New Study Seeks to Understand Sepsis in the Global Epicenter

In low- and middle-income countries (LMICs), adopting a one-size-fits-all treatment approach to critical illness based off clinical trials in the US and Europe has been known to cause harm.

Critical illnesses like sepsis, for example, have been long studied in high-income countries (HICs), leading to evidence-based treatment strategies and improved patient outcomes. However, according to Dr. Matthew Cummings, Assistant Professor of Medicine in the Division of Pulmonary, Allergy, and Critical Care Medicine at CUIMC, there is much work to be done to understand the illness where the global burden is heaviest, in sub-Saharan Africa. In fact, as Dr. Cummings explains, if you do a literature search on the pathobiology of sepsis, you get tens of thousands of articles. But when you add “Africa” less than 0.5% of articles even mention sub-Saharan Africa, let alone contain data from the region.

“40% of all sepsis cases occur in sub-Saharan Africa, where up to 65% of all deaths may be sepsis related. Despite this extraordinary burden, and a high prevalence of HIV, tuberculosis, and malaria—infections uncommon in HICs - we have very poor mechanistic understanding of sepsis in the region.”

This is the basis of Dr. Cummings’ recent R01 grant from the National Institute of Allergy and Infectious Diseases (NIAID), which will continue his work related to critical illness in sub-Saharan Africa. In September 2024, he began a five-year study involving a multicenter cohort in Uganda, where he will engage in translational research to understand the pathobiology of sepsis in sub-Saharan Africa.

“We need to take a step back and understand which aspects of sepsis biology are globally generalizable and which are impacted by diverse host and pathogen factors. This is essential to achieve equitable access to precise and effective treatment strategies. In sub-Saharan Africa, most of our critically ill sepsis patients are young adults living with HIV, many of whom have severe malaria or disseminated tuberculosis. The interplay between these host and pathogen features during critical illness, and the mechanisms by which they cause organ dysfunction, are very poorly understood. This isn’t particularly surprising, since nearly all sepsis research emerges from HICs, where sepsis typically affects older adults with advanced multimorbidity and a narrow spectrum of infections. We've been trying to fit a square peg in a round hole by treating sepsis in LMICs how we treat it in the US and Europe. Data from clinical trials conducted over the past decade shows that this approach causes harm.”

The R01 grant focuses around three major aims: First, to establish molecular sepsis endotypes in Uganda using machine learning methods applied to a multi-center prospective cohort of adult sepsis patients. Second, to determine temporal dynamics of sepsis pathobiology in Uganda using high dimensional proteomics generated serially throughout acute and post-acute phases of sepsis. And lastly, to leverage single cell immune profiling to develop mechanistic understanding of sepsis in people living with HIV.

Ultimately, Dr. Cummings hopes to design an innovative clinical trial of immunomodulatory treatments informed by this biological work and tailored to sub-Saharan Africa.

Dr. Cummings credits the training and mentorship he received from Columbia as he reflects on his R01 achievement. Specifically, his long-time mentors Max O’Donnell, MD, Florence Irving Associate Professor of Medicine and Associate Professor of Epidemiology and W. Ian Lipkin, MD, John Snow Professor of Epidemiology, Professor of Neurology, and Professor of Pathology & Cell Biology, have been champions of his work and allies of his research.

Coupled with individual mentorship is the training and funding Dr. Cummings received on his way to receiving the R01 grant. He received F32 and K23 awards from NIAID and was able to draw on many resources from the Biostatistics, Epidemiology, and Research Design (BERD) Resource to aid his research, especially the Biostatistics Consultation Service. He also received his Master’s in Patient-Orientated Research (POR) from the Irving Institute’s TRANSFORM Resource at the Irving Institute for Clinical and Translational Research.

More recently, Dr. Cummings explains, “I participated in the K to R Scholars’ Program, which was extremely helpful in terms of finding a peer network of colleagues at a similar career stage. The peer networking and mentorship from Drs. Daichi Shimbo and Marisa Spann was incredibly helpful.”

To early-career faculty at Columbia, Dr. Cummings gives the following advice, “If you have any interest in research from an early stage, take advantage of the opportunities to pursue that training when you can, and try and find a mentor you connect with not only from a research perspective, but as a friend.”

With his work rooted in a commitment to global health equity, Dr. Cummings stresses the importance of building trust among his colleagues and collaborators. “I’m a really strong believer in long-term commitment - to a place and to your colleagues. All this work has been built on nearly two decades of relationships with colleagues in Uganda and friendships and collaborations built on mutual trust and reciprocity”.