假体关节相关感染.doc

假体关节相关感染A 62-year-old woman with osteoarthritis presents with a 7-month history of progressively worsening left hip pain radiating to the groin, 8 months after undergoing total left-hip arthroplasty. The pain has not responded to nonsteroidal anti-inflammatory drugs. Physical examination reveals a sinus tract overlying her left hip. Her leukocyte count is 8000 per cubic millimeter, and the C-reactive protein (CRP) level is 15.5 mg per liter. A radiograph shows loosening of the prosthesis at the bonecement interface. Synovial-fluid aspirate shows 15103 cells per cubic millimeter (89% neutrophils); cultures of an aspirate from the hip grow Staphylococcus epidermidis. How should her case be managed? 1名62岁女性骨性关节炎患者，左侧THA术后8个月，左髋渐进性疼痛并向腹股沟放射7个月。服用非甾类抗炎药疼痛无缓解。查体示左髋有一窦道形成。白细胞计数为8000个/mm3，C-RP为15.5mg/L。放射线检查示假体和骨水泥界面有松动。关节液检查示15X103个细胞/mm3，中性粒细胞比例为89；关节炎培养示为表皮葡萄球菌阳性。该如何对这一病例进行处理？The Clinical ProblemThe numbers of primary total hip and total knee arthroplasties have been increasing over the past decade, with nearly 800,000 such procedures performed in the United States in 2006 (Fig. 1A).1 Procedures to replace the shoulder, elbow, wrist, ankle, temporomandibular, metacarpophalangeal, and interphalangeal joints are less commonly performed.临床问题：过去10年间，行首次髋膝关节置换的病例数有了大幅的增长，到2006年美国约进行了800000例此类手术。而行肩、肘、腕、踝、颞下颌、掌指和指间关节置换则少见的多。Prosthetic joints improve the quality of life, but they may fail, necessitating revision or resection arthroplasty. Causes of failure include aseptic loosening, infection, dislocation, and fracture of the prosthesis or bone. Infection, although uncommon, is the most serious complication, occurring in 0.8 to 1.9% of knee arthroplasties3-5 and 0.3 to 1.7% of hip arthroplasties.5-7 The frequency of infection is increasing as the number of primary arthroplasties increases (Fig. 1B).2 Patient-related risk factors for infection include previous revision arthroplasty or previous infection associated with a prosthetic joint at the same site, tobacco abuse, obesity, rheumatoid arthritis, a neoplasm, immunosuppression, and diabetes mellitus. Surgical risk factors include simultaneous bilateral arthroplasty, a long operative time (2.5 hours), and allogeneic blood transfusion, and postoperative risk factors include woundhealing complications (e.g., superficial infection, hematoma, delayed healing, wound necrosis, and dehiscence), atrial fibrillation, myocardial infarction, urinary tract infection, prolonged hospital stay, and S. aureus bacteremia.3-6,8-11假体关节能够提高患者的生活质量，但是一旦失败则必须进行翻修或是截骨矫形术。导致失败的原因包括了无菌性松动、感染、脱位和假体或是假体周围的骨折。感染虽不常见，但是却是最为严重的并发症，在膝关节置换中其发生率约为0.3-0.7，在髋关节置换中约为0.3-1.7。随着初次关节置换手术量的增加，术后感染的发生率也有所上升。与患者相关的感染危险因素包括同一关节已行翻修手术或是已发生过假体关节相关感染、吸烟、肥胖、类风湿性关节炎、有赘生物、免疫抑制和未控制的糖尿病等。而手术相关的危险因素包括了同期行双侧置换、手术时间长（大于2.5小时）以及输血等。术后的感染危险因素包括伤口愈合相关并发症（表浅感染、血肿、延迟愈合、泌尿系感染、住院时间延长以及金葡菌菌血症等。Staphylococci (S. aureus and coagulase-negative staphylococcus species) account for more than half of cases of prosthetic-hip and prosthetic-knee infection12 (Fig. 2). S. aureus infection is particularly common in patients with rheumatoid arthritis.13 Other bacteria and fungi cause the remainder of cases.14,15 Propionibacterium acnes is a common cause of infection associated with shoulder arthroplasty.16 Up to 20%of cases are polymicrobial, most commonly involving methicillin-resistant S. aureus (MRSA) or anaerobes.17 Approximately 7% of cases are culture-negative, often in the context of previous antimicrobial therapy.18葡萄球菌（金葡菌和凝血酶阴性类葡萄球菌）约与半数髋膝假体相关感染有关。金葡菌感染在类风湿性关节炎患者中尤为常见。剩余的感染病例则是由其他细菌或真菌引起的。丙酸菌属粉刺是造成肩关节置换感染的常见原因之一。有高达20的感染病例是由多处微生物感染引起的，其中多包括了MRSA（甲氧西林耐药金葡菌）或是厌氧菌。接近7的病例是关节炎培养阴性的，此类病例多是已经接受过抗生素治疗的患者。The pathogenesis of infection associated with a prosthetic joint involves interactions among the implant, the hosts immune system, and the involved microorganism or microorganisms. Only a small number of microorganisms is needed to seed the implant; such organisms adhere to the implant and form a biofilm in which they are protected from conventional antimicrobial agents and the host immune system.19 Associated microorganisms are often skin bacteria that are inoculated at joint implantation. In some cases, organisms seed the implant hematogenously or through compromised local tissues.假体关节相关感染的发病机制涉及到内置物、宿主免疫系统和微生物三方面的相互作用。只需极少量的微生物种植于内置物上就能引起感染，微生物粘附在内置物上，并在其表面形成1层生物膜，这可以使微生物抵抗传统抗生素和宿主免疫系统。Infection with virulent organisms (e.g., S. aureus and gram-negative bacilli) inoculated at implantation is typically manifested as acute infection in the first 3 months (or, with hematogenous seeding of the implant, at any time) after surgery, whereas infection with less virulent organisms (e.g., coagulase-negative staphylococci and P. acnes) is more often manifested as chronic infection several months (or years) postoperatively. The most common symptom of infection associated with a prosthetic joint is pain. In acute infection, local signs and symptoms (e.g., severe pain, swelling, erythema, and warmth at the infected joint) and fever are common. Chronic infection generally has a more subtle presentation, with pain alone, and it is often accompanied by loosening of the prosthesis at the bonecement interface and sometimes by sinus tract formation with discharge. 接种于内置物上的高毒性病原体（如金葡菌和革兰氏阴性菌）所引起的感染通常表现为典型的急性感染，症状多在3个月内出现，而且术后血源性感染虽表现与之类似，但是可以出现在术后的任何时候。术后因低毒性微生物（如凝固酶阴性的葡萄球菌感染和丙酸粉刺所引起的感染）感染所引起的症状多表现为慢性感染，可在术后数月或是数年出现。最为常见的假体相关感染的症状是疼痛。在急性感染时，还可有局部的症状和体征（如剧烈疼痛、肿胀、发红和局部皮温升高），同时患者发热也是常见的全身症状。在慢性感染是，症状多表现的较为轻微，常常仅表现为有疼痛症状，但是常常会伴有骨水泥界面的假体松动，同时在部分病例中会有窦道的形成，并有分泌物流出。Strategies and Evidence治疗的策略和相应的证据Diagnostic Approach诊断方式It is important to accurately diagnose prostheticjoint-associated infection because its management differs from that of other causes of arthroplasty failure. Although there is no universally accepted definition of this type of infection, the criteria listed in Table 1 have been applied in a number of studies.9,12,16,18,20,21对假体关节相关感染而言，准确诊断是非常重要的。这是因为假体关节相关感染所导致的关节成形术失败不同于其他。虽然目前尚没有被普遍接受的对这种感染的定义。而Table1所列的标准是多个研究中所采用的标准。Establishing the presence of acute infection or, in the presence of a draining sinus, chronic infection, is uncomplicated. In these situations, testing may be limited to that needed to establish the microbiologic diagnosis. Chronic infection manifested as localized joint pain alone poses more diagnostic difficulty, warranting additional testing. The criteria for interpreting laboratory and imaging findings in patients with a prosthetic joint are distinct from those applied in patients with a native joint. In addition to establishing the diagnosis, the identification of the involved organism or organisms and their antimicrobial susceptibility (i.e., on the basis of cultures of synovial fluid, periprosthetic tissue, the implant, or a combination of such cultures) is important in order to guide antimicrobial therapy.当有急性感染的表现，或是窦道内有分泌物流出的慢性感染，确定感染并不复杂。在这些情况下，所作的检测往往是为了确定微生物诊断。而对仅表现为局部关节疼痛的慢性感染，诊断的确立会更加困难，这就需要进行更多的检测。对假体关节相关的X线检查和实验室检测的标准并不同于一般的没有进行关节置换的患者。除确定感染诊断之外，还需要鉴别出感染所涉及的病原体和它们的药物敏感性，（这是基于对关节炎、假体周围组织、植入物的单独或是联合培养）这对指导抗生素治疗是非常重要的。C-Reactive ProteinC反应蛋白In the absence of underlying inflammatory conditions, CRP measurement is the most useful preoperative blood test for detecting infection associated with a prosthetic joint. CRP testing has a sensitivity of 73 to 91% and a specificity of 81 to 86% for the diagnosis of prosthetic-knee infection with the use of a cutoff point of 13.5 mg per liter or more.22,23 It has a sensitivity of 95% and a specificity of 62% for the diagnosis of prosthetic-hip infection with the use of a cutoff point of more than 5 mg per liter.24 Although the CRP level and erythrocyte sedimentation rate are elevated after uncomplicated arthroplasty, the CRP level returns to the preoperative level within 2 months, whereas the erythrocyte sedimentation rate may remain elevated for several months.25 A normal CRP level generally indicates an absence of infection, although false negative results may occur in patients who have been treated with antimicrobial agents or who have infection that is caused by lowvirulence organisms such as P. acnes. Elevations in the peripheral-blood leukocyte count and levels of procalcitonin have low sensitivity for detecting infection.在排除其他的潜在的炎症后，CRP检测是最为有效的确定假体关节相关感染的指标。CRP水平达到13.5mg或以上时，对诊断膝关节假体相关感染的敏感性达到7391，特异度达到8186。对髋关节假体相关感染的诊断时，如果达到5mg/L时，则敏感性为95，特异度为62。虽然CRP和ESR的水平在关节置换术后均会升高，但是CRP水平一般会在术后2个月内降至术前水平，而ESR则可能会在术后数月仍高于术前水平。正常的CRP水平往往会提示没有感染发生，但是在接受抗生素治疗的患者或是发生如丙酸菌属低毒性感染的患者也会出现CRP检测的假阴性结果。而外周血白细胞计算和原降钙素水平的上升对诊断感染的敏感性较低。ImagingPlain radiography has low sensitivity and low specificity for detecting infection associated with a prosthetic joint.26 Periprosthetic radiolucency, osteolysis, migration, or all of these features may be present on radiographs in patients with either infection or aseptic loosening of the prosthesis. Diagnostic studies with the use of computed tomography (CT) or magnetic resonance imaging (MRI) are hampered by artifacts produced by prostheses, although implants that are not ferromagnetic (i.e., titanium or tantalum) are associated with minimal MRI artifacts, and MRI scans of such implants provide good resolution for detecting soft tissue abnormalities. Bone scans obtained after the administration of technetium-99m-labeled methylene diphosphonate are sensitive for detecting failed implants but nonspecific for detecting infection, and they may remain abnormal for more than a year after implantation. Some studies suggest that combined bone and gallium-67 scans are more specific than bone scans alone. However, labeled-leukocyte imaging (e.g., leukocytes labeled with indium-111) combined with bone marrow imaging with the use of technetium-99m-labeled sulfur colloid is more accurate than bone imaging alone, combined bone and gallium-67 imaging, or labeled-leukocyte and bone imaging when compared head to head, and it is considered the imaging test of choice when imaging is required.26 18F-fluorodeoxyglucose positron-emission tomography (PET) has a sensitivity of 82% and a specificity of 87% for the detection of prosthetic-knee or prosthetic-hip infection, on the basis of pooled data from several studies, but it is not widely available.27 Newer imaging strategies such as scintigraphy with antigranulocyte monoclonal antibodies and hybrid imaging (e.g., combined PET and CT) (see Fig. 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org) are under investigation.X线摄片X线平片对诊断假体关节相关感染的敏感性和特异度均较低。而假体周围的透光线、骨质吸收、假体的移位在假体相关感染或是假体无菌性松动均有可能单独或是联合出现。虽然目前所使用的假体关节都是低磁性的（如钛、钽等），而且此类金属所产生的伪影非常小，MRI扫描能够很好的发现假体周围软组织异常，但是使用CT或是MRI对感染进行诊断仍会受到伪影的影响。注射塔99标记的亚甲基二磷酸盐后，行骨扫描能够对诊断假体植入失败提供足够的敏感性，但是对诊断感染的特异度仍显不够，在假体植入后1年，骨扫描结果仍有可能显示为非正常。在有些研究中认为联合骨扫描和镓67扫描将比单独进行骨扫描的特异度更高。但是，经标记的白细胞摄片（使用经铟111标记白细胞）联合注射经塔99标记的硫磺胶体的骨髓摄片将比单独骨扫描、骨和镓67联合摄片以及经标记的白细胞和骨联合摄片的特异性都要高，当需要进行摄片检测时应考虑选择这种方式进行检查。使用18F氟脱氧葡萄糖的PET检查对髋膝假体相关感染的敏感性可达到82，而特异度为87，虽然得出这一结果是通过统计众多研究的数据所得到的，但是这一方法并不能广泛的应用。更新的摄片方法如抗粒细胞单克隆抗体标记的闪烁照相以及杂交摄片（如PET和CT的联合）技术均处于观察中。Synovial-Fluid StudiesIf there is uncertainty about the diagnosis, the most useful preoperative diagnostic test is aspiration of joint synovial fluid for a total and differential cell count and culture. Aspiration should not be performed through overlying cellulitis. Hip aspiration may require imaging guidance. A synovial fluid leukocyte count of more than 1.7103 per cubic millimeter or a differential count with more than 65% neutrophils is consistent with prosthetic knee infection.28 A synovial-fluid leukocyte count of more than 4.2103 per cubic millimeter or more than 80% neutrophils is consistent with prosthetichip infection.29 The leukocyte count cutoffs are dramatically lower than those used to diagnose native-joint infection. Synovial-fluid culture has a sensitivity of 56 to 75% and a specificity of 95 to 100%,12,22,30 and to achieve optimal sensitivity and specificity, it should be performed by means of inoculation into a blood-culture bottle.31 If an organism of questionable clinical significance is isolated, repeat synovial-fluid aspiration for culture should be considered. Previous antimicrobial treatment reduces the sensitivity. 关节液研究如果感染的诊断尚未确定，最为有效的诊断感染的术前检查是对关节穿刺液的全细胞或部分细胞计数以及培养。关节穿刺应该避开潜在的蜂窝质炎部位。行髋关节穿刺时有可能需要在X线辅助下进行。膝关节液中，白细胞计数超过1.7103个/mm3或是中性粒比例超过65即提示有假体膝关节感染。如果髋关节液的白细胞计数超过4.2103个/mm3或是中性粒比例超过80则提示假体髋关节的感染。这一白细胞计数的诊断标锥远低于诊断正常关节感染的标准。关节液培养的敏感性为56755，特异度为95100，如果使用血培养基进行孵育，将使关节液培养的敏感性和特异度进一步提高。如果某种微生物的培养结果为阳性，则应考虑反复进行关节液的穿刺和培养。穿刺前的抗生素治疗，将会降低关节液培养的敏感性。Histopathological Examination of Periprosthetic TissueIn patients in whom the diagnosis of prosthetic joint-associated infection has not been established preoperatively, an intraoperative frozen section may be obtained to look for evidence of acute inflammation. In studies that used a polymorphonuclearcell count ranging from more than 5 to 10 or more cells per high-power field as a positive test, sensitivity for infection ranged from 50 to 93% and specificity ranged from 77 to 100%32-35; the rate of interobserver agreement was 86%.36 假体周围组织的组织病理学检查对于术前尚未确诊为假体关节相关感染的患者，术中应行冰冻切片检查以寻找急性炎症的证据。在研究中表明，多形核细胞计数超过510个/高倍视野，对感染的敏感性可达到5093，而特异度为77100，这一结果的观察者内在一致性为86。Intraoperative Microbiologic Testing Identification of the pathogen or pathogens is critical for choosing the antimicrobial regimen; if microbiologic testing has not been done preoperatively, specimens should be collected for microbiologic study at the time of surgery. Antimicrobial therapy should be discontinued at least 2 weeks before surgery, and perioperative antimicrobial coverage should be deferred until culture specimens have been collected. Cultures of sinus tract exudates should be avoided; these are often positive because of microbial skin colonization and correlate poorly with cultures of surgical specimens.术中微生物检测确定病原体的种类是选择抗生素的关节，如果术前没有进行相关的微生物检测，则术中应将样本收集起来进行微生物学检测。术前应该停用抗生素至少2周，围手术期内的抗生素应用应在标本收集完成后进行。窦道渗出液的培养是没有必要的，因为培养所得出的阳性结果多是皮肤上的微生物群落，而极少与标本的培养结果相关。If periprosthetic tissue is obtained, collection of multiple periprosthetic -tissue specimens for aerobic and anaerobic bacterial culture is imperative because of the poor sensitivity of a single culture and to distinguish contaminants from pathogens. A study that used mathematical modeling to estimate yield based on the number of cultures concluded that to maximize accuracy, five or six specimens should be submitted for culture, and two or three culture-positive samples would be considered to be diagnostic.37获得假体周围组织后，对多个假体周围组织样本进行需氧和厌氧培养是必须的检查，这是因为进行单种培养对病原体的检出敏感性极低。有研究使用数学模型证实为获得最大的检查准确率，需要用56个样本进行培养，而且只有有23个样本培养结果为阳性时才能作为诊断的依据。Periprosthetic-tissue cultures may be falsely negative because of previous antimicrobial therapy, leaching of antimicrobial agents from antimicrobial- impregnated cement, biofilm growth on the surface of the prosthesis (but not in the surrounding tissue), a low number of organisms in tissue, an inappropriate culture medium, an inadequate culture incubation time, or a prolonged time to transport the specimen to the laboratory. Because of poor sensitivity, neither intraoperative swab cultures38 nor Grams staining of the periprosthetic tissue37 is recommended. Fungal cultures, mycobacterial cultures, or both may be considered (e.g., if bacterial cultures are negative in a patient with apparent infection), but they are not routinely recommended.有多种原因均可导致假体周围组织培养的假阴性结果，包括了先前进行了抗生素治疗、使用了抗生素骨水泥、生物膜仅在假体表面形成和生长（但未在假体周围组织形成）、组织中的微生物数量过低、培养介质不合适、孵育时间不够、样本送至实验室的时间过长等等。同时由于敏感性过低，也不推荐对假体周围组织的革兰氏染色和术中拭子培养等检测。如果在感染可疑的患者中，细菌培养为阴性，可考虑进行真菌和或分枝杆菌培养，但这也不是常规的检测。Microorganisms form a biofilm on the prosthesis; therefore, if the prosthesis is removed, obtaining a sample from its surface is useful for microbiologic diagnosis.12 The implant is removed and transported to the laboratory in a sterile jar. After the addition of Ringers solution, the container is vortexed and sonicated (frequency, 40 kHz; power density, 0.22 W per square centimeter) for 5 minutes in a bath sonicator, and the resultant fluid is cultured. This technique is more sensitive than and as specific as multiple periprosthetic-tissue cultures for diagnosing infection of a prosthetic hip, knee, or shoulder, provided that an appropriate cutoff for significant results is applied (Table 1).12,16 This technique is particularly helpful in patients who have received previous antimicrobial therapy. In a study involving patients receiving antimicrobial agents within 2 weeks before surgery, the sensitivity of periprosthetic-tissue culture was 45%, whereas the sensitivity of sonicate-fluid culture was 75% (P0.001).12 Sonication in bags is not recommended because of the potential for contamination.39,40微生物会在假体表面形成一层生物膜，所以移除假体后，在其表面获取的样本对进行微生物诊断是非常有用的。移除假体后，将其装在无菌罐中送至实验室，再加入Ringers液，进行蜗旋和超声振荡处理5分钟，所得到的液体进行培养。这一技术将比进行多块假体周围组织培养更为敏感的对髋、膝和肩假体关节感染进行诊断，能够更为容易的获得有诊断价值的培养结果。这一技术对先前已使用抗生素治疗的患者的诊断更有帮助。在一项对术前2周已接受抗生素治疗的患者的研究中，超声处理后液的培养的敏感性可以达到75P0.001。由于在塑料袋中进行超声处理会有污染的风险，所以不推荐作为检查手段。TreatmentThe goal of treatment is to cure the infection, prevent its recurrence, and ensure a pain-free, functional joint. This goal can best be achieved by a multidisciplinary team consisting of an orthopedic surgeon, an infectious -disease specialist, and a clinical microbiologist. On the basis of clinical experience, the use of antimicrobial agents alone, without surgical intervention, ultimately fails in most cases. Careful surgical dbridement is critical.治疗治疗的目的是治愈感染、防止复发同时确保患者获得无痛的，有功能的关节。为达到这一目的，治疗小组应有多学科的医师组成，包括了骨科医师、感染性疾病专家和临床微生物专家。根据临床实践经验，单独使用抗生素治疗，而没有外科干预，在大多数的病例中均会导致最终的失败。细致的外科清创将是治疗的关键。A general approach to surgical management is outlined in Figure 321,38,41; different centers and surgeons may use slightly different strategies. Chronic infections require resection arthroplasty either as a one-stage exchange (i.e., removal of the infected prosthesis and reimplantation of a new prosthesis during the same surgical procedure) or a two-sta