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Toll-Like Receptor-Induced Immune Responses During Early Childhood and Their Associations With Clinical Outcomes Following Acute Illness Among Infants in Sub-Saharan Africa


Severely ill children in low- and middle-income countries (LMICs) experience high rates of mortality from a broad range of infectious diseases, with the risk of infection-related death compounded by co-existing undernutrition. How undernutrition and acute illness impact immune responses in young children in LMICs remains understudied, and it is unclear what aspects of immunity are compromised in this highly vulnerable population. To address this knowledge gap, we profiled longitudinal whole blood cytokine responses to Toll-like receptor (TLR) ligands among severely ill children (n=63; 2-23 months old) with varied nutritional backgrounds, enrolled in the CHAIN Network cohort from Kampala, Uganda, and Kilifi, Kenya, and compared these responses to similar-aged well children in local communities (n=41). Cytokine responses to ligands for TLR-4 and TLR-7/8, as well as Staphylococcus enterotoxin B (SEB), demonstrated transient impairment in T cell function among acutely ill children, whereas innate cytokine responses were exaggerated during both acute illness and following clinical recovery. Nutritional status was associated with the magnitude of cytokine responses in all stimulated conditions. Among children who died following hospital discharge or required hospital re-admission, exaggerated production of interleukin-7 (IL-7) to all stimulation conditions, as well as leukopenia with reduced lymphocyte and monocyte counts, were observed. Overall, our findings demonstrate exaggerated innate immune responses to pathogen-associated molecules among acutely ill young children that persist during recovery. Heightened innate immune responses to TLR ligands may contribute to chronic systemic inflammation and dysregulated responses to subsequent infectious challenges. Further delineating mechanisms of innate immune dysregulation in this population should be prioritized to identify novel interventions that promote immune homeostasis and improve outcomes.

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Childhood mortality during and after acute illness in sub-Saharan Africa and South Asia – The CHAIN cohort study


Objectives Mortality during acute illness among children in low- and middle-income settings remain unacceptably high and there is increasing recognition of the importance of post-discharge mortality. A comprehensive understanding of pathways underlying mortality among acutely ill children is needed to develop interventions and improve guidelines. We aimed to determine the incidence, timing and contributions of proximal and underlying exposures for mortality among acutely ill young children from admission to hospital until 6 months after discharge in sub-Saharan Africa and South Asia in the context of guideline-based care.

Design A prospective stratified cohort study recruiting acutely ill children at admission to hospital with follow up until 180 days after discharge from hospital (November 2016-July 2019).

Setting Nine urban and rural hospitals in sub-Saharan Africa and South Asia across a range of facility levels, and local prevalences of HIV and malaria.

Participants Inclusion criteria were age 2-23 months, admission to hospital with acute, non-traumatic medical illness and stratified into three groups by anthropometry. Children were excluded if currently receiving pulmonary resuscitation, had a known condition requiring surgery within 6 months or known terminal illness with death expected within 6 months.

Main outcome measures Acute mortality occurring within 30-days from admission; post-discharge mortality within 180-days from discharge; characteristics with direct and indirect associations with mortality within a multi-level a priori framework including demographic, clinical, anthropometric characteristics at admission and discharge from hospital, and pre-existing child-, caregiver- and household-level characteristics.

Results Of 3101 participants (median age 11 months), 1218 were severely wasted/kwashiorkor, 763 moderately wasted and 1120 were not wasted. Of 350 deaths, 182 (52%) occurred during index admission, 234 (67%) within 30-days of admission and 168 (48%) within 180-days post-discharge. Ninety (54%) post-discharge deaths occurred at home. The ratio of inpatient to post-discharge mortality was consistent across anthropometric strata and sites. Large high and low risk groups could be disaggregated for both early and post-discharge mortality. Structural equation models identified direct pathways to mortality and multiple socioeconomic, clinical and nutritional domains acting indirectly through anthropometric status.

Conclusions Among diverse sites in Africa and South Asia, almost half of mortality occurs post-discharge. Despite being highly predictable, these deaths are not addressed in current guidelines. A fundamental shift to a risk-based approach to inpatient and post-discharge management is needed to further reduce childhood mortality and clinical trials of these approaches with outcomes of mortality, readmission and cost are warranted.

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Gender-related influences on adherence to advice and treatment-seeking guidance for infants and young children post-hospital discharge in Bangladesh


Background: Post-hospital discharge mortality risk is high among young children in many low and middle-income countries (LMICs). The available literature suggests that child, caregiver and health care provider gender all play important roles in post-discharge adherence to medical advice, treatment-seeking and recovery for ill children in LMICs, including those with undernutrition.

Methods: A qualitative study was embedded within a larger multi-country multi-disciplinary observational cohort study involving children aged less than 2 years conducted by the Childhood Acute Illness and Nutrition (CHAIN) Network. Primary data were collected from family members of 22 purposively selected cohort children. Family members were interviewed several times in their homes over the 6 months following hospital discharge (total n = 78 visits to homes). These in-depth interviews were complemented by semi-structured individual interviews with 6 community representatives, 11 community health workers and 12 facility-based health workers, and three group discussions with a total of 24 community representatives. Data were analysed using NVivo11 software, using both narrative and thematic approaches.

Results: We identified gender-related influences at health service/system and household/community levels. These influences interplayed to family members’ adherence to medical advice and treatment-seeking after hospital discharge, with potentially important implications for children’s recovery. Health service/system level influences included: fewer female medical practitioners in healthcare facilities, which influenced mothers’ interest and ability to consult them promptly for their child’s illnesses; gender-related challenges for community health workers in supporting mothers with counselling and advice; and male caregivers’ being largely absent from the paediatric wards where information sessions to support post-discharge care are offered. Gendered household/community level influences included: women’s role as primary caretakers for children and available levels of support; male family members having a dominant role in decision-making related to food and treatment-seeking behaviour; and greater reluctance among parents to invest money and time in the treatment of female children, as compared to male children.

Conclusions: A complex web of gender related influences at health systems/services and household/community levels have important implications for young children’s recovery post-discharge. Immediate interventions with potential for positive impact include awareness-raising among all stakeholders – including male family members – on how gender influences child health and recovery, and how to reduce adverse consequences of gender-based discrimination. Specific interventions could include communication interventions in facilities and homes, and changes in routine practices such as who is present in facility interactions. To maximise and sustain the impact of immediate actions and interventions, the structural drivers of women’s position in society and gender inequity must also be tackled. This requires interventions to ensure equal equitable opportunities for men and women in all aspects of life, including access to education and income generation activities. Given patriarchal norms locally and globally, men will likely need special targeting and support in achieving these objectives.

Keywords: Bangladesh; Children; Gender relations; Hospitalization; Treatment-seeking; Undernutrition.

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Model for developing context-sensitive responses to vulnerability in research: managing ethical dilemmas faced by frontline research staff in Kenya


Health research in low-resource settings often involves individuals and populations defined as ‘vulnerable’. There is growing attention in the literature to the ethical dilemmas that frontline research staff face while conducting such research. However, there is little documented as to how research staff might support one another in identifying and handling these dilemmas in different contexts. Over the course of conducting empirical ethics research embedded in the Childhood Acute Illness & Nutrition Network, we developed an approach to examine and respond to the ethical issues and dilemmas faced by the study teams, particularly frontline staff. In this paper we describe the specific tools and approach we developed, which centred on regular cross-team ethics reflection sessions, and share lessons learnt. We suggest that all studies involving potentially vulnerable participants should incorporate activities and processes to support frontline staff in identifying, reflecting on and responding to ethical dilemmas, throughout studies. We outline the resources needed to do this and share piloted tools for further adaptation and evaluation. Such initiatives should complement and feed into-and certainly not in any way replace or substitute for-strong institutional ethics review, safeguarding and health and safety policies and processes, as well broader staff training and career support initiatives.

Keywords: child health; hospital-based study; paediatrics; public health.

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Vulnerability, Agency, and the Research Encounter: Family Members’ Experiences and Perceptions of Participating in an Observational Clinical Study in Kenya


Pediatric clinical research in low-resourced countries involves individuals defined as “vulnerable” in research ethics guidance. Insights from research participants can strengthen the design and oversight of studies. We share family members’ perspectives and experiences of an observational clinical study conducted in one Kenyan hospital as part of an integrated empirical ethics study. Employing qualitative methods, we explored how research encounters featured in family members’ care-seeking journeys. Our data reveals that children’s vulnerability is intricately interwoven with that of their families, and that research processes and procedures can inadvertently add to hidden burdens for families. In research, the potential for layered and intersecting situational and structural vulnerability should be considered, and participants’ agency in constrained research contexts actively recognized and protected.

Keywords: agency; childhood acute illness; integrated empirical ethics; low- and middle-income countries; vulnerability.

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Strengthening the role of community health workers in supporting the recovery of ill, undernourished children post hospital discharge: qualitative insights from key stakeholders in Bangladesh and Kenya


Background: Undernourished children in low- and middle-income countries remain at elevated risk of death following hospital discharge, even when treated during hospitalisation using World Health Organisation recommended guidelines. The role of community health workers (CHWs) in supporting post-discharge recovery to improve outcomes has not been adequately explored.

Methods: This paper draws on qualitative research conducted as part of the Childhood Acute Illnesses and Nutrition (CHAIN) Network in Bangladesh and Kenya. We interviewed family members of 64 acutely ill children admitted across four hospitals (a rural and urban hospital in each country). 27 children had severe wasting or kwashiorkor on admission. Family members were interviewed in their homes soon after discharge, and up to three further times over the following six to fourteen months. These data were supplemented by observations in facilities and homes, key informant interviews with CHWs and policy makers, and a review of relevant guidelines.

Results: Guidelines suggest that CHWs could play a role in supporting recovery of undernourished children post-discharge, but the mechanisms to link CHWs into post-discharge support processes are not specified. Few families we interviewed reported any interactions with CHWs post-discharge, especially in Kenya, despite our data suggesting that opportunities for CHWs to assist families post-discharge include providing context sensitive information and education, identification of danger signs, and supporting linkages with community-based services and interventions. Although CHWs are generally present in communities, challenges they face in conducting their roles include unmanageable workloads, few incentives, lack of equipment and supplies and inadequate support from supervisors and some community members.

Conclusion: A multi-pronged approach before or on discharge is needed to strengthen linkages between CHWs and children vulnerable to poor outcomes, supported by clear guidance. To encourage scale-ability and cost-effectiveness of interventions, the most vulnerable, high-risk children, should be targeted, including undernourished children. Intervention designs must also take into account existing health worker shortages and training levels, including for CHWs, and how any new tasks or personnel are incorporated into hospital and broader health system hierarchies and systems. Any such interventions will need to be evaluated in carefully designed studies, including tracking for unintended consequences.

Keywords: Acute illness; Children; Community health workers; Post-hospital discharge; Undernutrition.

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Applying a gender lens to understand pathways through care for acutely ill young children in Kenyan urban informal settlements


Background: In many African settings, gender strongly influences household treatment-seeking and decision-making for childhood illnesses. While mothers are often the primary engagers with health facilities, their independence in illness-related decisions is shaped by various factors. Drawing on a gender lens, we explored treatment-seeking pathways pre- and post-hospital admission for acutely ill young children living in low income settlements in Nairobi, Kenya; and the gendered impact of child illness both at the household and health system level.

Methods: Household members of 22 children admitted to a public hospital were interviewed in their homes several times post hospital discharge. In-depth interviews covered the child’s household situation, health and illness; and the family’s treatment-seeking choices and experiences. Children were selected from an observational cohort established by the Childhood Acute Illness and Nutrition (CHAIN) Network.

Results: Treatment-seeking pathways were often long and complex, with mothers playing the key role in caring for their children and in treatment decision-making. Facing many anxieties and dilemmas, mothers often consulted with significant influencers – primarily women – particularly where illnesses were prolonged or complex. In contrast to observations in rural African contexts, fathers were less prominent as influencers than (often female) neighbours, grandparents and other relatives. Mothers were sometimes blamed for their child’s condition at home and at health facilities. Children’s illness episode and associated treatment-seeking had significant gendered socio-economic consequences for households, including through mothers having to take substantial time off work, reduce their working hours and income, or even losing their jobs.

Conclusion: Women in urban low-income settings are disproportionately impacted by acute child illness and the related treatment-seeking and recovery process. The range of interventions needed to support mothers as they navigate their way through children’s illnesses and recovery include: deliberate engagement of men in child health to counteract the dominant perception of child health and care as a ‘female-domain’; targeted economic strategies such as cash transfers to safeguard the most vulnerable women and households, combined with more robust labour policies to protect affected women; as well as implementing strategies at the health system level to improve interactions between health workers and community members.

Keywords: Child health; Gender; Pathways to care; Urban health; Urban informal settlements.

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Vulnerability and agency across treatment-seeking journeys for acutely ill children: how family members navigate complex healthcare before, during and after hospitalisation in a rural Kenyan setting.


Background: Child mortality rates during hospitalisation for acute illness and after discharge are unacceptably high in many under-resourced settings. Childhood vulnerability to recurrent illness, and death, is linked to their families’ situations and ability to make choices and act (their agency). We examined vulnerability and agency across treatment-seeking journeys for acutely ill children and considered the implications for policy and practice.

Method: A qualitative sub-study was embedded within the prospective CHAIN Network cohort study, which is investigating mechanisms of inpatient and post-hospital discharge mortality among acutely ill young children across a spectrum of nutritional status. Primary data were collected from household members of 20 purposively selected cohort children over 18 months through formal interviews (total n = 74), complemented by informal discussions and observations. Data were analysed using narrative and thematic approaches.

Results: Treatment-seeking pathways were often long and complex, particularly for children diagnosed as severely malnourished. Family members’ stories reveal that children’s carers, usually mothers, navigate diverse challenges related to intersecting vulnerabilities at individual, household and facility levels. Specific challenges include the costs of treatment-seeking, confusing and conflicting messaging on appropriate care and nutrition, and poor continuity of care. Strong power inequities were observed between family members and health staff, with many mothers feeling blamed for their child’s condition. Caregivers’ agency, as demonstrated in decision-making and actions, often drew on the social support of others but was significantly constrained by their situation and broader structural drivers.

Conclusion: To support children’s care and recovery, health systems must be more responsive to the needs of families facing multiple and interacting vulnerabilities. Reducing incurred treatment costs, improving interpersonal quality of care, and strengthening continuity of care across facilities is essential. Promising interventions need to be co-designed with community representatives and health providers and carefully tested for unintended negative consequences and potential for sustainable scale-up.

Keywords: Agency; Childhood acute illness; Treatment-seeking; Vulnerability.

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The impact of malnutrition on childhood infections

Judd L. Walson and James A. Berkley


Purpose of review

Almost half of all childhood deaths worldwide occur in children with malnutrition, predominantly in sub- Saharan Africa and South Asia. This review summarizes the mechanisms by which malnutrition and serious infections interact with each other and with children’s environments.

Recent findings

It has become clear that whilst malnutrition results in increased incidence, severity and case fatality of
common infections, risks continue beyond acute episodes resulting in significant postdischarge mortality.
A well established concept of a ‘vicious-cycle’ between nutrition and infection has now evolving to
encompass dysbiosis and pathogen colonization as precursors to infection; enteric dysfunction constituting
malabsorption, dysregulation of nutrients and metabolism, inflammation and bacterial translocation. All of
these interact with a child’s diet and environment. Published trials aiming to break this cycle using
antimicrobial prophylaxis or water, sanitation and hygiene interventions have not demonstrated public
health benefit so far.

As further trials are planned, key gaps in knowledge can be filled by applying new tools to re-examine old questions relating to immune competence during and after infection events and changes in nutritional status; and how to characterize overt and subclinical infection, intestinal permeability to bacteria and the role of antimicrobial resistance using specific biomarkers.

clinical trial, children, colonization, dysbiosis, environmental, growth, malnutrition, mortality, survival,
susceptibility, undernutrition

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CHAIN in pictures









CHAIN Coordination and Blantyre Team during a site visit in October 2022

CoMs Research Dissemination Conference 2018

Blantyre site coordinator Emily Mbale shares a light moment with Clinician Prisca during the Gates visit in September

Blantyre clinician Prisca, explaining CHAIN procedures in QUECH wards to Gates team.

Coordination team visit outside Migori CHAIN office during visit in April

Christine McGrath and Johnstone taking notes during coordination visit in Migori site, April 2018

Meeting with Mental Health Director, Prof. Pamela Collins during the Annual Coordination meeting in July

Team discussing lab data during the Coordination meeting in Seattle.

Eric and Narshion with Uganda data team during recent site visit in September.