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 Study 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.
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.
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