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It is time to tackle sepsis in a tractable and sustainable manner – an interview to raise awareness on World Sepsis Day 2022

September 13th marks World Sepsis Day (WSD), an event dedicated to raise public awareness about this global health problem and how to address it. We spoke to four researchers from the Ineos Oxford Institute (IOI) for Antimicrobial Research to learn more about sepsis, how it is related to their work, and how the Institute is marking this year’s event.

World Sepsis Day (WSD) is a yearly event that has been commemorated on September 13th since 2012 to promote global awareness about this life-threatening medical condition. Sepsis, also known as septicaemia or blood poisoning, occurs when the immune system overreacts to an infection, leading to systemic damage across tissues and organs, potentially resulting in death.

With almost 50 million cases of sepsis estimated to occur every year and leading to approximately 11 million annual deaths (which represents nearly 1 in 5 of all global deaths), this condition represents a major global health problem, particularly in children and in low- and middle-income countries (LMICs). The prevention, management and treatment of sepsis is further complicated by antimicrobial resistance (AMR), with a substantial number of sepsis-causing infections being resistant to antibiotics (you can read more about this here, here and here).

Despite its substantial health and economic burden, there are major gaps in sepsis awareness, with many people, patients and even health care professionals not knowing what sepsis is nor how it can be prevented, diagnosed or treated. Therefore, there is a clear need to raise sepsis awareness, and WSD provides a useful platform for public engagement. As part of this initiative, we talked to four IOI researchers, Prof. Tim Walsh, Dr. Katy Thomson, Dr. Kirsty Sands, and Dr. Refath Farzana, to learn more about their work on sepsis – including leading several international studies aimed at characterising the burden of sepsis and AMR, with a focus in LMICs.

From left to right: Prof. Tim Walsh, Dr. Katy Thomson, Dr. Kirsty Sands, and Dr. Refath Farzana

Thank you all for joining us to mark this year’s World Sepsis Day. For those who don’t know you, can you start by saying a bit about who you are and why you think it’s important to mark WSD?

Tim Walsh (TW): My name is Tim Walsh, and I am the Director of Biology at the IOI and Professor of Medical Microbiology in the Department of Biology at the University of Oxford. I started my training in Tasmania, where I grew up and ran a microbiology diagnostics lab in Hobart. I completed my PhD in Bristol and then worked at the MRC, London. After medical microbiology teaching posts at both Bristol and Cardiff, with brief sabbaticals in Norway and Queensland, I joined Oxford in July 2020 where I was key in establishing the IOI. I have studied sepsis since 2003 but it has been since 2015, when our “Burden of Antibiotic Resistance in Neonates from Developing Societies” study, or BARNARDS, was funded by the Gates Foundation, that we have undertaken more extensive studies. These include not only examining the links between AMR and sepsis, but also understanding the health economics around the management of sepsis. I’d say that over 90% of our work on sepsis has been in LMICs, and as part of this we have also tried to raise awareness around sepsis. For example, we encouraged our teams in Pakistan, Bangladesh, and Nigeria to mark WSD, which they are doing with local seminars, posters, banners and even printed T-shirts worn by our collaborators. Our international friends are very enthusiastic, and we are overwhelmed with their positive contribution to WSD.

Kirsty Sands (KS): Hi, I’m Kirsty Sands and I’ve been working with Prof. Walsh’s group since 2016, after completing my PhD in Microbiology. I joined the team to work on the BARNARDS study, and I have been working on BARNARDS since! We are about to go into our second phase, BARNARDS II. As Tim mentioned, as part of this project we’re also trying to build awareness about sepsis, and some of our collaborators are organising various events to help promote WSD, including sessions whereby Neonatology and Medicine departments will share their experiences in Pakistan, and similar activities including sepsis leaflets in Kano, Nigeria.

Katy Thomson (KT): I am Katy Thomson, a postdoc on the BARNARDS II project researching neonatal sepsis, and I’ve been working on BARNARDS in Tim’s group since 2015. I think it is important to mark WSD sepsis day to raise awareness, as sepsis causes at least 11 million deaths globally each year and is a leading cause of neonatal mortality. As a researcher in the field, I have witnessed the devastating impacts of sepsis, particularly in LMICs, and how it is worsened by recent rises in AMR. I think it’s important to share these stories about the real-life impact of sepsis, and our partners in Pakistan are holding a short symposium and awareness session, where doctors will share their experiences of dealing with adult and neonatal sepsis, as well as patient stories and reflections of dealing and surviving sepsis, its impact on family structure and psychological aspects.

Refath Farzana (RF): Hi, I am Refath Farzana. I’m a medical graduate, but decided to build my career as a scientist, rather than being a clinician. So, after medical school, I did my masters and PhD on medical microbiology, with a transition of 4.5 years between the two degrees when I was involved with undergraduate microbiology teaching in several medical institutes of Bangladesh. My research has focused on molecular epidemiology of AMR. Currently, I’m a postdoctoral researcher in a Wellcome Trust-funded project called COVID-19/DRI, to understand the impact of the COVID-19 pandemic on bacterial sepsis, antimicrobial usage and resistance through a global network involving 10 countries, including Bangladesh. As part of this project, our team in Bangladesh is marking WSD at Dhaka Medical College Hospital (DMCH), with a workshop funded by the Wellcome Trust. The workshop will include the presentation of scientific posters stating the importance of raising public awareness for sepsis, the significance of meticulous management of sepsis, the need for prevention of sepsis in the community, and also the briefs about the COVID-19/DRI project. We will also have a rally where doctors and nurses will participate. The DMCH Director will also give a talk during the workshop about our broader engagement with sepsis management in the hospital, through upcoming sepsis projects such as BARNARDS II, which focuses on neonatal sepsis, and BALANCE, which will look at older children and adults.

You’ve mentioned several ongoing projects, like BARNARDS, BALANCE and COVID-19/DRI. Can you tell us a bit more about these and how they relate to sepsis? And why do you think it’s important to carry on these studies?

RF: At the moment I am mainly focused of the COVID-19/DRI project, which explores how the COVID-19 pandemic impacts bacterial sepsis, antimicrobial usage, and resistance. Sepsis is a life-threatening medical emergency caused by the body’s immune response to an infection. Although bacterial sepsis is most common, sepsis can also be the consequence of viral, fungal, or parasitic infections. However, diagnosing sepsis is complicated, as it has a varied clinical presentation including hypothermia or fever, drowsiness, confusion, rapid heart rate and breathing, jaundice, low urinary output, etc. Given these challenges, and since blood cultures to confirm sepsis were not routinely performed in healthcare settings during the peak of the pandemic (even in high-income countries, or HICs), we hypothesized that during the pandemic many cases of sepsis caused by bacterial infections were mistakenly assumed to be caused by SARS-CoV-2 (the virus responsible for COVID-19). The pandemic also changed other aspects of healthcare, including how antibiotics were used. For example, empirical antibiotic usage during the pandemic was clinically justified, given that severe COVID-19 infection leads to the dysregulation of the immune system meaning that patients may be vulnerable to secondary bacterial and fungal infections. As a result, we decided to investigate how changes in practice – including blood culturing and antimicrobial consumption – from the pre-pandemic to pandemic period are linked to the incidence rate of bacterial sepsis and to AMR.

I am also involved in other projects, like BARNARDS and BALANCE – for which my doctoral research can be considered a pilot for both these studies in Bangladesh. For example, our previous study at DMCH identified several outbreaks by multidrug resistant (MDR) bacteria during one-year sampling period. This seems to be the reflection of management of sepsis mostly by empirical antimicrobials and indicates the need for increasing microbiology capacity in public hospitals to improve clinical outcome of sepsis. We are now hoping to extend these studies as part of those larger projects, but I will let my colleagues explain more about those.

TW: As Refath mentioned, aside from the current COVID-DRI study, we are undertaking two very large international studies: BARNARDS, which focuses on neonatal sepsis; and BALANCE, looking at paediatric and adult sepsis. For BALANCE, we are interested in comparing how sepsis is managed in LMICs compared to HICs. For BARNARDS, we are building on our experience from the first BARNARDS study and will extend the project to include additional sites per country, with additional countries, particularly in Africa. Maybe Katy can say a bit more on that, including about why we are very keen to explore how policies and economics affect the management and outcome of newborns presenting with sepsis.

KT: Neonatal mortality remains high, particularly in LMICs. Sepsis is one of the leading causes of neonatal mortality and so it is important to investigate associated causes further, gather more data on common pathogens and resistance profiles to help decipher suitable empirical treatments and establish common routes of transmission within hospitals to try to reduce outbreaks. As such, we are currently working on a project called ‘BARNARDS II’, which will assess the prevalence of neonatal sepsis and antibiotic resistance in sepsis-causing pathogens, building on work from the previous BARNARDS study. We will investigate issues of access and affordability of antibiotics and healthcare for these neonates, and how this may impact on neonatal mortality. In addition, we will assess potential transmission of bacteria at clinical sites in the occurrence of outbreaks. This study is currently being set up and some sites are still to be confirmed, but we are hoping to commence enrolment at the start of 2023.

KS: I work across many studies and projects within the IOI, but my primary focus and interest is within microbial genomics, and the implementation of microbial genomics in surveillance and medical microbiology research. For example, all bacterial isolates that are recovered from blood cultures – from BARNARDS, BALANCE, etc – are sequenced and their genomes analysed to characterise both their genotype and the antibiotic resistance markers they carry. I have worked on the BARNARDS study since July 2016, and it is very much a project that I am very attached to, both scientifically and emotionally. In sepsis, it is not always easy to determine whether cultured bacterium originated in the blood or is a contaminant acquired during sampling or in the laboratory. So, improving these processes and generating data with translational potential that may be useful to improve how sepsis is diagnosed and controlled is what I am primarily interested in.

Some of the awareness posters used by the team in Bangladesh for WSD 2022

The IOI is primarily dedicated to research on antimicrobials and AMR. For some people it may not be clear how these topics are connected to sepsis. Would you mind explaining this to our readers? What motivated you to start looking at sepsis in the first place?

KT: AMR affects all aspects of healthcare, increasing risks of undergoing surgery, chemotherapy, or minor wounds due to the risk of infections resistant to treatment. Infections that enter the bloodstream induce inflammatory pathways and can lead to septic shock, organ dysfunction and death if not treated. Therefore, work on sepsis is critical to assess rates of AMR in these pathogens to inform effective treatment strategies. Furthermore, it is important to understand the burden of resistance to know where the need is for designing new antimicrobials.

KS: While our work is rooted in AMR research, as mentioned earlier, Tim has been looking at sepsis since 2003. This has intensified over the past decade, with our participation in some large sepsis studies, like BARNARDS and PANORAMA, which was the predecessor of BALANCE. With increasing levels of AMR worldwide, it is not surprising that sepsis caused by AMR bacteria is also increasing, so I expect that we will continue to focus on sepsis going forward.

RF: I would like to bring attention to two critical aspects in this link between AMR and sepsis. First, in a public health context; the increasing trend of AMR has a huge impact on bacterial sepsis, causing additional deaths due to treatment failure. Second, looking at blood cultures from sepsis patients can also help to get better estimates of the burden of AMR. This is because blood is considered a sterile specimen and unlikely to contain any contaminants if blood collection is made aseptically. By contrast, estimating the burden of AMR from non-sterile specimens, such as wound swabs, urine, etc., is more challenging, since this can lead to misdiagnosis, for example by considering other bacteria that colonise these specimens as infectious agents. Therefore, putting the emphasis on blood stream infections to calculate the burden of AMR will provide robust data which is scientifically more justified.

TW: Katy, Kirsty and Refath have perfectly addressed this question above.

A lot of your work happens in LMICs, why is this focus important? And are there some specific challenges associated with doing research in these settings, and with trying to coordinate efforts across such a range of locations?

KT: There is still a sparsity of data from LMICs regarding AMR, where the burden of AMR is the highest, therefore more work is needed to understand the extent of AMR in these countries. For BARNARDS, we work in LMICs where the highest rates of neonatal mortality exist, with ten times the burden of HICs. In the previous BARNARDS study, we found extremely high levels of resistance to the WHO recommended empirical therapy for treating neonatal sepsis, which is based on data from HICs. Therefore, more work is needed to assess effective recommendations for empirical therapy, which is why we feel that it is crucial to focus on these locations. In terms of challenges, many clinical sites in LMICs do not have microbiology facilities or expertise available or cannot cover the cost of taking and assessing blood samples, and so rely heavily on clinical diagnosis and advised empirical treatment. A lot of times there is also a lack of standardised procedures, which we aim to implement in BARNARDS where needed. We have also heard from our colleagues that the unpredictable supply or lengthy shipping of consumables can halt analyses of blood samples.

KS: While occurring globally, sepsis related to antimicrobial resistant bacteria has huge ramifications in LMICs. Access to healthcare, diagnosis, and treatment is not uniform worldwide and therefore the consequences of sepsis are amplified in LMICs. This is why we feel the need to look at LMICs, where the burden is the highest. In addition, large research studies are difficult to coordinate and standardise, and whilst this is useful from a data comparison angle, it is also important to consider each hospital site and data collected will represent a different population dynamic.

RF: Being a Bangladeshi, I am passionate about expanding research in LMICs. Encouraging the academics of LMICs to take part in research studies, and developing human resources for conducting science, can ensure sustainability which I found as the key to capacity building. Moreover, as my colleagues mentioned, there are significant data gaps about the burden of AMR in LMICs compared to HICs, so collaboration with the LMICs is particularly important to narrow those gaps. There are of course challenges, including with communication and coordination across heterogenous institutions, but these can be mitigated when the collaboration stands on trust and mutual understanding. I have learnt through involvement in multiple research projects that a stepwise approach to initiate a collaboration with any researcher, institute and country seems very effective. This involves meeting the collaborators in person, followed by a scoping exercise of the sites to evaluate capacity for operating the project, then selecting appropriate sites, and include a plan for capacity building where appropriate. I also think it is important that sites are never selected based solely on their capacity, but rather prioritised due to the collaborators’ enthusiasm in joining and strengthening a project.

TW: Working in LMICs is incredibly rewarding but it is also where the burden of AMR is highest and therefore there is a great need to understand the issues that drive AMR in poorer societies. In addition to Kirsty, Katy and Refath’s comments, I’d add that the use of antibiotics in farming in LMICs is often very poorly regulated, which brings additional challenges. For example, we have seen that the emergence of both MCR and TetX has been driven by the agriculture use of colistin and tetracycline, which leads to resistance that impacts the effectiveness of antibiotic treatment in humans. Accordingly, one of the key initiatives of the IOI is to have a focused programme on removing all human antibiotics from farming by creating and producing suitable and cost-effective substitutes that do not mediate cross-resistance to human antibiotics. This initiative, if successful, will help preserve precious human antibiotics for treating life-threatening infections such as sepsis.

With regards to specific challenges associated with our sepsis work for BALANCE and BARNARDS, we must make sure that our implementation initiatives are cost-effective. We believe that the total diagnosis of sepsis should cost no more than $10 per infection, so have designed a diagnostic protocol that is simple, effective, affordable, and therefore sustainable. I would also argue that we should place the emphasis on the rewards, rather than the challenges of these projects. Working across many countries and sites is extremely rewarding as we are able to create networks that would otherwise not happen, including to gather data in real-time to tackle sepsis in LMICs. In our large project meetings, doctors, nurses, scientists, project managers from many countries meet, mingle, and learn from each other's experiences. Thus, whilst it may be particularly challenging for us in dealing with each country’s peculiarities and administrative bureaucracy, it is nonetheless incredibly satisfying and certainly one of the few things that gets us out of bed in the morning.

The team in Bangladesh marked WSD 2022 with a workshop at Dhaka Medical College Hospital (DMCH)

Reflecting on your work on sepsis over the last decade, what are the main lessons learned? And what’s been your favourite part of being involved in these projects?

TW: My favourite part is meeting new people and making new friends in LMICs - the international network and team we were able to create was, and continues to be, truly amazing. In every hospital and country we work with, we learn many new aspects about international health matrices and cultural sensitivities. The international travelling can be exhausting but the rewards in aiding and facilitating positive change far outweigh these challenges. For example, in Kano, we erected a purpose-built lab in a carpark during the first phase of BARNARDS, which was associated with a reduction in neonatal mortality from 32 to 14%, helping hundreds of newborns - a remarkable achievement thanks to our amazing team in Nigeria. For lessons learnt, the most critical issue is to address the accuracy and robustness of data. The validity of our studies and their subsequent impact depend, for example, on being able to accurately record patient outcomes (i.e., whether the patient lived or died) and capturing that data when the patient has left the hospital has been very challenging. The other big challenge is to capture economic data that is accurate and real such as income and cost of healthcare. However, in both BALANCE and BARNARDS II, we are determined to make these studies seminal in how we both capture and analyse these datasets.

KS: For me the main lesson learnt was that by performing whole genome sequencing on neonatal sepsis bacterial isolates in the first phase of BARNARDS, we found out just how diverse the microbiology of sepsis is. Therefore, understanding the clinical context, the source, and whether we can implement infection control measures ultimately brings multiple teams together. My favourite thing is being involved in generating powerful and meaningful data (and a lot of learning along the way) with a fantastic global group of researchers and medical staff.

KT: I think we learned a lot from the first phase of BARNARDS, which we are improving on in BARNARDS II. As Tim mentioned, we now know specific data that we need to collect in order to better answer our research questions. We will additionally focus on antibiotic usage, dosing, and costs to better understand current treatment of neonatal sepsis and causes of neonatal mortality to better delineate the burden of AMR on mortality and other contributing factors. My favourite part of being part of these projects is helping to build capacity at sites and contributing large datasets to the literature that can be used to inform better healthcare.

RF: Although I joined the group back in 2016, my involvement with the big sepsis projects is quite recent. But my favourite thing is that these projects will enable us to try to understand how treatment factors impact on AMR-associated and AMR-attributable mortality and morbidity, and will hopefully help to design better strategies for prevention and treatment. As an example, certain strains of bacteria are associated with higher mortality, so if we can take steps to eradicate those strains or to move forward to prevent that particular infection through development of vaccines, we can improve patient outcomes. But addressing these questions is complex, and requires merging epidemiological, clinical, genomics data and data on functional properties of the bacteria of interest.

Looking ahead, what are the likely next steps for these projects? What are the biggest gaps that still need to be addressed so that we can better prevent, manage, and control sepsis?

KS: For me, the biggest gap to address is how we can better use our quantitative data for greater impact. I think we need to reach out more to other disciplines that have a big influence in healthcare, like economics or anthropology.

KT: I agree with Kirsty, and this is why the second phase of BARNARDS will investigate antibiotic usage, prescriptions and dosing in more detail, and reasons for any changes in therapy. We’ll be looking at the economics of this, assessing costs of antibiotics, who pays for it and how this may affect treatment, providing more data on access and affordability. Furthermore, we’re aiming to obtain more comprehensive data that will allow per site analyses. We will also have a more comprehensive environmental sampling strategy which can allow us to investigate potential sources and routes of transmission of hospital-acquired infections.

RF: I find it hard to make comment on next steps now as research is a continuous process. Perhaps the next steps will be planned to mitigate the limitations we will identify and to address unresolved research questions.

TW: These projects are currently just starting and there is a massive amount of work to do in the next few months to make them live, including site visits, training, completion of the necessary paperwork, etc. But for us the main gap is that BALANCE and BARNARDS II are not global projects and, owing to limitations in both financial and non-financial resources, we are restricted in scope. Ideally, we would like to see similar projects across all LMICs but, regrettably, despite the increased awareness around sepsis – including as a result of WSD – the financial backing still appears to be lacking. For example, there are well over 300 large clinical trials on COVID-19, but in the last decade only a handful on neonatal sepsis, despite its clinical burden and high mortality. We sometimes find it hard to understand how that discrepancy can be justified.

It is time global funders commit to help LMICs tackle sepsis in a tractable and sustainable manner

Before I let you go, can I ask you a hypothetical question: if you could snap a finger and change just one thing in the sepsis space, what would that be?

RF: I would go for radical reduction of sources of sepsis, including via the implementation of proper infection control policies, both in the community and in hospitals.

KS: I have to say better access to diagnostics and microbiology data, to inform effective treatments.

KT: Sorry, I have to do two. First, for all patients to have access to affordable healthcare. And second, to reiterate Kirsty’s point, that all clinical sites should have microbiology facilities and means to properly diagnose and assess sepsis cases, enabling informed treatment choices.

TW: To compliment my colleague’s answers, I’d say that for newborns, we need better healthcare facilities, including resuscitaires and incubators. We also need sufficient numbers of adequately trained staff - both on the ward and in the lab. These are achievable goals, and it is time global funders commit to help LMICs tackle sepsis in a tractable and sustainable manner.