Role of LTA4H Polymorphism in Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Occurrence and Clinical Severity in Patients Infected with HIV

Abstract

BackgroundParadoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory phenomenon complicating HIV management in coincidental tuberculosis (TB) infection, upon immune reconstitution driven by antiretroviral therapy (ART). Leukotriene A4 hydroxylase (LTA4H), an enzyme which converts LTA4 to LTB4, regulates the balance between the anti-inflammatory lipoxins and pro-inflammatory LTB4, with direct implications in TB-driven inflammation. In humans, a single nucleotide polymorphism (SNP) in the LTA4H promoter which regulates its transcriptional activity (rs17525495) has been identified and described to impact clinical severity of TB presentation and response to corticosteroid therapy. Notably, the role of LTA4H on TB-IRIS has not been previously evaluated. Here, we performed an exploratory investigation testing the association of LTA4H polymorphism with respect to frequency of TB-IRIS occurrence and severity of TB-IRIS presentation in HIV-TB co-infected individuals.MethodsGenotypic evaluation of the LTA4H enzyme from available samples was retrospectively correlated with clinical data captured in case sheets including IRIS details. The cohort included patients recruited from a prospective cohort study nested within a randomized clinical trial (NCT0933790) of ART-naïve HIV+ patients with newly diagnosed rifampicin sensitive pulmonary TB in South India. Frequency of the wild type genotype (CC), as well as of the mutant genotypes (CT or TT) in the IRIS and non-IRIS patients was estimated. Comparative analyses were performed between wild genotype (CC) and the mutant genotypes (CT or TT) and tested for association between the LTA4H polymorphisms and IRIS incidence and clinical severity.ResultsA total of 142 eligible ART-naïve patients were included in the analyses. Eighty-six individuals exhibited the wild genotype (CC) while 56 had mutant genotypes (43-CT and only 13-TT). Variant allele frequency was 0.23 and 0.26 in non-IRIS group and in IRIS group, respectively. Upon ART initiation, 51 patients developed IRIS while 91 did not. IRIS incidence was 34% and 37% in the wild (CC) and mutant type (CT/TT), respectively (p = 0.858) with a higher frequency of severe IRIS presentation in the mutant genotype group compared to the wild type genotype (p = 0.0006). A logistic regression model confirmed the association between the presence of CT/TT genotypes and occurrence of severe IRIS. Corticosteroid therapy successfully resolved IRIS in all cases irrespective of the LTA4H genotype.ConclusionA higher incidence of severe IRIS among patients with mutant LTA4H genotypes (CT and TT) was observed compared to the wild type, despite similar IRIS incidence and immune restoration in both groups. Steroids were effective in alleviating IRIS in all the genotypes.

The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy

“…It results in increased neutrophil recruitment ( Nakiwala et al, 2018 ), and up-regulation of MMP-1, -3, -7, -8, and -10 ( Tadokera et al, 2014 ; Ravimohan et al, 2016 ; Walker et al, 2017 ). LT4AH also appears to play a role, as more severe TB-IRIS has been reported in patients with mutant (TT and CT) LTA4H genotypes ( Narendran et al, 2016 ).…”

“…In patients with tuberculous meningitis, the effect of corticosteroids was found to be LTA4H genotype modulated, with only patients with the mutant TT genotype, leading to a higher inflammatory response, benefitting from steroid treatment ( Tobin et al, 2012 ). In patients with TB-IRIS, however, this difference in genotype on the effect of steroid treatment was not confirmed ( Narendran et al, 2016 ). The effect of corticosteroid treatment and TB-IRIS on pulmonary function is being assessed in a substudy of the PredART trial ( Meintjes et al, 2017 ).…”

Association of Leukotriene A4 Hydrolase with Tuberculosis Susceptibility Using Genomic Data in Portugal

“…We compared 113 SNPs between the groups, but detected no significant difference, either considering individual SNPs (with and without adjustment for covariates), specific haplotypes or overall haplotype composition. The rs17525495 SNP has previously been associated with both TB and bacterial meningitis susceptibility [7,13], and has been suggested as a candidate for extensive genotyping as a TB response predictor [14].…”

Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections

“…Similarly, a common haplotype of the IL-4 promoter was over-represented in patients with CDC [92]. Also, a single nucleotide polymorphism in the promoter of leukotriene A4 hydroxylase (LTA4H) regulating the balance between anti-inflammatory lipoxins and the pro-inflammatory LTB4 is responsible for a higher incidence of severe tuberculosis-associated IRIS [93]. One could easily hypothesize that polymorphisms of the human IFNγ receptor may lead to different susceptibility patterns to IRIS.…”