脊柱结核的微生物学诊断

Microbiological diagnosis of spinal tuberculosisInternational Orthopaedics (SICOT) (2012)脊柱结核的微生物学诊断,AbstractPurpose The purpose of this study was to review the clinical features and diagnosis of spinal tuberculosis cases reported in the literature.Methods A medical literature search in the Medline Pubmed database was undertaken to review tuberculosis spinal infection and extra-pulmonary tuberculosis diagnosis improvement.摘要目的：本研究的目的是回顾文献已报道的脊柱结核病例的临床特点及诊断。方法：在MEDLINE PubMed数据库中进行了医学文献检索以便研究脊柱结核感染及肺外结核病诊断的改进。,We introduced the following search items and boolean operators: spinal infection, spinal tuberculosis infection, microbiological diagnosis of spinal tuberculosis and spinal tuberculosis PCR. Single cases or series without microbiological diagnosis were rejected. Manuscript language was restricted to Spanish, French, and English versions.我们引用了以下的搜索项目和布尔运算符：“脊柱感染”，“脊柱结核感染”，“脊柱结核的微生物学诊断”和“脊柱结核聚合酶链反应。”未经微生物学诊断的单病例或系列研究被拒绝纳入。手稿语言仅限于西班牙语，法语和英语版本。,Results and conclusions Spinal tuberculosis is more common in developing countries and is probably underdiagnosed. Delayed diagnosis is characteristic; it worsens the prognosis and increases morbidity. The microbiological diagnosis is crucial for several reasons. Despite surgical treatment, medical treatment with anti-tuberculous drugs is always necessary. A total of 2040% of the spinal tuberculosis patients show another locus of infection.结果与结论脊柱结核在发展中国家更为普遍且常被漏诊。延误诊断具有特征性，它使预后恶化并增加发病率。脊柱结核微生物学诊断的至关重要性有几种原因。尽管行手术治疗，抗结核药物治疗总是必要的，共有20-40%的脊柱结核患者表现出另有感染源。,Pulmonary location can become a public health problem. Previously treated patients for other tuberculosis locations, incomplete treatments, or poor adherence can change the M. tuberculosis sensitivity pattern. Drug resistance test becomes a major need in the microbiology laboratory. PCR diagnostic techniques advance the diagnosis and increase the sensitivity and specificity rate.肺部结核病灶可以成为一个公共健康问题。先前治疗的其他部位结核病灶，不完全治疗或依从性差的患者可以改变结核分枝杆菌的敏感性。耐药性试验成为微生物学实验室中的主要需求。聚合酶链反应诊断技术的进展，提高了诊断的敏感性和特异性。,IntroductionThe principal infection causing death in the world is tuberculosis (TB). It is estimated two billion people are infected with TB, who can develop TB disease 1. The risk of developing the disease depends on the patient (host characteristics) and the geographical precedence because of the different incidence of TB in each country. 引言结核病(TB)是世界上导致死亡的主要传染病。据估计有20亿人感染了结核菌，并发展成结核病。结核病的发病风险取决于病人（宿主特点）和地理位置，因为在每个国家的结核病有不同的发病率。,In a study made in the United Kingdom, the risk in the white population increases with age from 0.8 to 10.9/100,000, whereas, the risk in people from the Indian subcontinent increases with age from 28.7 to 405.7/100,000; thus, they realised that anyone of any ethnic group has an increased risk of 1020 times, but this reduces after five years in the United Kingdom 2.在英国进行的一项研究显示，白种人口的结核病发病风险随着年龄的增大而增高，从0.8到10.9/10万；然而，在来自印度次大陆（主要在喜马拉雅山以南直到印度洋一带，包括印度、巴基斯坦、孟加拉等国家 ）等地区的人群中结核病的发病风险随着年龄增高从28.7到405.7/10万。因此，他们认识到，任何民族的每个人都有10-20倍的风险增加，但这风险在英国5年后就降低。,Extrapulmonary tuberculosis affects 1520% of patients with TB. The most common are pleural and lymphatic disease. Skeletal TB occurs in 10% of extrapulmonary manifestations, of which spinal TB accounts for approximately 50%. This gives an incidence of between one and two percent for osteoarticular TB and half to one percent for spinal TB 1,3. Most postoperative infections following spine surgery are caused by bacterial organisms. 结核病患者中肺外结核占有1520% ，最常见的是胸膜和淋巴管疾病。骨结核的发生率在肺外结核中占10%，而其中脊柱结核约占50%。这表明，骨关节结核的发生率为1-2%，其中脊柱结核的发生率约占一半。脊柱外科手术后的大多数术后感染是由细菌感染引起的。,Staphylococcus aureusis known to be the most common single pathogen, and the earlier postoperative infection is related to methicillin-resistant Staphylococcus aureus (MRSA) or Gram-negative bacteria. However, there are few reports of postoperative infection with Mycobacterium tuberculosis4. Spinal infection is a relatively rare condition and accounts for 216.7% of all cases of osteomyelitis 5.金黄色葡萄球菌是最常见的单一病原体，术后早期感染是与甲氧西林金黄色葡萄球菌（MRSA）或革兰氏阴性菌相关。然而，很少有报道说，术后感染与结核分枝杆菌有关。脊柱感染是一种比较罕见的情况，占所有骨髓炎病例的216.7% 。,Spinal TB accounts for one to three percent of all TB infections 6. Spinal tuberculosis is the most common and the most serious form of tuberculosis lesions in the skeleton.A total of 101 countries reported notifications of new cases of extrapulmonary TB (these countries accounted for 50% of total notifications of extrapulmonary TB). There were 195,002 male cases and 180,310 female cases, giving a male: female ratio of 1:1.脊柱结核占所有结核感染的1-3%，脊柱结核是骨结核中最常见、最严重的一种形式。共有101个国家报道了肺外结核新发病例的通知（这些国家占肺外结核总通知的50）。男性195002例，女性180310例，男：女比例为1:1。,Among new extra-pulmonary patients, this is much lower than the ratio for smear-positive TB patients. Understanding the reasons for this difference and the logistical implications requires further investigation and research. The resurgence of TB can be expected to be associated with a concomitant increase in the incidence of extra-pulmonary TB, including Potts disease.在新发的肺外结核患者中，这是远远低于涂片阳性结核患者的比例。了解这种差异的原因和后勤的影响，还需要进一步的调查和研究。结核病的复发有望与肺外结核发病率的增加有关，包括potts 病。,The incidence of patients with spinal infection has been reported to have increased 7. This is probably a result of an aging population, easy access to better diagnostic methods including magnetic resonance imaging (MRI) and an increase in the prevalence of immunocompromised hosts 8. Most recent studies highlight their appearance in elderly patients (mean age of 5060 years) with a clear predominance of males 9.发生脊柱感染的患者的报道逐渐增多，这可能是由于人口老龄化、易于获得更好的诊断方法，如磁共振成像（MRI）和免疫功能低下患者的患病率增加等有关。最近的研究表明，在老年患者（平均年龄为5060岁）具有明显的优势。,Studies in Spain have shown a similar incidence (0.72.4 cases per 100,000 inhabitants) with a tendency towards the disappearance of spondylodiscitis caused by Brucella and stabilisation of pyogenic and tubercular spondylodiscitis 10.Neurological deficit due to spinal infection can pose a wide range of problems for the patient and the surgeon. Most spinal infections in developed regions are the result of pyogenic organisms, whereas non-pyogenic organisms are responsible for most spinal infections in areas of the developing world, and in the immunocompromised population of developed nations. 研究表明在西班牙有相似的发生率(0.72.4例每100000居民)，显示了布鲁氏杆菌性椎间盘炎的消失和化脓性及结核性椎间盘炎的稳定趋势。由脊柱感染引起的神经功能缺陷可以给病人和外科医生带来广泛的问题。发达地区的大多数脊柱感染是由化脓菌引起的，而非化脓性球菌是引起发展中国家一些地区的大多数脊柱感染和发达国家免疫功能低下的人口的主要致病菌。,Mycobacterium tuberculosis is the most common organism among these areas. Accurate diagnosis is essential in order to effectively eradicate the infecting organisms. Subsequent management of the diagnosed infection remains controversial with the National Tuberculosis Control Programmes 11.结核分枝杆菌是在这些地区中最常见的病原体。准确的诊断是必要的，以有效地根除感染生物体。已经诊断的感染性疾病的后期治疗在国家结核病控制方案中仍有争议。,Tuberculosis has a propensity to spread along soft tissue planes, particularly anteriorly under the anterior longitudinal ligament, involving multiple vertebrae, in time giving the so-called “aneurysmal syndrome” (scalloping of the anterior vertebral margins) 12. Tuberculosis demonstrates a variety of clinical and radiological findings and shows a known propensity for dissemination from its primary site; therefore, it can mimic a number of disorders.结核病具有沿软组织平面传播的倾向，特别是在前纵韧带前下方，累及多个椎体，在此给予所谓的“动脉瘤样综合征”（椎体前缘的扇形结构）。结核病表现了各种临床和影像学检查结果，并显示出一个已知的倾向：从它的病灶部位往外播散;因此，它可以相似许多病症。,Tubercular spinal epidural abscess is usually secondary to tubercular spondylitis, but may rarely develop by haematogenous spread from any primary focus 13.The symptoms of tuberculous bone and joint infections are nonspecific, and the clinical course is often indolent, usually leading to significant delays in diagnosis and resultant bone or joint destruction. About 50% of the patients with bone and joint tuberculosis have chest radiographs suggestive of tuberculous infection, further obscuring the diagnosis 14.结核性脊椎硬膜外脓肿常继发于结核性脊椎炎，但可能很少从其他原发病灶通过血源性传播途径发展而来。骨与关节结核性感染的症状是非特异性的，其临床病理过程往往是惰性的，通常导致诊断的显著延误和由此产生骨或关节的破坏。约50%的骨与关节结核患者胸片提示有结核性感染，从而进一步模糊诊断。,Differentiation between pyogenic spondylodiscitis (PS) and tuberculous spondylodiscitis (TS) is essential to decide on the appropriate therapeutic regimen. The aim of this study was to compare the characteristics of the two forms of spondylodiscitis. TS was frequently associated with active tuberculosis of other organs (0% in PS vs. 31.9% in TS), and longer diagnostic delay (47.6 days in PS vs. 106.3 days in TS) 15.区分化脓性椎间盘炎(PS)和结核性椎间盘炎(TS)之间的差异对决定适当的治疗方案而言是至关重要的。本研究的目的是比较这两种炎性病变的特点。TS常伴有其他器官的活动性结核病( PS 为0，TS为31.9)，和较长的诊断延迟时间(PS 为47.6天，TS为106.3天)。,The clinical non-specificity of mycotic aneurysm or infective spondylitis makes diagnosis in the affected patients challenging. Although neurological deficit was statistically significant in patients with spontaneous infective spondylitis with mycotic aneurysm, this unique clinical characteristic was always noted in late stages of infective spondylitis 16.真菌性动脉瘤或感染性脊柱炎的临床非特异性使受累患者的诊断具有挑战性。虽然神经功能缺损在患有自发感染脊柱炎及真菌性动脉瘤的患者中有统计学意义，但这种独特的临床特征往往是在感染性脊柱炎的晚期才能发现。,If the patients are diagnosed early, they can be treated medically. This situation is a major problem in bone and joint TB, due to the delay in the diagnosis; therefore many patients need surgical treatment 17. Nevertheless, spinal tuberculosis progresses slowly and insidiously, and early diagnosis before abscess formation and disc affectation is difficult. For this reason, a detailed patient history is very important in these cases. In the early stages, single-level disc degeneration can be detected by MRI. Despite this, disc degeneration may be suspected, and the probability of diagnosing the condition as an infection is very low.如果患者得以早期诊断，可以进行药物治疗。这种情况是骨与关节结核的一个主要问题，由延误诊断所引起，因此许多患者需要行手术治疗。然而，脊柱结核进展缓慢而隐匿，并在脓肿形成和椎间盘受累前的早期诊断是困难的。因为这个原因，在这些病例中，详细的病史是非常重要的。在早期阶段，单节段椎间盘退变可以通过MRI得以检出。尽管这样，怀疑有可能为椎间盘退变时，诊断该条件为感染的概率是非常低的。,In either case, painful symptoms of patients can be relieved with medical treatment. If there is a tuberculosis history (in the patient or a family member), night sweats and weight loss, detailed MRI investigations focusing on the lesion are necessary for an early diagnosis and allow medical therapy. The diagnosis of spinal tuberculosis (ST) is difficult and it commonly presents at an advanced stage. The management and follow-up is complicated by a lack of guidance on the appropriate use and interpretation of spinal magnetic resonance studies (MR) 5.在这两种情况下，患者的疼痛症状可经内科治疗得以缓解。如果有结核病史(在病人或一个家庭成员)，盗汗和体重减轻，以病灶为中心的详细的MRI检查对早期诊断和行药物治疗而言是必须的。脊柱结核（ST）的诊断是很困难的，它通常呈现在晚期阶段。治疗和随访是复杂的，因为缺乏脊髓磁共振(MR)研究的正确使用指导和解释,The microbiological diagnosis is a problem in some parts of the world. For example, in the busiest clinics in Cape Town, up to 46% of pulmonary TB cases are not confirmed bacteriologically, and South Africa has one of the highest rate of tuberculosis infection 1. Positive cultures were reported in only 27 (62%) of 47 patients with tuberculous spondylitis18. Nevertheless, many spinal tuberculosis cases are diagnosed after the progressive degenerative process. These cases must be treated surgically 19.世界上有些地区，微生物学诊断是一个问题。例如，在开普敦最繁忙的一个诊所，将近有46%的肺结核病人没有经过细菌学确诊，而南非有最高的结核感染率。研究报道47例结核性脊柱炎患者中，只有27例（62%）培养结果阳性。然而，许多脊柱结核病例在进行性退变期后才得以诊断，这些病例必须手行术治疗。,Potts disease, an extra-pulmonary form of TB, is marked by the weakening and resorption of spinal vertebrae. This role could be related to the physical depletion of calcium in bones and/or the disruption of calcium signalling in host cells during long-term TB infection 20,21. The diagnosis of extra-pulmonary tuberculosis (EPTB) remains an important clinical problem, primarily because of the inadequate sensitivity of conventional bacteriological methods for detecting Mycobacterium tuberculosis in extra-pulmonary specimens.Potts病，是肺外结核病的一种形式，其标志性特点是椎体骨质的脆弱和吸收。这种作用可能与长期结核感染时骨骼中钙的物理消耗和/或宿主细胞中钙信号的中断有关。肺外结核(EPTB)的诊断仍然是一个重要的临床问题，主要是因为用于检测肺外组织标本中结核分枝杆菌的常规细菌学方法灵敏度不高。,The recent demonstration that nucleic acid amplification techniques are rapid and sensitive has modified strategies for the detection of Mycobacterium tuberculosis. Since the application of the polymerase chain reaction (PCR) in the diagnosis of TB, diagnostic protocols using varying methods of DNA purification and different M. tuberculosis target sequences have been evaluated 23, 24. 近期的研究表明，快速、灵敏的核酸扩增技术对结核分枝杆菌的检测有了新的改进策略。由于聚合酶链反应(PCR)在结核病诊断中的应用，采用不同的DNA纯化方法和不同结核病目标序列的诊断方法进行了评价。,Early diagnosis followed by proper medication is essential to prevent both morbidity and mortality. PCR is a good option for the rapid diagnosis of tuberculosis 22. Although the conventional technique of direct smear examination is cheap and easy to perform, its low sensitivity is a major drawback. On the other hand, the molecular-based diagnosis by PCR technique is faster and more sensitive 25. Serological tests are frequently used in developing countries, but a lot of work is yet to be done to consider them optimal 26.早期诊断及适当的药物治疗是必不可少的，以防止发病率和死亡率。聚合酶链反应(PCR)是结核病快速诊断的一种很好的选择，虽然直接涂片检查的常规技术是价格低并易于执行，但它的低灵敏度是一个主要的缺点。另一方面，分子诊断技术更快速、更灵敏，在发展中国家，经常使用血清学检查，但许多工作有待完成，以考虑它们为最佳方法。,All patients with tuberculosis should be referred to a chest physician trained in managing tuberculosis, but patients often return to their general practitioner with questions about their drugs. Antituberculous drugs interacting with other drugs is also a major concern. Sometimes, side effects of treatment may present, such as rashes caused by isoniazid 27. The detection of smear-negative and extra-pulmonary cases also lags behind the Global Plan, and by a larger amount (51% estimated for 2007 compared with the Global Plan Milestone of 69%) 23.所有结核病患者均应转诊给胸科医师以培训如何管理肺结核，但患者往往回到自己的全科医生咨询有关其药物的问题。抗结核药物与其他药物的相互作用也是一个重要的问题。有时发生治疗的副作用，如异烟肼引起的皮疹。涂片染色阴性和肺外结核病例的检测也落后于全球计划，并且数量很大（2007估计为51%，而Milestone全球计划为69% ）。,MethodsA medical literature search in PubMed Medline database was undertaken to review spinal tuberculosis infection and extra-pulmonary tuberculosis diagnosis improvement. On one hand, we selected studies to review the length of symptoms before diagnosis, concomitant pulmonary TB, success of treatment, microbiological diagnosis, as Ziehl-Neelsen staining results and resistant strains.方法在MEDLINE PubMed数据库中进行了医学文献检索以便研究脊柱结核感染及肺外结核病诊断的改进。一方面，我们选择了相关文献以复习诊断前症状持续时间、伴有肺结核、治疗成果、微生物学诊断及抗酸染色结果和耐药菌株等内容。,On the other hand, we chose studies about the sensitivity of molecular biology techniques for the diagnosis of spinal TB. We introduce the following search and boolean operators items: spinal tuberculosis infection, microbiological diagnosis of spinal tuberculosis and spinal tuberculosis PCR. No publication date restriction was applied. Manuscript language restriction was to English, French, and Spanish versions.另一方面，我们选择了用于脊柱结核诊断的分子生物学技术之敏感性的相关文献。我们引用了以下的搜索项目和布尔运算符：“脊柱感染”，“脊柱结核感染”，“脊柱结核的微生物学诊断”和“脊柱结核聚合酶链反应” 。没有设置发布日期限制。手稿语言仅限于英语、法语和西班牙语版本。,Inclusion criteria of studies:Data from case series studies or meta-analysis that provided spinal TB cases diagnosed by microbiological tests.Studies that provided data on the microbiological diagnosis of spinal tuberculosis.Exclusion criteria:Studies performed only in the paediatric population.Items with unique cases or case reports.研究纳入标准：病例系列研究或荟萃分析的数据，其能提供通过微生物学检查诊断的脊柱结核病例。能提供脊柱结核微生物学诊断数据的研究。排除标准：仅在儿童人群中进行的研究。具有独特病例或病例报告的项目。,DiscussionSpinal tuberculosis is not a very common entity. It causes significant morbidity and important consequences and sequelae. In our review, we observed that the time until the diagnosis is achieved remains very long, which indicates that the diagnostic techniques should be improved. It should also become part of regular differential diagnosis by physicians, especially in patients and areas where the prevalence of tuberculosis is high.讨论：脊柱结核不是一个很常见的实体(疾病)。它会导致明显的发病率和严重的后果及后遗症.。在本研究中,我们观察到得出诊断的时间很长,这表明诊断技术需要提高,也应该成为医生定期鉴别诊断的一部分,尤其是在结核病高度流行的患者和地区中。,It is relevant that 2040% of patients have active tuberculosis at other sites, so the diagnosis can be performed on clinical specimens as sputum, urine, or lymph node aspirate9 and we also believe that it is important to check that no other microorganisms are implicated 16.The TB diagnosis, and specifically spinal TB, should be based on clinical and serological testing (Mantoux test, I, IFN-, which are more specific for M. tuberculosis than PPD, because they appear in M. tuberculosis genes, but are not present in BCG strains provided for vaccination) 2.相关的2040%患者有其他部位的活动性结核病，因此对临床标本如痰液、尿液和淋巴结穿刺等进行诊断。我们也认为，重要的是要检出没有其他微生物感染。结核病的诊断，特别是脊柱结核的诊断应根据临床和血清学检测（结核菌素试验，I ，IFN-等对结核分枝杆菌而言比PPD试验更有特异性，因为它们出现在结核分枝杆菌基因中，但不存在于疫苗接种用的BCG菌株中）。,One of the main challenges in the microbiological diagnosis of TB has always been the time for culture of M. tuberculosis. Microbiological diagnosis is important as it provides aetiology and the foundation for adequate antibiotic treatment. New techniques provide pulmonary and extra pulmonary tuberculosis diagnosis. Aetiology and early diagnosis must be ensured to commence prompt and specific treatment.结核病微生物学诊断的主要挑战之一，一直就是培养结核分枝杆菌所需要的时间。微生物学诊断是重要的，因为它会提供病因和足够的抗生素治疗基础。新技术能够诊断肺结核及肺外结核，必须保证找出病因和早期诊断以便开始及时和具体的治疗。,PCR is very successful for the rapid diagnosis of several infectious diseases. Achieving this test for TB diagnosis is a major target. This will allow an early diagnosis, earlier targeted treatment and prevention of the spread of the disease, and in the case of TB, a public health problem. Even today these tests are not routinely used for TB management, yet many tests of this type are performed in many parts of the world, as in India, with more than 1.5 million tests 26.PCR是在几种感染性疾病的快速诊断中非常成功的，实现结核病诊断的这种试验是一个主要目标。这将允许有早期诊断、早期靶向治疗和预防疾病的传播，就如公共健康问题的结核病等。到今天，这些测试并不常规用于结核病的治疗，但这种类型的测试是已在世界许多地方进行，如在印度，有超过150万的测试。,Imaging tests such as CT and MRI are very useful in spinal TB diagnosis. Described by Polley et al. 1, may also help to determine different locations in the spine, as in many patients there is no single locus but several. It is also important to monitor disease progression and treatment 8.Providing orthopaedic physicians the microbiological diagnosis remains a challenge. The delay in the microbiological results in this disease delays the diagnosis and, therefore, the treatment. Even today, most laboratories do not have PCR techniques to facilitate the diagnosis, as seen in the studies analysed 31, 32.影像学检查如CT和MRI