Sepsis Clinical Trial
Official title:
Building the Evidence Base for Appropriate Care of the Sick, Undernourished Child in Limited Resource Settings
The CHAIN Network aims to identify modifiable biomedical and social factors driving the
greatly increased risk of mortality among young undernourished children admitted to hospital
with acute illness, as inpatients and after discharge. The study will inform priorities,
risks and targeting for multi-faceted interventional trials.
CHAIN is a multi-centre cohort study with a nested case control analysis of stored biological
samples. Study sites are located in Africa and South Asia. Children will be recruited at
admission to hospital, stratified by nutritional status. Exposures will be assessed at
admission, during hospitalisation, at discharge, and at two time points after discharge. The
main outcomes of interest are mortality, re-admission to hospital and failure of nutritional
recovery up to 180 days after discharge. To determine community health norms, an additional
sample of children living in the same communities will be enrolled and assessed at one time
point only.
Despite an overall reduction of child mortality in LMICs, acutely-ill undernourished children
continue to have a greatly elevated risk of death, both during hospitalisation and following
discharge. However, we currently lack robust evidence for their management. Factors
underlying the risks of mortality may relate to the acute illness itself, to children's
longer term health trajectories, or to the home nutritional and care environment. The
ultimate goal of the CHAIN Network is to identify and prioritize actionable intervention
targets to reduce mortality among acutely ill undernourished children.
CHAIN's initial aim is to better understand the characteristics that determine increased risk
of mortality in this vulnerable population, whether biological (related to infection,
immunity and metabolism), nutritional (intake and anthropometry), health system factors
(affecting management and discharge) or behavioural (community/caregiver interactions). CHAIN
brings clinicians and scientists together from a variety of high-burden settings in Africa
and South Asia. CHAIN will establish prospective cohorts of acutely ill young children across
different geographies with differing population, social and environmental characteristics
(stunted vs. wasting, rural vs. urban and presence of risk factors such as malaria and HIV).
Eight sites will be involved, including three hospitals in Kenya (Kilifi County, Migori
County and Mbagathi District), two in Bangladesh (Matlab and the icddr,b Dhaka), and one in
each of Uganda (Mulago), Malawi (Queen Elizabeth Community Hospital), Pakistan (Civil
Hospital Karachi) and in West Africa (TBA). Site will enroll children at admission to
hospital, and assess their clinical, social and economic status at admission, during
hospitalisation, at discharge and during follow up for 180 days after discharge. The sites
will also enrol children from the community to determine community norms (where ill and
undernourished children would be expected to typically recover to). Protocols and procedures
will be carefully harmonised across sites.
Children aged 2 months to 2 years admitted to hospital will be considered for inclusion and
enrolment stratified by nutritional status. Following informed consent, baseline data of
prognostic importance, including demographic and social information, a detailed clinical
examination, anthropometry and measurement of vital signs, including pulse oximetry, will be
collected using a standard proforma. A research blood sample will be collected together with
the routine clinical blood draw to minimize the patient's discomfort. Rectal swabs and faecal
sample will also be obtained from all children.
During admission, care will be provided according to WHO and national guidelines. Children
will be reviewed daily and clinical features, progress and treatment received recorded on a
structured case report form. In the event of death in hospital, a standard audit
questionnaire will be completed. During admission, primary caregivers, usually the mother,
will be interviewed screened for mental health problems. At discharge, anthropometry, a
clinical assessment and blood, rectal swab and whole stool collected. Families will be linked
with chronic care services where needed.
A home visit will be conducted for all participants, the GPS location recorded. Information
homestead infrastructure, water and sanitation, population, livelihood, child care and
socioeconomic characteristics. Children will be followed up at 45, 90 and 180 days after
discharge. A health questionnaire will document health and social events, and dietary intake.
Anthropometry, and faecal and blood samples collected.
Caregivers will be asked to attend the study hospital should the caregiver believes they may
require hospitalisation. Study participants who are re-admitted to hospital will undergo
standardised clinical assessment including history, examination and sample collection. In the
event of death occurring outside the study hospital, a standard verbal autopsy (VA) will be
completed by trained staff within 28 days of becoming aware of a death. VAs along with all
available information will be used to ascribe causes of death.
Community participants will be invited to the study clinic for assessment. Following informed
consent, they will have a clinical examination, anthropometry, blood and stool samples as
children who are admitted. Children requiring non-urgent medical care will be eligible for
inclusion as community participants but will be given basic treatment in the study clinic
and/or referred to appropriate treatment centres. Study staff will refer community
participants with incomplete vaccination or requiring care for chronic conditions as needed.
Several domains of exposure will be assessed: demographic, nutrition and metabolism; acute
and chronic conditions; community-acquired and nosocomial infections (including antimicrobial
resistance); gut function & dysbiosis; inflammation; responses to treatment; and the home
care environment.
Successful design of an intervention package to address post-discharge child mortality will
require attention social and economic agency and vulnerability, access and interactions with
health services, and ethical considerations. A qualitative sub-study will examine these
factors in context in rural and urban sites in Kenya and Bangladesh to identify critical
social limitations and potential approaches to intervention. These data will inform the
network's development, piloting, and implementation of interventions.
Additional sub-studies at a subset of sites will also examine in more detail the diagnosis
and role of TB; and changes in functional immune responses; body composition and
neurodevelopment during follow up.
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