Narendran Gopalan, Kavitha Dhanasekaran, Karunaianantham Ramesh, Gil-Santana Leonardo, Almeida-Junior Jilson L, Reddy Sirasanambatti Devarajulu, Kumar Marimuthu Makesh, Hemalatha Haribabu, Jayanthi Nagesh Nalini, Ravichandran Narayanan, Krishnaraja Raja, Prabhakar Angamuthu, Manoharan Tamizhselvan, Nithyananthan Lokeswaran, Arjunan Gunasundari, Natrajan Mohan, Swaminathan Soumya, Andrade Bruno B
National Institute for Research in Tuberculosis, Chennai, India.
Unidade de Medicina Investigativa, Laboratótio Integrado de Microbiologia e Imunorregulação, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.
PLoS One. 2016 Sep 19;11(9):e0163298. doi: 10.1371/journal.pone.0163298. eCollection 2016.
Paradoxical 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.
Genotypic 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.
A 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.
A 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.
矛盾性结核相关免疫重建炎症综合征（TB-IRIS）是一种炎症现象，在同时感染结核（TB）的情况下，抗逆转录病毒疗法（ART）驱动免疫重建时会使HIV管理变得复杂。白三烯A4羟化酶（LTA4H）是一种将LTA4转化为LTB4的酶，可调节抗炎性脂氧素和促炎性LTB4之间的平衡，直接影响由结核驱动的炎症。在人类中，已鉴定并描述了LTA4H启动子中的一个单核苷酸多态性（SNP）（rs17525495），其调节转录活性，会影响结核病表现的临床严重程度和对皮质类固醇治疗的反应。值得注意的是，LTA4H在TB-IRIS中的作用此前尚未得到评估。在此，我们进行了一项探索性研究，测试LTA4H多态性与HIV-TB合并感染个体中TB-IRIS发生频率和TB-IRIS表现严重程度之间的关联。
对现有样本中的LTA4H酶进行基因型评估，并回顾性地与病历中记录的临床数据（包括IRIS细节）相关联。该队列包括从一项前瞻性队列研究中招募的患者，该研究嵌套在印度南部一项针对未接受过ART的新诊断为利福平敏感肺结核的HIV+患者的随机临床试验（NCT0933790）中。估计了IRIS患者和非IRIS患者中野生型基因型（CC）以及突变基因型（CT或TT）的频率。对野生基因型（CC）和突变基因型（CT或TT）进行了比较分析，并测试了LTA4H多态性与IRIS发病率和临床严重程度之间的关联。
共有142名符合条件的未接受过ART的患者纳入分析。86人表现出野生基因型（CC），而56人具有突变基因型（43人-CT，仅13人-TT）。非IRIS组和IRIS组中的变异等位基因频率分别为0.23和0.26。开始ART治疗后，51名患者发生了IRIS，而91名患者未发生。野生型（CC）和突变型（CT/TT）的IRIS发病率分别为34%和37%（p = 0.858），与野生型基因型相比，突变基因型组中严重IRIS表现的频率更高（p = 0.0006）。逻辑回归模型证实了CT/TT基因型的存在与严重IRIS发生之间的关联。无论LTA4H基因型如何，皮质类固醇治疗均成功解决了所有病例中的IRIS。
与野生型相比，观察到具有突变LTA4H基因型（CT和TT）的患者中严重IRIS的发生率更高，尽管两组的IRIS发生率和免疫恢复情况相似。类固醇对所有基因型的IRIS均有效缓解。
