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The Association of Cytokines and Micronutrients with Hepatitis E Virus Infection During Pregnancy and the Postpartum Period in Rural Bangladesh

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  • Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland; Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, Maryland; The JiVitA Maternal and Child Health Research Project, Gaibandha, Bangladesh; Hepatitis Viruses Section, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services, Rockville, Maryland

Hepatitis E virus (HEV) infection is severe during pregnancy, with a pregnant case fatality rate around 30%. In Bangladesh, plasma samples from 1,100 women during the first trimester (TM) and third TM of pregnancy and 3 months postpartum (PP) were tested for anti-HEV IgG. During this time, 40 women developed antibody responses to HEV. These seroconverters are classified as the cases (incidence = 46 infections per 1,000 person-years). All except one seroconversion occurred between the third TM and 3 months PP. The cases and 40 matched non-seroconverters (controls) underwent analysis of a panel of 10 cytokines, 12 vitamins and minerals, and two markers of inflammation. Throughout pregnancy, seroconverting cases displayed higher concentrations of both pro- and anti-inflammatory cytokines compared with the non-seroconverting controls, even prior to infection. In the first TM, seroconverters had lower circulating zinc concentrations (P = 0.03), an increased prevalence of vitamin D deficiency (25-hydroxy vitamin D [25(OH)2D] < 50 nmol/L, P = 0.08), and anemia (hemoglobin < 110 g/L, P = 0.05) compared with controls. There were no differences in C-reactive protein or α-1-acid glycoprotein. Antecedent micronutrient deficiencies may lead to dysregulated cytokine expression and immunologic compromise, increasing the risk of HEV infection, especially during pregnancy. This exploratory analysis reveals potential novel associations that deserve further study.

Author Notes

* Address correspondence to Alain Labrique, Johns Hopkins School of Public Health, W5501, 615 N Wolfe Street, Baltimore, MD 21205. E-mail: alabriqu@gmail.com

Financial support: This work was funded by NIH R56 award number AI068813-01A2. Support was also provided by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. The field trial was supported through grant 614 (Global Control of Micronutrient Deficiency) from the Bill & Melinda Gates Foundation, Seattle, WA (Ellen Piwoz, Senior Program Officer) and through additional support from the Sight and Life Global Nutrition Research Institute, Baltimore, MD; DSM N.V., Kaiseraugst (Switzerland), Bombay (India), and Singapore formulated, prepared, and delivered in-country micronutrient premixes for supplement production and Beximco Pharmaceuticals, Ltd., Dhaka produced, bottled, labeled, and delivered tablets during the trial, both gratis; and the Ministry of Health and Family Welfare, Government of Bangladesh, Dhaka.

Authors' addresses: Brittany L. Kmush, Kerry Schulze, Lee Wu, Sucheta Mehra, Parul Christian, and Keith West Jr., Department of International Health, Johns Hopkins School of Public Health, Baltimore, MD, E-mails: bkmush1@jhu.edu, kschulz1@jhu.edu, leewu@jhmi.edu, smehra5@jhu.edu, pchrist1@jhu.edu, and kwest1@jhu.edu. Alain Labrique and Kenrad Nelson, Departments of International Health and Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, E-mails: alabriqu@gmail.com and knelson3@jhu.edu. Wei Li, Food Science and Human Nutrition, Michigan State University, East Lansing, MI, E-mail: wli@anr.msu.edu. Sabra L. Klein, Departments of Molecular Microbiology and Immunology and Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, E-mail: sklein2@jhu.edu. Saijuddin Shaikh and Hasmot Ali, The JiVitA Maternal and Child Health Research Project, Gaibandha, Bangladesh, E-mails: saiju.jivita@gmail.com and hasmot.jivita@gmail.com. Ronald E. Engle and Robert H. Purcell, Hepatitis Viruses Section, NIAID, National Institutes of Health, DHHS, Rockville, MD, E-mails: rengle@niaid.nih.gov and roberthpurcell@gmail.com.

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