Leukotriene A4 Hydrolase (LTA4H Rs17525495) Gene Polymorphisms and Paradoxical Reactions in Extrapulmonary Tuberculosis

Paradoxical reactions (PRs) are poorly studied complex immunological phenomena, among patients with tuberculosis (TB). When PRs involves critical structures like the central nervous system (CNS), immunomodulatory therapy is often required. Predictors for PRs in TB to pre-empt appropriate treatment strategies in high-risk groups are lacking. TT genotype of Leukotriene A4 hydrolase (LTA4H) promoter region rs17525495 polymorphisms are associated with exaggerated immune responses in Tuberculous meningitis (TBM), the most severe form of extrapulmonary tuberculosis (EPTB). The association of these polymorphisms with PRs is not known. We evaluated this plausibility among 113 patients with EPTB, at high risk of PRs. Majority [81 (71.7%)] had disseminated tuberculosis with prominent CNS [54 (47.8%)] and lymph node involvement [47 (41.6%)]. Human immunodeficiency Virus (HIV) co-infection was seen among 23 (20.3%) patients. PRs were noted in 38.9% patients, at a median duration of 3 months (IQR 2-4). LTA4H rs17525495 single nucleotide polymorphism (SNP) analysis showed 52 (46%) patients had CC, 43 (38.1%) had CT and 18 (15.9%) had TT genotypes. There was no statistically significant difference in occurrence [CC 38.5% vs CT 39.5% vs TT 38.7%] and time of onset [median (IQR)] of PRs across the genotypes [CC 3 (1-4.7), CT 3 (2-5), TT 2 (2-3)]. PRs was shown to be significantly linked with HIV co-infection (RR 0.6, 95% CI 0.29-1.28), culture positivity (RR 0.5, 95% CI 0.28-1.14), TB Lymphadenitis (RR 0.7, 95% CI 0.44-1.19) and CNS involvement RR 2.1, 95% CI 1.27-3.49) in the univariate analysis (p < 0.2). On multivariate analysis, CNS involvement alone was associated with PRs (aRR 3.8 (1.38-10.92); p < 0.01). PRs were associated with CNS involvement but not with LTA4H rs17525495 polymorphisms.