Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA.
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
Lancet Respir Med. 2017 Apr;5(4):282-290. doi: 10.1016/S2213-2600(17)30060-7. Epub 2017 Feb 16.
The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. We aimed to investigate the relation between QuantiFERON-TB Gold In-Tube (QFT) conversion interferon-γ values and risk of subsequent active tuberculosis disease and of QFT reversion.
We analysed data from a reported vaccine efficacy trial of the tuberculosis vaccine MVA85A in South Africa. QFT negative, HIV uninfected young children aged 18-24 weeks were enrolled. We stratified participants by quantitative QFT result (interferon-γ <0·35 IU/mL, 0·35-4·00 IU/mL, and >4·00 IU/mL) at the intermediate study visit (day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6-24 months. No QFT differences were observed between placebo and MVA85A groups at day 336 or end of study; therefore, both groups were included in analyses. Study clinicians were not masked to QFT values, but strict case definitions were used that excluded QFT results. We used generalised additive models to evaluate the quantitative relation between day 336 QFT value and subsequent disease risk, and we compared disease rates between QFT strata using a two-sample Poisson test.
Among 2512 young children with QFT tests done at day 336, 172 (7%) were positive; 87 (7%) of 1267 in placebo group and 85 (7%) of 1245 in the MVA85A group (p=1·00). Compared with QFT non-converters (tuberculosis disease incidence 0·7 per 100 person-years [95% CI 0·4-1·1]), children with QFT conversion at interferon-γ values between 0·35-4·00 IU/mL did not have significantly increased risk of disease (2·5 per 100 person-years [95% CI 0·4-9·4]; incidence rate ratio (IRR) 3·7 (95% CI 0·4-15·8; p=0·23). However, QFT conversion at interferon-γ values higher than 4·00 IU/mL was associated with substantially increased disease incidence (28·0 per 100 person-years [95% CI 14·9-45·7]) compared with non-converters (IRR 42·5 [95% CI 17·2-99·7]; p<0·0001), and compared with children with interferon-γ values between 0·35-4·00 IU/mL (IRR 11·4 [95% CI 2·4-107·2]; p=0·00047). Among 91 QFT converters who were given a repeat test, 53 (58%) reverted from positive to negative. QFT reversion risk was inversely associated with interferon-γ value at QFT conversion and was highest with interferon-γ values less than 4·00 IU/mL (47 [77%] of 61).
In young children, tuberculosis disease risk was not significantly increased, and QFT reversion was common, following QFT conversion at interferon-γ values up to 10 times the recommended test threshold (0·35 IU/mL). By contrast, QFT conversion at very high interferon-γ values (>4·00 IU/mL) warrants intensified diagnostic and preventive intervention because of the extremely high risk of tuberculosis disease in these young children.
Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC) were the funders of the MVA85A 020 Trial. National Institute of Allergy and Infectious Diseases supported this analysis.
定量干扰素-γ释放试验（QuantiFERON-TB Gold In-Tube，QFT）结果预测结核分枝杆菌感染向活动性疾病进展的价值尚不清楚。本研究旨在探讨 QFT 转换后干扰素-γ值与随后发生活动性结核病的风险以及 QFT 逆转的关系。
我们分析了南非 MVA85A 结核疫苗疗效试验的报告数据。纳入的是无 HIV 感染、18-24 周龄的 QFT 阴性的儿童。我们根据中间研究访视（第 336 天）时的定量 QFT 结果（干扰素-γ＜0·35 IU/ml、0·35-4·00 IU/ml 和＞4·00 IU/ml）将参与者分层，并确定随后 6-24 个月内进展为活动性结核病的风险。第 336 天或研究结束时，安慰剂组和 MVA85A 组之间 QFT 结果无差异；因此，两组均纳入分析。临床医生对 QFT 值不设盲，但采用严格的病例定义排除 QFT 结果。我们使用广义加性模型评估第 336 天 QFT 值与后续疾病风险之间的定量关系，并使用两样本泊松检验比较 QFT 分层之间的疾病发生率。
在 2512 名在第 336 天进行 QFT 检测的儿童中，172 名（7%）呈阳性；安慰剂组 87 名（7%），MVA85A 组 85 名（7%）（p=1·00）。与 QFT 未转换者（每 100 人年结核病发病 0·7 例[95%CI 0·4-1·1]）相比，干扰素-γ值在 0·35-4·00 IU/ml 之间的 QFT 转换者疾病风险无显著增加（每 100 人年 2·5 例[95%CI 0·4-9·4]；发病率比[IRR]3·7[95%CI 0·4-15·8]；p=0·23）。然而，干扰素-γ值高于 4·00 IU/ml 的 QFT 转换与显著增加的疾病发病率相关（每 100 人年 28·0 例[95%CI 14·9-45·7]），与未转换者相比（IRR 42·5[95%CI 17·2-99·7]；p＜0·0001），与干扰素-γ值在 0·35-4·00 IU/ml 之间的儿童相比（IRR 11·4[95%CI 2·4-107·2]；p=0·00047）。在 91 名接受重复检测的 QFT 转换者中，53 名（58%）从阳性转为阴性。QFT 逆转风险与 QFT 转换时的干扰素-γ值呈负相关，与干扰素-γ值小于 4·00 IU/ml 时的相关性最高（47[77%]例）。
在儿童中，QFT 转换时干扰素-γ值高达推荐检测阈值（0·35 IU/ml）的 10 倍时，结核病发病风险没有显著增加，QFT 逆转较为常见。相比之下，QFT 转换时干扰素-γ值非常高（＞4·00 IU/ml）时，这些儿童患结核病的风险极高，需要强化诊断和预防干预。
Aeras、威康信托基金会和牛津新兴结核病联盟（OETC）为 MVA85A 020 试验提供了资金。美国国立过敏和传染病研究所支持了本分析。
