiamine study: open science framework, 2019. Available: [Accessed 31 July 2019].
    1. Perkins NJ, Schisterman EF. The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am J Epidemiol 2006;163:670–5. 10.1093/aje/kwj063
    1. American Pharmacists Association Lexicomp drug information Handbook: a clinically relevant resource for all healthcare professionals. 27 ed Wolters Kluver: 2018–9.
    1. International Committee of Medical Journal Editors Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals: ICMJE, 2019. Available: [Accessed November 19 2019].
    1. Collins GS, Reitsma JB, Altman DG, et al. . Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. BMJ 2014;350:g7594 10.1136/bmj.g7594
    1. Equator Network Enhancing the quality and transparency of health research, 2019. Available: [Accessed 9 Sep 2019].
    1. Whitfield KC, Kroeun H, Green T, et al. . Thiamine dose response in human milk with supplementation among lactating women in Cambodia: study protocol for a double-blind, four-parallel arm randomised controlled trial. BMJ Open 2019;9:e029255 10.1136/bmjopen-2019-029255
    1. Bergeron G, Bourassa M. Overcoming the current challenges of thiamine deficiency disorders (P10-091-19). Curr Dev Nutr 2019;3:nzz034.P10-91-19 10.1093/cdn/nzz034.P10-091-19

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir