Reply to Acuña-Villaorduña et al.
Reply to Acuña-Villaorduña et al.
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回复 Acuña-Villaorduña 等人。
DOI：
10.1093/cid/ciad376
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Williams CM
中科院分区：
文献类型：
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作者：
Williams CM
家庭接触者（HHC）中的结核分枝杆菌感染是一个重要的进展[1]。暴露于高FMS生产者的HHC感染风险增加3倍，通过干扰素γ释放测定（IGRA）转换或基线和6个月之间的绝对增加（> 1 IU/mL）来测量。这些发现与我们在巴西和乌干达使用咳嗽气溶胶采样系统（卡斯）报告的结果相似。作者解释了这两种方法之间的大部分相似之处，因此我们认为关注方法和解释的差异将是有益的。首先，FMS和卡斯之间的敏感性存在显著差异。除了作者提到的原因（游离DNA和差异培养的微生物）外，另一种可能的解释是抗分枝杆菌治疗的效果[2]。威廉姆斯研究的一个主要优势是排除了接受任何治疗的患者;而当我们从部分未治疗的肺结核（TB）患者转移到未治疗的肺结核（TB）患者时，总体卡斯阳性率从25%增加到65%，高气溶胶产生者（≥ 10个菌落形成单位[CFU]）的比例保持稳定（约30%-40%的气溶胶阳性病例）。在乌干达，我们还观察到暴露于低或卡斯阴性的HHC中有21/83（25%）的IGRA读数增加≥ 1，而暴露于高气溶胶结核病例的HHC中有14/22（64%）（P=. 001，比值比[OR]：5.2，95%置信区间[CI] 1.8-14.9），与TB治疗时间无关[3-4]。我们怀疑高生产者FMS和高卡斯表型之间存在显著重叠，我们认为这代表了疾病的超级传播者。其次，我们使用结核菌素皮肤试验（TST）而不是IGRA转换作为主要结果，并使用TST和IGRA，而不是单独使用IGRA。这避免了使用制造商临界值时广泛报道的IGRA特异性问题，并确定了TST和IGRA反应中重要但知之甚少的差异，我们假设这些差异与暴露强度可变有关[5]。第三，威廉姆斯及其同事的研究排除了儿童，从而消除了最有可能反映新感染的接触人群。对我们理解FMS的一个重要限制是缺乏颗粒尺寸数据。在补充信息中，作者建议他们收集有关咳嗽和说话的数据，这两者都会产生比呼出气更大尺寸的气溶胶[6]，并且可以预测气溶胶颗粒是否会保持在空气中并存款在肺泡中。肺部区域，如其他呼吸道病原体所示[7]。我们将感谢他们分享这些数据，这些数据可以表明收集到的颗粒的来源，并帮助我们更好地了解结核病的发病机制和传播。总之，威廉姆斯等人的研究证实，与广泛使用的痰液AFB涂片相比，气溶胶采样是一种更好、更精确的传染性标志物;卡斯和更简化、更易于使用的FMS的适应性也可用作吸入感染性接种物的测量，并允许针对高气溶胶产生者接触者的靶向预防性治疗策略。
Mycobacterium tuberculosis infection among household contacts (HHCs) is an important advance [1]. HHCs exposed to high FMS producers had a 3-fold increase in infection risk, measured by interferon gamma release assay (IGRA) conversion or an absolute increase (> 1 IU/mL) between baseline and 6 months. These findings are similar to those we reported in Brazil and Uganda using a cough aerosol sampling system (CASS). The authors explain most of the similarities between the 2 methods, so we thought it would be informative to focus on the differences in methodology and interpretation. First, there is significant difference in sensitivity between FMS and CASS. In addition to the reasons mentioned by the authors (free DNA and differentially culturable organisms), another potential explanation is the effect of antimycobacterial treatment [2]. A major strength on Williams’ study was the exclusion of patients on any treatment; whereas the overall CASS positivity increased from 25% to 65% as we moved from partially to untreated pulmonary tuberculosis (TB) patients, the proportion of high aerosols producers (≥ 10 colony-forming units [CFU]) remained stable (∼ 30%–40% of aerosol positive cases). In Uganda, we also observed an increase of≥ 1 in IGRA readouts in 21/83 (25%) of HHCs exposed to low or CASS negative versus 14/22 (64%) in those exposed to high aerosol TB cases (P=. 001, odds ratio [OR]: 5.2 95% confidence interval [CI] 1.8–14.9) irrespective of time of TB treatment [3–4]. We suspect there is significant overlap between high producers FMS and high CASS phenotypes, which we posit represent disease superspreaders. Second, we used tuberculin skin tests (TST) rather that IGRA conversion as primary outcome and used both TST and IGRA rather than IGRA alone. This avoided the widely reported issues with IGRA specificity when using the manufacturer’s cutoff and identified important yet poorly understood differences in TST and IGRA responses that we have hypothesized are related to variable intensities of exposure [5]. Third, the Williams and colleagues’ study excluded children which eliminated the contact population most likely to reflect new infection. An important limitation to our understanding of FMS is the lack of particle size data. In the supplementary information, the authors suggest they collected data on coughing and talking, both of which create larger size aerosols than exhaled breath [6] and could predict if the aerosol particles would remain airborne and to deposit in the alveolar region of the lung as shown with other respiratory pathogens [7]. We would appreciate them sharing such data, which could suggest the origin of the collected particles and help us better understand the pathogenesis and transmission of TB. In conclusion, the study by Williams et al confirms that aerosol sampling is a better, more refined marker of infectiousness that the widely used sputum AFB smear; the adaptation of CASS and the more simplified, easier to use FMS could also work as a measure of the inhaled infectious inoculum and allow targeted preventive therapy strategies focused on contacts of high aerosol producers.