An Observational Study Designed to Elucidate the Pathways by Which Inflammation Contributes to Anaemia in Sick Rural African Children From 6 Months to 36 Months

An Observational Trial Designed to Elucidate the Pathways by Which Inflammation Contributes to Anaemia in Sick Rural African Children From 6 Months to 36 Months

The Investigator have previously shown that hepcidin is up-regulated even by low levels of inflammation and, according to our prior stable isotope studies, is predicted to block iron absorption. In this follow-up observational study, the investigator aim to characterise the relationship between infections, acute inflammation, hepcidin and iron iron deficiency anaemia in rural African children. The Investigator will study 200 sick children (6-36 months of age) living in the rural region of West Kiang.

The Investigator will:

1. Recruit 50 sick febrile children in each of 4 categories; Upper Respiratory tract infections, Lower respiratory tract infections (pneumonia), Urinary tract infections, gastroenteritis.
2. Assess iron absorption and its relationship to iron and anaemia status, inflammation, EPO, erythroferrone and hepcidin.

Study Overview

• Status: Recruiting
• Conditions: Iron Deficiency, Anaemia in Children
• Intervention / Treatment: Procedure: blood sampling

Detailed Description

Aim 1: To test whether non-malarial infections increase hepcidin levels and for how long in sick children (note that the investigator exclude malaria because the investigator and others have previously examined the effect of malaria).

Hypothesis 1: On day 0, 3 and 7 of acute illness, hepcidin will be higher when compared to levels in well children. On Day 14 iron absorption and hepcidin levels will have returned to baseline.

Research Question 1: What affect do non-malarial infections (upper respiratory tract infections, lower respiratory tract infections, urinary tract infections and gastroenteritis) have on hepcidin levels and how long does this effect last?

Aim 2: To retest our existing hepcidin threshold for discriminating iron absorbers from non-absorbers by repeating our prior ROC analysis based on a much larger sample.

Hypothesis: On day 0, 3 and 7 of acute illness, iron absorption will be lower. On Day 14, iron absorption will be equivalent to iron absorption in well children. Note that the Hepcidin levels and iron absorption data obtained in this study will be compared with the results obtained from similarly aged children in IDeA Study 1 (SCC 1664). Also note that The investigator anticipate that most of the children enrolled in this study will have a base-line level of anaemia (eg Hgb<11g/dL).

Research Question: What is the relationship between hepcidin and oral iron absorption in acute illness and convalescence and how does this differ from the relationship in well children?

Aim 3: To examine EPO synthesis and EPO resistance in children with acute non-malarial infections?

Hypotheses:

1. Children with acute non-malaria infections will have both acute and chronic anaemia of inflammation.
2. EPO is increased during acute infection.

Research Question: Is there decreased EPO synthesis and/or increased EPO resistance in children with acute non-malarial infections living in rural Gambia?

Aim 4: To examine erythroferrone in children with acute non-malarial infections leaving in rural Gambia.

Hypothesis: First The investigator will conduct a hypothesis-free exploratory analysis to assess whether erythroferrone behaves as predicted based upon mouse models (ie up-regulated by stress erythropoiesis and inversely related to hepcidin). The investigator additionally hypothesize that there may be a vicious cycle initiated by inflammation and then perpetuated by the consequent low levels of (iron-restricted) erythropoiesis, leading to low erythroferrone and loss of hepcidin suppression.

Research Question: What is the relationship between erythroferrone, iron status, inflammation, hepcidin, EPO and CRP in anaemic and non-anaemic children living in rural Gambia? This is an observational study of 200 sick children who will be recruited at the Keneba clinic. Each child will be seen four times (at day 0, 3, 7 14).

200 subjects aged 6 -36m brought to Keneba clinic with an acute illness. 50 patients from each category: Upper respiratory tract infections (including ear, nose and throat infections), Lower respiratory tract infections, urinary tract infections and gastroenteritis.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Carla Cerami, MD; Phone Number: 00220-4495442-6; Email: ccerami@mrc.gm
• Study Contact Backup: Name: Elizabeth Ledger, BMBCh; Phone Number: +220-4495442-6; Email: eledger@mrc.gm

Study Locations

• Gambia
  • Banjul
    • West Kiang, Banjul, Gambia, 0000
      • Recruiting
      • Keneba MRC Unit
      • Contact: Elizabeth Ledger, MBBCh; Phone Number: +220 4495442-6; Email: eledger@mrc.gm
      • Principal Investigator: Carla Cerami, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

sick children with fever

Description

Inclusion Criteria:

• Male or female children ages 6-36 months
• Fever ( > 37.5C) and/or signs of illness.
• Signed or fingerprinted or personally marked written informed consent obtained from their parent/guardian.
• Parent/guardian plans for subject to reside in study site area and are able and willing to adhere to all protocol visits and procedures.

Exclusion Criteria:

1. Critically unwell requiring stabilisation and transfer i.e. scores 3 on initial assessment
2. Sickle cell disease
3. Evidence of hookworm infection by stool microscopy
4. Administration of immunosuppressants or other immune-modifying agents within 90 days prior to study IP administration (e.g., systemic corticosteroids at doses equivalent to ≥ 0.5 mg/kg/day of prednisone for more than 14 days; topical steroids including inhaled and intranasal steroids are not exclusionary).
5. Administration of systemic antibiotic treatment within 3 days prior to study enrolment.
6. Any history of or evidence for chronic clinically significant (as per investigator assessment) disorder or disease (including, but not limited to, immunodeficiency, autoimmunity, malnutrition*, congenital abnormality, bleeding disorder, and pulmonary, cardiovascular, metabolic, neurologic, renal, or hepatic disease). * Other than the exclusionary clinical diagnosis of malnutrition for all subjects, in children 2 to 5 years of age, malnutrition is also defined as a weight-for-height Z-score of less than -3 as per WHO reference standards.
7. Any history of human immunodeficiency virus, chronic hepatitis B or chronic hepatitis C infections.
8. Any condition that in the opinion of the investigator might compromise the safety or well-being of the subject or compromise adherence to protocol procedures
9. Participation in another MRC study

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Urinary Tract Infection; Inclusion criteria (one from the list below): Positive leukocytes, positive nitrites on dipstick; Negative leukocytes, Positive nitrites on dipstick; Positive leukocytes, negative nitrites, plus bacteriuria on microscopy; Positive leukocytes, negative nitrities plus no bacteriuria, only pyuria on microscopy PLUS clinical features e.g. fever, pain on urination, offensive smelling urine. Exclusion criteria (one from the list below): 1. No evidence of UTI on dipstick	Procedure: blood sampling; observational study and no intervention will be given. only blood samples collected and treated with iron supplements
Upper respiratory tract infection; Inclusion criteria (one from the list below):: Evidence of nasal discharge AND/OR; Inflammation throat/ tonsils on direct examination AND/OR; Inflammation of middle or outer ear on direct examination; History of fever AND history of stridor/ barking cough; History of fever AND lymphadenopathy AND/ OR URTI symptoms i.e sore throat/ cough Exclusion criteria (one from the list below):: Foreign body inserted in either nose/ ear; Traumatic perforation of ear drum; Allergic rhinitis i.e. good contact history; Evidence of LRTI	Procedure: blood sampling; observational study and no intervention will be given. only blood samples collected and treated with iron supplements
Lower respiratory tract infection; Inclusion criteria (one from the list below): Focal signs on auscultation of the chest i.e crepitations/ wheeze/ reduced air entry; Fever > 38.5C AND chest recessions AND/OR raised respiratory rate; Radiological evidence of LRTI Exclusion criteria (one from the list below): 1. Positive malaria test OR suspicion of metabolic acidosis causing tachypnoea and fever	Procedure: blood sampling; observational study and no intervention will be given. only blood samples collected and treated with iron supplements
Diarrhoea/ gastroenteritis; Inclusion criteria (one from the list below): Abrupt onset of 3 or more loose/liquid stools/ day; Ova, cysts, parasites identified on stool microscopy PLUS symptomatic diarrhoea,and/ or fever and/or vomiting; Fever AND vomiting WITHOUT other source of fever i.e UTI/LRTI/URTI Exclusion criteria (one from the list below): Normal breast milk stool; Neurological cause of vomiting	Procedure: blood sampling; observational study and no intervention will be given. only blood samples collected and treated with iron supplements

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Serum hepcidin from baseline to day 14	Day 14
Change in Clinical score of site and severity of infection and inflammation from baseline to day 14	Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum iron levels	Increase in serum iron levels above baseline following an oral ferrous fumarate dose as a measure of iron absorption	Day 0, 3, 7 & 14
Erythropoietin		Day 0, 3, 7 & 14
Erythroferrone		Day 0, 3, 7 & 14

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2019
• Primary Completion (Anticipated): January 1, 2023
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: September 4, 2019
• First Submitted That Met QC Criteria: September 18, 2019
• First Posted (Actual): September 19, 2019

Study Record Updates

• Last Update Posted (Actual): January 9, 2020
• Last Update Submitted That Met QC Criteria: January 6, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Hematologic Diseases; Inflammation; Anemia
• Other Study ID Numbers: SCC 17097

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No