Abstract
Leprosy continues to be an important public health problem, particularly in endemic regions such as Brazil, India, and Indonesia. Household contacts of multibacillary (MB) patients represent a high-risk group for subclinical infection due to prolonged exposure and high bacillary load. Host biomarkers have emerged as promising tools for identifying early infections and guiding prophylactic interventions. This systematic review aimed to identify and synthesize evidence on inflammatory and immune biomarkers associated with susceptibility to leprosy and disease progression among contacts of index cases, evaluating their potential predictive and diagnostic value. The study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) 2020 guidelines and was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251111469). We searched CAPES, SciELO, PubMed, ScienceDirect, EMBASE, Scopus, and EBSCO databases for original studies published between 2012 and 2025, with no language restrictions. Two review authors independently selected studies using the Rayyan software, and methodological quality was assessed using the ROBIS tool. The biomarkers most frequently investigated in the studies were particularly tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-10, which play regulatory roles in the host. Elevated levels of TNF-α, interferon-γ (IFN-γ), IL-6, and IL-4 were associated with a higher risk of subclinical infection among contacts of MB patients, indicating a polyfunctional immune profile. On the other hand, paucibacillary (PB) contacts exhibited lower cytokine activation, suggesting partial protection. Additional promising markers included anti-Mce1A, PGL-I IgM, and CCL4, detected primarily by enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) methods. In summary, inflammatory and immune biomarkers-especially TNF-α, IL-10, IFN-γ, and anti-Mce1A-demonstrate potential as predictive indicators of subclinical leprosy infection. Their combined use may increase risk stratification and allow early therapeutic intervention in endemic settings. However, longitudinal validation studies are required prior to clinical application.