Title: NIHR Global Health Research Group on Sepsis at the Liverpool School of Tropical Medicine
Funder: Department of Health and Social Care

Abstract: Our aim is to improve the survival and quality of life of sepsis patients through multidisciplinary applied health research at the individual and health system level. The Group provides the framework to transform sepsis research, guided by the priorities of African stakeholders. We will develop capacity across the spectrum of translational research from training in research methods, through clinical skills and systems-level implementation science, and into policy. We will be multi-disciplinary and collaborative; within Africa, we have named partners representing African research units, Ministries of Health, non-governmental organisations, and medical societies. For each, we have counterparts in the UK and high-income countries (HICs), notably the NHS, who bring expertise in specific knowledge areas including patient safety and health economics (see “Partners”). With the African Institute for Development Policy (AFIDEP), the Group has explicit plans for ensuring results are incorporated into national and international policy. Our Centres for Sepsis Research Excellence are chosen for several reasons, including: representation of both low- (Malawi, Uganda) and middle-income (Gabon) countries; potential for South-South collaboration; existing laboratory and clinical infrastructure which will support the Group’s research; and long-standing research links with the investigators (Rylance in Malawi; Jacob in Uganda; Gorbusch in Gabon). Concentration of resources in 3 countries will allow for greater research impact. Baseline assessment of similarities and differences will describe the likely external validity of the work. Our ASA link will ensure that questions are relevant in other countries and studies can be expanded into new settings where appropriate. LEADERSHIP We have high-level commitment from LSTM, and our aim closely reflects the LSTM vision. The Dean of LSTM has allocated protected time to provide senior support and guidance to the two mid-career co-directors (Rylance, and Jacob, a recent strategic appointment as Senior Lecturer in Sepsis). This team have broad-ranging expertise in infection and sepsis research in Africa and have an existing portfolio of relevant research funding upon which this NIHR group builds (see CVs). If funded, 60% of the costs of the directors and senior investigator time will be core funded by LSTM, allowing 70% of the NIHR funding to be spent in Africa. SUPPORT FROM LSTM LSTM is a centre of excellence in Tropical Medicine, housing a critical mass of multidisciplinary researchers with extensive experience of undertaking clinical and health systems research in LMIC and developing successful partnerships. LSTM provides extensive infrastructural support and expertise, including a tropical Clinical Trials Unit (tCTU), the Technology Enhanced Learning Unit, communications, and shared working space with NHS colleagues (Co-I Nsutebu) in the Liverpool Life Sciences Accelerator at the Royal Liverpool University Hospital. Integrated social science research will ensure context appropriateness and acceptability of interventions (Tolhurst, Gooding). INNOVATIVE PARTNERSHIPS LSTM has a long history of successful partnerships with LMIC organisations through bilateral collaborations within LSTM-supported networks. Collaboration for Applied Health Research and Delivery (CAHRD), for example, led from LSTM, is a global network of individuals and organisations which implements research-driven effective, innovative, and affordable health practices. Building on this health systems experience, we will develop further collaborations: • South-South: The Group will foster new international multidisciplinary partnerships through the Centres of Sepsis Research Excellence in Uganda, Malawi, and Gabon. Each country has a strong sepsis research track record with complementary areas of expertise to be cross-pollinated through the grant activities (e.g., Malawi – epidemiology and severity scores[1, 2]; Uganda - sepsis intervention studies and quality improvement[3-5]; Gabon - co-infections and early recognition[6, 7]) • North-South: The African Sepsis Alliance (ASA, lead: Nsutebu), a regional network of 15 African countries and the UK comprises research expertise and a platform for rapid dissemination of good practice and strong sepsis advocacy. We will utilise the expertise of ASA’s 60+ clinicians and allied health professionals to enhance mentorship support across Africa, starting with linking mentorship and training in our Centres of Sepsis Research Excellence. Additional connections with NHS expertise (including NHS Improvement and the Advancing Quality Alliance[8, 9]) bring new perspectives and exciting opportunities to improve sepsis care and research in LMIC health systems. • South-North: Group members and ASA experts will work together to develop a sepsis module within the existing LSTM Diploma of Tropical Medicine and to deliver this teaching. • North-North: LSTM will benefit from the health systems research hub at Warwick University which houses the NIHR Unit on Improving Health in Slums and the NIHR Collaborations for Leadership in Applied Health Research and Care (CLAHRC) West Midlands which specialises in implementation methodology, research design, and Bayesian networks (led by Co-I Lilford). RESEARCH TRAINING We will use LSTM’s excellent track record in postgraduate education and research training (it hosts Wellcome and MRC-funded PhD schemes) to grow junior African academics to high-level independent scientific careers. The Group will deliver tailored Global Health research training to 3 postdoctoral “Sepsis Fellows” based in Gabon, Malawi and Uganda, respectively. As part of the LSTM Skills Development Programme (see “Research Capacity”), Fellows will have UK and in-country mentorship structures, undergo integrated training in quantitative methods, and have opportunities for 10-week learning placements with strategic partners. We will identify, through the ASA, other talented individuals at an early career stage (“Sepsis Scholars”), to undergo a series of 1-week Africa-based residential science-training workshops focused on respiratory and critical care (PATS-MECOR, see “Research capacity”). ASA partners will act as faculty and scholarships will be competitively awarded for African students to attend and complete their own small research projects. VALUE FOR MONEY The Group will share resources and maximise efficiency by: learning from the setup phase of the NIHR Lung and Tuberculosis Unit; extending existing trial design skills within the tCTU; adapting research methodology developed by the NIHR Unit on Improving Health in Slums for measuring care quality; sharing meeting venues with CAHRD (see “Partners”); and using infrastructure and methods common to extant projects (FIEBRE, JGHT see “Additional Information”). SUSTAINABILITY The Group will induce sustainable change through: 1) Research tools (including measures of quality of sepsis care) 2) Research training (see “Research capacity”) 3) Channels for engagement with policy makers at national (Ministry of Health as Co-Investigators) and international level (WHO collaboration) Success and sustainability will require additional grant applications. Whilst core funding will launch this Group, we expect budget contributions from future awards resulting from outputs from this award, including: a) scaling-up successful pilot interventions; b) addressing priority research questions identified; and c) using our pre-tested clinical trial platforms.

Lay abstract: We propose a Group on sepsis, a condition affecting 30 million people each year and resulting in 6 million deaths worldwide. Sepsis occurs during infection when a loss of control of the body’s normal responses leads to damage of vital organs. It can be the final common pathway to death for many infections, including outbreak-prone disease such as meningococcal meningitis, pandemic influenza, and Ebola. Despite its global health significance, the effectiveness of many aspects of sepsis care in Low- and Middle-Income Countries (LMIC) are unknown, even for simple therapies such as intravenous fluid (drips). The Group will utilise expertise across the applied health spectrum from LSTM, the University of Warwick, the NHS, and UK and international professional societies. We will develop capacity and skills to address relevant sepsis research questions by embedding in-country directors within local research and clinical organisations, partnering with government, non-government organizations, and commercial sectors in Africa. In collaboration with African partners, we will translate UK’s experience in reducing sepsis mortality through the NHS focus on quality of care and patient safety. Our aims: 1) Sustainably improve sepsis research training 2) Reach consensus on research priorities and sepsis care quality indicators for Africa 3) Pilot test innovative sepsis care interventions 4) Test novel clinical trial platforms to answer key sepsis questions for Africa Unique features to ensure success include: • Establishing Centres of Sepsis Research Excellence in three core countries (Uganda, Malawi, and Gabon) taking advantage of the Group’s existing local leadership and sepsis research experience. Within these centres, we will conduct pilot evaluations such as Africa-optimised programmes to rapidly identify critically unwell patients (triage) and use of existing technology like bedside ultrasound to monitor heart and lung function in patients receiving sepsis treatment. We will evaluate feasibility of innovative data-capture infrastructure for future “adaptive” clinical trials. We will work collaboratively with Ministries of Health to build their capacity for adopting research findings into policy and practice. • The African Sepsis Alliance (ASA), a newly established organisation with over 60 members from 15 sub-Saharan countries with potential to extend impact beyond the Centres of Sepsis Research Excellence. Through the ASA, we will deliver the first multinational study of sepsis disease burden in Africa. We incorporate broad experience and knowledge from ASA stakeholders into identifying key performance indicators which could drive local and national quality improvement work. • Multifaceted training and mentoring programme to develop regional leaders in sepsis research. We will use established schemes in postgraduate research methodology at LSTM and in Africa (with the Pan African Thoracic Society and ASA). We will train frontline staff in sepsis recognition and response with WHO implementing partners (Walimu) and clinician-researchers in skills such as ultrasound (with the NHS) to pilot a sustainable approach to enhancing skills in applied sepsis research from early to mid-career researchers. • Strong multidisciplinary governance structures (see Organogram) which include global leaders in sepsis with expertise in clinical trials (CRISMA, ICNARC), implementation science (KEMRI), quality improvement (NHS), and global advocacy (GSA; ASA).

Research activity codes: 7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM