Murphy Michael E, Phillips Patrick P J, Mendel Carl M, Bongard Emily, Bateson Anna L C, Hunt Robert, Murthy Saraswathi, Singh Kasha P, Brown Michael, Crook Angela M, Nunn Andrew J, Meredith Sarah K, Lipman Marc, McHugh Timothy D, Gillespie Stephen H
UCL Centre for Clinical Microbiology, Department of Infection, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK.
Medical Research Council UK Clinical Trials Unit at University College London, Aviation House, 125 Kingsway, London, WC2B 6NH, UK.
BMC Med. 2017 Oct 27;15(1):192. doi: 10.1186/s12916-017-0947-9.
The use of early morning sputum samples (EMS) to diagnose tuberculosis (TB) can result in treatment delay given the need for the patient to return to the clinic with the EMS, increasing the chance of patients being lost during their diagnostic workup. However, there is little evidence to support the superiority of EMS over spot sputum samples. In this new analysis of the REMoxTB study, we compare the diagnostic accuracy of EMS with spot samples for identifying Mycobacterium tuberculosis pre- and post-treatment.
Patients who were smear positive at screening were enrolled into the study. Paired sputum samples (one EMS and one spot) were collected at each trial visit pre- and post-treatment. Microscopy and culture on solid LJ and liquid MGIT media were performed on all samples; those missing corresponding paired results were excluded from the analyses.
Data from 1115 pre- and 2995 post-treatment paired samples from 1931 patients enrolled in the REMoxTB study were analysed. Patients were recruited from South Africa (47%), East Africa (21%), India (20%), Asia (11%), and North America (1%); 70% were male, median age 31 years (IQR 24-41), 139 (7%) co-infected with HIV with a median CD4 cell count of 399 cells/μL (IQR 318-535). Pre-treatment spot samples had a higher yield of positive Ziehl-Neelsen smears (98% vs. 97%, P = 0.02) and LJ cultures (87% vs. 82%, P = 0.006) than EMS, but there was no difference for positivity by MGIT (93% vs. 95%, P = 0.18). Contaminated and false-positive MGIT were found more often with EMS rather than spot samples. Surprisingly, pre-treatment EMS had a higher smear grading and shorter time-to-positivity, by 1 day, than spot samples in MGIT culture (4.5 vs. 5.5 days, P < 0.001). There were no differences in time to positivity in pre-treatment LJ culture, or in post-treatment MGIT or LJ cultures. Comparing EMS and spot samples in those with unfavourable outcomes, there were no differences in smear or culture results, and positive results were not detected earlier in Kaplan-Meier analyses in either EMS or spot samples.
Our data do not support the hypothesis that EMS samples are superior to spot sputum samples in a clinical trial of patients with smear positive pulmonary TB. Observed small differences in mycobacterial burden are of uncertain significance and EMS samples do not detect post-treatment positives any sooner than spot samples.
使用清晨痰标本（EMS）诊断结核病（TB）可能会导致治疗延迟，因为患者需要带着EMS返回诊所，这增加了患者在诊断检查过程中失访的可能性。然而，几乎没有证据支持EMS优于即时痰标本。在这项对REMoxTB研究的新分析中，我们比较了EMS和即时痰标本在治疗前和治疗后识别结核分枝杆菌的诊断准确性。
将筛查时涂片阳性的患者纳入研究。在治疗前和治疗后的每次试验访视时收集配对的痰标本（一份EMS和一份即时痰标本）。对所有标本进行抗酸染色镜检以及在固体LJ培养基和液体MGIT培养基上培养；将缺少相应配对结果的标本排除在分析之外。
对REMoxTB研究中1931例患者的1115份治疗前和2995份治疗后配对标本的数据进行了分析。患者来自南非（47%）、东非（21%）、印度（20%）、亚洲（11%）和北美（1%）；70%为男性，中位年龄31岁（四分位间距24 - 41岁），139例（7%）合并感染HIV，CD4细胞计数中位数为399个/μL（四分位间距318 - 535个/μL）。治疗前即时痰标本抗酸染色涂片阳性率（98%对97%，P = 0.02）和LJ培养阳性率（87%对82%，P = 0.006）高于EMS，但MGIT培养阳性率无差异（93%对95%，P = 0.18）。EMS标本中污染和假阳性MGIT培养的情况比即时痰标本更常见。令人惊讶的是，治疗前EMS在MGIT培养中的涂片分级更高，阳性时间更短，比即时痰标本早1天（4.5天对5.5天，P < 0.001）。治疗前LJ培养、治疗后MGIT或LJ培养的阳性时间无差异。在预后不良的患者中比较EMS和即时痰标本，涂片或培养结果无差异，在Kaplan - Meier分析中，EMS或即时痰标本均未更早检测到阳性结果。
我们的数据不支持在涂片阳性的肺结核患者临床试验中EMS标本优于即时痰标本的假设。观察到的分枝杆菌载量的微小差异意义不确定，且EMS标本在检测治疗后阳性方面并不比即时痰标本更早。
