Infection, inflammation and hepcidin-mediated iron deficiency anaemia in African children

Lead Research Organisation: London School of Hygiene & Tropical Medicine
Department Name: MRC Unit The Gambia at LSHTM

Abstract

Iron deficiency (ID), and the more serious iron deficiency anaemia (IDA), causes multiple health problems especially in reproductive women and young children in low-income settings. Iron is crucial for neural development and early deficiencies during foetal and infant growth cause irreparable damage to brain development and cognition. Figures from the latest Global Burden of Disease analysis estimate that 1.225 billion people suffer from IDA worldwide and it is the fourth largest contributor to years lived with disability (YLD). This burden is concentrated in sub-Saharan Africa and South Asia.

It has been thought that IDA is largely caused by diets low in iron and by the effects of infections such as malaria and intestinal helminths. However carefully controlled trials of iron supplements have very poor efficacy in Africa. The recent discovery of the hormone hepcidin - which acts as the master regulator of iron - throws a new light on the causes of IDA and may guide future therapeutic pathways. We have recently discovered that even low-grade inflammation is a major contributor to IDA in rural African children because it up-regulates hepcidin levels with a consequent blockade of intestinal absorption of iron.

This project will try to identify the sources of this low-grade inflammation in well and sick Gambian children. It will additionally try to understand the complex interacting mechanisms linking iron absorption, distribution and erythropoiesis to the effects of inflammation mediated through hepcidin, erythropoietin (EPO) and the newly discovered hormone erythroferrone (ERFE) which signals to the liver that the bone marrow requires iron. Finally we will conduct a randomised controlled trial to test whether it is possible to circumvent the inflammation-induced blockade of iron absorption by administering iron in the form of haem. Another arm of this trial will be a proof-of-principle trial to assess the impact of reducing systemic and gut inflammation by co-administering azithromycin and galacto-oligosaccharides with iron.

These studies, if successful, would suggest the need for a radical revision of current policies to combat IDA. It is likely that children will require major improvements in their environment achieved through intensive efforts to improve water, sanitation and hygiene (WASH++). If, as we speculate, the origins of IDA are more strongly determined by inflammation than by low dietary iron this would have important implications for future nutritional, agricultural and livestock policies.

Technical Summary

The 2016 Global Burden of Disease analysis estimates that 1.225 billion people suffer from iron deficiency anaemia (IDA) and it is the fourth largest contributor to years lived with disability (YLD) globally. The burden is concentrated in sub-Saharan Africa and South Asia. Iron is crucial for neural development and early deficiencies during fetal and infant growth cause irreparable damage to brain development.

Until now IDA has been largely attributed to diets low in iron and to infections such as malaria and intestinal helminths. However carefully controlled trials of iron supplements (often with deworming and malaria control) have very poor efficacy in Africa. The discovery of hepcidin - the master regulator of iron - throws a new light on the causes of IDA and may guide future therapeutic pathways. We have recently shown that even low-grade inflammation is a major contributor to ID in rural African children due to hepcidin/ferroportin-mediated blockade of intestinal absorption of iron. IDA is likely further exacerbated by EPO resistance.

This project seeks to identify the sources of persistent low-grade inflammation in well and sick Gambian children. It will additionally try to understand the complex interacting mechanisms linking iron absorption, distribution and erythropoiesis to the effects of inflammation mediated through hepcidin, erythropoietin (EPO) and the newly discovered hormone erythroferrone (ERFE) which signals to the liver that the bone marrow requires iron. Finally we will conduct a randomised controlled trial to test whether it is possible to circumvent the hepcidin-induced blockade of iron absorption by administering iron in the form of haem. Another arm of this trial will be a proof-of-principle trial to assess the impact of reducing inflammation by co-administering azithromycin and galacto-oligosaccharides with iron.

These studies, if successful, would suggest the need for a radical revision of current policies to combat IDA

Planned Impact

The recently-published Global Burden of Disease estimates (Lancet, Sept 2017) estimates that 1.225 billion people suffer from iron deficiency anaemia (IDA) making it the fifth most prevalent health condition worldwide and fourth highest cause of YLDs (years lived with disability). The health cost of IDA outweighs all other nutritional deficiencies, haemoglobinopathies and haemolytic anaemias combined. The greatest burden is concentrated in West and Central Africa and South Asia. A 50% reduction in anaemia rates is one of WHO's 6 key Global Targets for 2025, but at current rates it would take another century to reach the target.
Our recent research has identified a key reason for the lack of efficacy of current iron supplementation programmes; namely hepcidin-mediated blockade of iron absorption/utilisation secondary to persistent low-grade inflammation. The work we propose here seeks to confirm this proposition, identify the infectious and possible other drivers of inflammation (eg gut dysbiosis) and better describe the metabolic pathways involving inflammation/EPO/erythroferrone/hepcidin interactions. Finally we will test two new strategies to circumvent the blockade with a specific goal of doubling the haemoglobin response to iron achievable by currently recommended interventions.

Iron deficiency of the foetus and young infant causes irreparable damage to the developing brain. If our hypothesis is correct it would explain why current interventional strategies have such low efficacy and could pave the way to a radically new approach that focuses on inflammation reduction rather than the current orthodoxy built solely upon augmentation of iron intake.

The evolution of a new strategy would first require the building of a strong evidence base to convince academic and clinical colleagues engaged in global health. The next step would be to devise and test alternative next-generation interventions against IDA and test them in larger field studies in multiple countries; a strategic priority for translation-focussed funders such as the Gates Foundation and CIFF. Finally such policies would need to be adopted by international bodies (primarily WHO with whom we engage closely) and by national governments. In the light of widespread frustration at the low efficacy of the current international guidance, and the consequent persistence of IDA as the leading micronutrient deficiency worldwide, any proven new approaches would be likely to have rapid uptake. Even if the ultimate solutions require complex interventions around improvements in water, sanitation and hygiene (WASH++) our work would have high value by signalling the need for a radical re-orientation of health investments in respect of combatting IDA.

Publications

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Brittenham GM (2023) Biology of Anemia: A Public Health Perspective. in The Journal of nutrition

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Churiwal M (2021) Assessment of the Field Utility of a Rapid Point-of-Care Test for SARS-CoV-2 Antibodies in a Household Cohort. in The American journal of tropical medicine and hygiene

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Abatan B (2021) Intense and Mild First Epidemic Wave of Coronavirus Disease, The Gambia. in Emerging infectious diseases

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Muller MS (2021) Practical strategies for SARS-CoV-2 RT-PCR testing in resource-constrained settings. in Diagnostic microbiology and infectious disease

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Cerami C (2022) Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in the United States: Living Density, Viral Load, and Disproportionate Impact on Communities of Color. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Lin JT (2021) The Consequences of Isolating at Home. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

 
Title Public Health Messages on COVID-19 for Gambian Public 
Description These were a set of posters and booklets designed to help explain COVID19 and COVID19 precautions to the Gambian public. 
Type Of Art Artwork 
Year Produced 2020 
Impact These posters were pasted on MRCG vehicles and in shop windows all over Gambia 
 
Description DFID/NIHR/MRC/Wellcome Joint Global Health Trials - Call 9
Amount £268,612 (GBP)
Funding ID MRT003960/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2020 
End 04/2021
 
Description Wageningen University - Hans Verhoef 
Organisation Wageningen University & Research
Department Division of Human Nutrition
Country Netherlands 
Sector Academic/University 
PI Contribution We work closely with Dr Verhoef and have weekly meetings.
Collaborator Contribution Dr Hans Verhoef, Associate Professor at Wageneingen University is the statistician on this trial. He advised on the statistical analysis plan and checked all the calculations made for the publication. In addition, he has contributed to mentoring of the PhD student, Mamadou Bah, who is working on the trial.
Impact (1) Early iron supplementation in exclusively breastfed Gambian infants: a randomized controlled trial. Bull World Health Organ Bah M, Stelle I, Verhoef H, Saidykhan A, Moore SE, Susso B, Prentice AM, Cerami C. . 2024 Mar 1;102(3):176-186. doi: 10.2471/BLT.23.289942. Epub 2024 Jan 29. PMID: 38420570; PMCID: PMC10898279. (2) Iron supplementation of breastfed Gambian infants from 6 weeks to 6 months of age: protocol for a randomised controlled trial. Stelle I, Bah M, Silverio SA, Verhoef H, Comma E, Prentice AM, Moore SE, Cerami C. Wellcome Open Res. 2022 Jan 18;7:16. doi: 10.12688/wellcomeopenres.17507.1. eCollection 2022. PMID: 36874582 (3) Early iron supplementation of exclusively breastfed African infants: a proof-of-principle, placebo-controlled, randomised, double-blinded efficacy trial Mamadou Bah, Isabella Stelle, Hans Verhoef, Alasana Saidykhan, Sophie E. Moore, Babucarr Susso, Andrew M. Prentice, Carla Cerami doi: https://doi.org/10.1101/2023.01.12.22284059 https://www.medrxiv.org/content/10.1101/2023.01.12.22284059v1
Start Year 2020
 
Title Haem iron 
Description Haem iron versus ferrous iron salts to treat iron deficiency anaemia in Gambian children: protocol for randomised controlled trial. Background: The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation. Methods: This will be a two-arm, randomised controlled trial. Gambian children aged 6-12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team. Linear regression will be used to analyse continuous outcomes, with log-transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor) Discussion: This study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6-12 months 
Type Preventative Intervention - Nutrition and Chemoprevention
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2024
Development Status Actively seeking support
Clinical Trial? Yes
UKCRN/ISCTN Identifier PACTR202210523178727
Impact None yet. 
 
Description Community and participant feedback 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact We returned to the communities (20 villages) were the study was done to report the results of the study.
Participants, their families and the general public were all invited.
These events were heavily attended.
Year(s) Of Engagement Activity 2023
 
Description Health and Fitness demonstrations for local Gambian Schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I did a demonstration on healthy eating and prevention of anaemia to children ages 7-18. The demonstration was filmed and broadcast on Gambian TV station (GRTS).
100 pupils attended the event which was held at the Banjul American International school. Other presentations/demonstrations included information on fitness, vaccines and water sanitation and hygiene.
Year(s) Of Engagement Activity 2020
 
Description Informational sessions on iron deficiency in young children 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The IDeA study trial team held over 30 community-based meetings. The purpose of the meetings was to engage community members, especially mothers of young children. Educational information about iron deficiency in young children was provided. Information about the "IDeA 3" trial was also given.
Year(s) Of Engagement Activity 2023
 
Description Invited talk entitled: "Systemic inflammation and nutrition" at the 5th Global Micronutrient Forum, Micronutrient Forum, November 2020, on-line. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a seminar presented as part of the Micronutrient biology and status assessment session.
It remains available on-line.
Year(s) Of Engagement Activity 2020
URL https://www.eventscribe.com/2020/MNF-CONNECTED/
 
Description Lancet Haematology Commission on Anaemia - Consensus meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact This was a symposium at the MicroNutrient Forum in The Hague October 2023
"Getting back on track to meet the 2030 anaemia reduction targets:
Lancet Haematology Commission "

Schedule
07:00-07:04 Welcome and introduction
Sarah Atkinson, Kenya
07:04-07:09 Overview of Lancet Commission
Sant-Rayn Pasricha, Australia
07:09-07:14 Defining the global burden of anemia
Sorrel Namaste, USA
07:14-07:19 Biology of anemia
Pattanee Winichagoon, Thailand
07:19-07:24 Optimizing nutritional responses to anemia
Martin Mwangi, Netherlands
07:24-07:29 Non-nutritional solutions to address anemia
Carla Cerami, Gambia
07:29-07:34 Implementation of solutions to improve anemia
Bianca Carducci, USA
07:34-07:39 Global targets for reducing anemia prevalence
Sant-Rayn Pasricha, Australia
07:39-07:49 Audience prioritization of draft recommendations
Parminder Suchdev, Guatemala
07:49-08:14 Moderated discussion, audience feedback, Q&A
All moderators and speakers
08:14-08:15 Closing Remark
Sarah Atkinson, Kenya.
Year(s) Of Engagement Activity 2023
 
Description Member. Gambian National Alliance for Food Fortification. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact This is a committee made up of representatives from:
The Food and Agriculture Organization, The World Food Programme, UNICEF, Medical Research Council Unit The Gambia at LSHTM and Gambian National Nutrition Agency.
The purpose is to guide and advise on technical issues related to food fortification in The Gambia.
Dr Cerami contributes advice and expertise on anaemia, iron deficiency, iron fortification and iron supplementation.
Year(s) Of Engagement Activity 2019
 
Description Member. USAID Anemia Task Force, USAID Advancing Nutrition 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The USAID Anemia Task Force is the primary advisory body for USAID Advancing Nutrition on its micronutrient investments and activities;
The Task Force helps to improve what USAID and other institutions consider that: a) anaemia is more than iron-deficiency; b) Look beyond treatment with IFA supplementation and/or iron-fortification of flours; and, c) explore whether anaemia/haemoglobin is to be considered a biomarker or a reflection of its multifactorial aetiology;
Year(s) Of Engagement Activity 2019
URL https://www.advancingnutrition.org