A refined symptom-based approach to diagnose pulmonary tuberculosis in children
A refined symptom-based approach to diagnose pulmonary tuberculosis in children
复制标题
DOI：
10.1542/peds.2006-0519
复制
发表时间：
2006-11-01
期刊：
影响因子：
8
通讯作者：
Beyers, Nulda
中科院分区：
文献类型：
--
作者：
Marais, Ben J.;Gie, Robert P.;Beyers, Nulda
背景。结核病控制项目几乎只把重点放在痰涂片阳性结核病的成年人身上，因为他们的传染性最强。然而，儿童在全球结核病病例中占很大比例，并经历了相当大的结核病相关发病率和死亡率，但在流行地区，很少有儿童能够获得抗结核治疗。在资源有限的流行地区，诊断困难已被确定为导致治疗机会不足的一个主要因素。一般来说，人们对基于症状的诊断方法的潜在价值持怀疑态度，因为目前的临床诊断方法往往缺乏验证。儿童结核病的自然史表明，如果症状定义明确，并采用适当的风险分层，可能具有良好的诊断价值。本研究旨在确定明确的症状在结核病流行地区诊断儿童肺结核的价值。在南非开普敦进行了一项前瞻性社区研究。在所有< 13岁的儿童中，均有明确的具体症状，报告持续2周的无缓解性咳嗽；对研究参与者进行了全面的结核病评估。此外，研究者对所有在研究期间接受抗结核治疗的儿童进行了回顾，无论是否纳入研究。这种同时进行的疾病监测提供了对所有儿童结核病病例的全面概述，从而能够准确评估与这种基于症状的诊断方法相关的可能缺点。在缺乏可接受的金标准测试的情况下，最佳案例定义是一个重要的考虑因素。儿童被分为“细菌学上确诊的肺结核”、“放射学上确定的肺结核”、“可能的肺结核”和“非肺结核”。细菌学上确诊的结核病定义为痰镜检发现抗酸杆菌和/或呼吸道标本培养的结核分枝杆菌。放射学上确定的结核病被定义为两个独立专家一致认为胸片显示在没有细菌学证实的情况下确定的结核病。可能的结核病被定义为在没有细菌学证实或放射学确定性的情况下，存在暗示的放射学征象和抗结核治疗的良好临床反应。良好的临床反应定义为症状完全缓解，体重增加>=诊断时体重的10%，开始抗结核治疗3个月内。非结核定义为在没有细菌学证实或提示结核的放射学征象的情况下，自发症状消退或对抗结核治疗无反应。肺结核定义为有以下症状的儿童：(1)细菌学证实的肺结核，(2)放射学证实的肺结核，或(3)可能的肺结核（按定义），不包括孤立性胸腔积液。总共有1024名儿童被转介接受评估。596名儿童（58.2%）报告症状缓解；428名（41.8%）儿童在评估时出现持续的、不缓解的症状，并接受了结核病调查。197名儿童被诊断患有肺结核；96例细菌学上确诊为结核病，75例放射学上确定为结核病，26例可能为结核病。结合持续2周的持续非缓解性咳嗽，记录的发育不良（前3个月）和疲劳，为未感染hiv的儿童提供了合理的诊断准确性（敏感性：62.6%，特异性：89.8%，阳性预测值：83.6%）；低危组（>= 3年，敏感性：82.3%，特异性：90.2%，阳性预测值：82.3%）优于高危组（< 3年，敏感性：51.8%，特异性：92.5%，阳性预测值：90.1%）。在就诊时诊断不明确的儿童中，临床随访是一种有价值的诊断工具，可进一步提高诊断准确性，特别是在低风险组中。基于症状的方法对艾滋病毒感染儿童的诊断价值不大。在20名被诊断为肺结核的艾滋病毒感染儿童中，有3名（15%）没有报告足够持续时间的症状，不足以纳入研究，而25%的儿童报告在没有结核病的情况下持续出现非缓解性症状。此外，在被诊断为肺结核的艾滋病毒感染儿童中，结核菌素皮肤试验阳性的< 20%。出现时3种明确的症状（持续2周的持续无缓解性咳嗽；前3个月的客观体重减轻[记录的发育不良]；报告的疲劳）为3岁未感染艾滋病毒的儿童提供了良好的诊断准确性，临床随访提供了额外的价值。该方法在< 3岁的儿童中效果较差。然而，持续的、非缓解型咳嗽并伴有发育不良仍然是相当准确的诊断（敏感性：68.3%；特异性：80.1%；阳性预测值：82.1%），说明了对幼儿进行定期体重监测的重要性。临床随访也提供了额外的诊断价值，但需要谨慎，因为非常年幼的儿童疾病快速进展的风险增加。这种方法在感染艾滋病毒的儿童中效果不佳。最近与成人病例的家庭接触似乎比结核菌素皮肤试验阳性提供更多的诊断价值，但基于t细胞的新型检测方法可能是唯一真正提高诊断艾滋病毒感染儿童结核分枝杆菌感染敏感性的方法。这种基于症状的诊断方法提供的可变诊断价值说明了风险分层的重要性，事实证明，12名未符合入境标准的严重疾病表现的儿童中有11名（91.7%）小于3岁或感染了艾滋病毒。应特别强调在记录暴露和/或感染这些高危儿童后提供预防性化疗。研究的局限性包括感染艾滋病毒的儿童人数较少，但从积极的方面来看，大量未感染艾滋病毒的儿童允许对这一重要群体进行充分的评价。人们常常忘记，未感染艾滋病毒的儿童占儿童结核病病例的大多数，即使在艾滋病毒流行的环境中也是如此。这项研究证明了在基于症状的诊断之前确定儿童艾滋病毒状况的重要性。由于儿童是在诊所和医院两级招募的，因此可能引入了一些选择偏差；然而，两组之间的唯一显著差异是感染艾滋病毒儿童的比例。肺结核诊断的确定程度不同，但两组间无显著差异。在未感染艾滋病毒的儿童中，使用简单的基于症状的方法可以以合理的准确度诊断肺结核。这为改善儿童获得治疗提供了令人兴奋的前景，特别是在资源有限的环境中，目前获得抗结核治疗的机会很少。
BACKGROUND. Tuberculosis control programs place an almost exclusive emphasis on adults with sputum smear-positive tuberculosis, because they are most infectious. However, children contribute a significant proportion of the global tuberculosis caseload and experience considerable tuberculosis-related morbidity and mortality, but few children in endemic areas have access to antituberculosis treatment. The diagnostic difficulty experienced in endemic areas with limited resources has been identified as a major factor contributing to poor treatment access. In general, there is a sense of scepticism regarding the potential value of symptom-based diagnostic approaches, because current clinical diagnostic approaches are often poorly validated. The natural history of childhood tuberculosis demonstrates that symptoms may offer good diagnostic value if they are well defined and if appropriate risk stratification is applied. This study aimed to determine the value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuber-culosis-endemic area.METHODS. A prospective, community-based study was conducted in Cape Town, South Africa. Specific well-defined symptoms were documented in all children < 13 years of age reporting a persistent, nonremitting cough of > 2 weeks' duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as "bacteriologically confirmed tuberculosis," "radiologically certain tuberculosis," "probable tuberculosis," or " not tuberculosis." Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of >= 10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion.RESULTS. In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of > 2 weeks' duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (>= 3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group (< 3 years; sensitivity: 51.8%; specificity: 92.5%; positive predictive value: 90.1%). In children with an uncertain diagnosis at presentation, clinical follow-up was a valuable diagnostic tool that further improved diagnostic accuracy, particularly in the low-risk group. Symptom-based approaches offered little diagnostic value in HIV-infected children. Three (15%) of the 20 HIV-infected children diagnosed with pulmonary tuberculosis failed to report symptoms of sufficient duration to warrant study inclusion, whereas 25% reported persistent, nonremitting symptoms in the absence of tuberculosis. In addition, the tuberculin skin test was positive in < 20% of HIV-infected children diagnosed with pulmonary tuberculosis.DISCUSSION. The combined presence of 3 well-defined symptoms at presentation (persistent, nonremitting cough of > 2 weeks' duration; objective weight loss [documented failure to thrive] during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children >= 3 years of age, with clinical follow-up providing additional value. The approach performed less well in children < 3 years. However, the presence of a persistent, nonremitting cough together with documented failure to thrive still provided a fairly accurate diagnosis (sensitivity: 68.3%; specificity: 80.1%; positive predictive value: 82.1%), illustrating the importance of regular weight monitoring in young children. Clinical follow-up also offered additional diagnostic value, but caution is required, because very young children have an increased risk of rapid disease progression. The approach performed poorly in HIV-infected children. Recent household contact with an adult index case seemed to provide more diagnostic value than a positive tuberculin skin test, but novel T-cell-based assays may offer the only real improvement in sensitivity to diagnose M tuberculosis infection in HIV-infected children. The variable diagnostic value offered by this symptom-based diagnostic approach illustrates the importance of risk stratification, as demonstrated by the fact that 11 (91.7%) of 12 children with severe disease manifestations who failed to meet the entry criteria were < 3 years of age or HIV infected. Particular emphasis should be placed on the provision of preventive chemotherapy after documented exposure and/or infection in these high-risk children. Study limitations include the small number of HIV-infected children, but on the positive side, the large number of HIV-uninfected children permitted adequate evaluation in this important group. It is often forgotten that HIV-uninfected children constitute the majority of child tuberculosis cases, even in settings where HIV is endemic. This study demonstrates the importance of ascertaining a child's HIV status before symptom-based diagnosis is attempted. Because children were recruited at both the clinic and hospital level, some selection bias may have been introduced; however, the only significant difference between the 2 groups was the proportion of HIV-infected children. Pulmonary tuberculosis was diagnosed with different levels of certainty, but no significant differences were recorded between these groups.CONCLUSIONS. Pulmonary tuberculosis can be diagnosed with a reasonable degree of accuracy in HIV-uninfected children using a simple symptom-based approach. This offers the exciting prospect of improving treatment access for children, particularly in resource-limited settings where current access to antituberculosis treatment is poor.