The Lancet Infect Dis：新型免疫标志物可预测HIV/TB并发症

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近日，发表在国际杂志The Lancet Infectious Diseases上的一篇研究论文中，来自宾夕法尼亚大学等处的研究人员通过研究在进行抗逆转录病毒疗法的患者机体中鉴别出了新型的免疫生物标志物，这种新型的生物标志物或可帮助预测携带肺结核（TB）的HIV患者的早死及并发症风险。

研究者Ravimohan教授表示，患者中不同的免疫和炎性反应往往可以告知我们一些有价值的线索，来帮助指导未来进行治疗的疗法；更重要的是我们的研究发现，晚期的HIV/TB患者是一种异质性群体，这些患者对于免疫干预疗法的反应并不一致；此前研究中研究者重点对TB-免疫重建炎症综合征（IRIS）患者进行研究，但当时并没有比较早期死亡患者和经历免疫重建炎症综合征患者之间的免疫反应及生物标志物特性的差异。

这项研究中，研究人员对201名来自博茨瓦纳的患者进行分析研究，研究人员评估了患者在进行抗逆转录病毒疗法前后的反应情况，结果显示，患者机体中较低水平的8种生物标志物和其患IRIS的风险增加直接相关，这8种生物标志物分别包括IL-6， IL-15及GM-CSF等；研究者表示，高水平的MCP-1及TNF-α和患者的死亡风险增加直接相关。

然而IRIS及早期死亡的患者在进行抗逆转录病毒疗法开始后的免疫反应和炎性反应会明显增加，包括IL-6， TNF-α及G-CSF在内的四种生物标志物也和患者的TB-IRIS风险增加存在独立相关的关系，而另外五种生物标志物则和患者死亡风险增加相关，包括IL-1RA和G-CSF。

研究者表示，不同的进行抗逆转录病毒疗法的患者其机体早期的免疫恢复（CD4细胞数）发生着明显的不同，而开始进行抗逆转录病毒疗法及早期死亡的患者，当其机体的免疫系统不足以控制结核病时就会增加其患炎症的风险，而IRIS患者却恢复地较快。Bisson博士说道，通过观察疾病得到有效控制的患者群及发生并发症(IRIS)的患者群之间在治疗效果上的差异，就可以影响我们对易感人群的后期研究，当然有效抑制IRIS的干预措施或许也会不经意地增加个体的死亡风险。

最后研究者表示，本文研究对于开发新型疗法从而降低患者机体炎症，同时还可以促进患者的免疫恢复提供了新的研究线索，相关研究由美国国立卫生研究院等机构提供资助。

Immunological profiling of tuberculosis-associated immune reconstitution inflammatory syndrome and non-immune reconstitution inflammatory syndrome death in HIV-infected adults with pulmonary tuberculosis starting antiretroviral therapy: a prospective observational cohort study

Dr Shruthi Ravimohan, PhD, Neo Tamuhla, MPH, Andrew P Steenhoff, MBBCh, Rona Letlhogile, BNS, Kebatshabile Nfanyana, BSc, Scarlett L Bellamy, ScD, Prof Rob Roy MacGregor, MD, Robert Gross, MD, Prof Drew Weissman, MD, Gregory P Bisson, MD

Background Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation. Methods We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ2 tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls. Findings Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18–0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0–80·0]) and tumour necrosis factor (TNF)α (7·8 [1·1–55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2–2·5]) and TNFα (1·5 [1·0–2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3–6·1]), IL-12p40 (1·8 [1·0–3·4]), and IL-15 (2·0 [1·1–3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006). Interpretation Distinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis. Funding National Institutes of Health and the Penn Center for AIDS Research.