Identification of predictive biomarkers for severe acute leptospirosis and its long-term sequelae

Leptospirosis is a potentially life-threatening zoonosis with protean manifestations and a leading cause of acute febrile illness (AFI) in the tropics. The acute phase of leptospirosis can trigger a systemic inflammatory response, leading to multiorgan failure, including liver failure, acute kidney injury (AKI), and pulmonary hemorrhage, significantly increasing mortality, and

potentially resulting in long-term complications. Early prediction of severe disease progression and long-term consequences is of utmost importance. The proposed studies will involve collaborations between the Principal Investigator and renowned researchers in the field of leptospirosis. We have outlined two related but independent aims. Aim 1 focuses on

characterizing the host response and identifying novel biomarkers predictive of severe acute leptospirosis using a multi-omics approach. We will analyze blood specimens and clinical data from our existing biorepository and prospective patient recruitment, employing established and novel machine learning analytical methods to refine proteomic, cytokine-based, and host gene

expression severity classifiers, accurately identifying patients at risk of severe disease. Our existing biorepository contains samples collected at baseline from 218 patients with confirmed leptospirosis, including 73 severe cases and 145 non-severe cases. Longitudinal follow-up clinical data and blood specimens per patient are also available, enabling us to study the

temporal dynamics of the host response and disease progression. Aim 2 focuses on identifying risk factors and novel biomarkers for leptospiral CKD and its progression. We have been concurrently conducting a prospective multicenter cohort study and a clinical trial titled "Leptospirosis Care Bundle Study" across several hospitals in endemic areas. We have, and will

continue to collect long-term follow-up data on adverse outcomes, including major kidney adverse events (MAKEs), such as all-cause mortality, dialysis, and new-onset CKD in patients with leptospirosis at baseline. Combining data from these two ongoing projects, totaling 160 patients, will provide us with a better understanding of the mechanisms and risk factors

associated with leptospiral CKD.