New Study Seeks to Understand How Sepsis Biology Differs Globally

Historically, critical illnesses like sepsis have been studied almost exclusively in high-income countries (HICs). Yet despite five decades of research, there are still no approved targeted therapeutics for sepsis, an outcome that may, in part, reflect the fact that these studies were conducted in settings that represent less than 10% of the global sepsis burden. This narrow evidence base has likely limited our ability to identify critical biological mechanisms that differ across regions and patient populations.

According to Dr. Matthew Cummings, Assistant Professor of Medicine in the Division of Pulmonary, Allergy, and Critical Care Medicine at CUIMC, understanding how sepsis biology differs globally is essential for scientific progress. “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 mention sub-Saharan Africa, let alone contain data from the region,” he explains. This imbalance limits care in low- and middle-income countries (LMICs) but also restricts discovery of targetable biological pathways that could benefit critically ill patients everywhere, including in the US, where sepsis remains a leading cause of death.

“Forty percent 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 the high prevalence of HIV, tuberculosis, malaria, and other infections uncommon in HICs, we have a very poor mechanistic understanding of sepsis in the region.” Dr. Cummings’ new R01 grant from the National Institute of Allergy and Infectious Diseases (NIAID) will support research aimed at addressing these global knowledge gaps. In September 2024, he began a five-year study involving a multicenter cohort in Uganda, where he will engage in translational research to define how sepsis biology varies across global settings.

“We need to take a step back and understand which aspects of sepsis biology are globally generalizable and which are shaped by specific host and pathogen factors,” he explains. “This is essential to improve access to precise and effective treatments. In sub-Saharan Africa, critically ill adults are often younger and more likely to be living with HIV. The interplay between these host and pathogen factors and related mechanisms driving organ dysfunction are poorly understood. Without data from the regions where most of the world’s sepsis cases occur, we miss key components of pathobiology, and this limits therapeutic development not only for LMICs but also for patients in the US.”

The R01 grant focuses on 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 biological data 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.

Dr. Cummings’ early results demonstrate the scientific value of expanding sepsis research globally.  “Supported by our R01 award, we recently derived and validated innovative multi-omic sepsis endotypes in our Uganda cohorts, and these endotypes show biological and clinical utility in US sepsis cohorts. This early evidence highlights how dissecting sepsis biology in global populations can reveal conserved and actionable pathways that inform treatment strategies for critically ill patients worldwide, including in the US” Ultimately, Dr. Cummings hopes to design an innovative clinical trial of immunomodulatory treatments informed by this biological work and tailored to global settings.

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 drew 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-Oriented Research (POR) from the Irving Institute’s TRANSFORM Resource.

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 longstanding commitment to global health, 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.”