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李园园 中南大学湘雅医院呼吸与危重症医学科 发布于2022-07-06 浏览 5108
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作者：李园园
军团菌肺炎（Legionella pneumonia）是由军团杆菌引起的以肺炎为主要表现，可能合并全身多器官受损的感染性疾病，是一种相对少见的肺炎类型。军团菌肺炎全球发病率目前尚未明确，占社区获得性肺炎（community-acquired pneumonia，CAP）的1%～10%[1,2]。相较其他大多数呼吸道非典型病原体肺炎，军团菌肺炎病情进展更快，尤其是未经及时救治患者的病情可能在第一周内迅速恶化，短时间内进展至重症肺炎甚至并发呼吸衰竭、休克、急性肾衰竭和多器官功能障碍等[3]，高达44%的患者需入住ICU[4]，病死率可达10%～15%，院内感染者死亡率甚至可达25%～50%，且延迟治疗往往与更高的死亡率相关[5-7]。早期诊断并及时恰当治疗是降低病死率的关键。
微生物学特征
临床特征
尽管军团菌广泛存在于温暖潮湿的环境中，但人类感染仍相对少见。既往研究证实年龄较大（大多超过50岁）、男性、吸烟、酗酒、免疫抑制、合并慢性心肺疾病等均为军团菌肺炎的危险因素[15-17]，而老年、免疫抑制、吸烟、合并多种基础疾病及诊治延误与其高病死率密切相关[18]。由于对抗军团菌的主要宿主防御机制为细胞免疫，因此对于免疫抑制，尤其是细胞免疫抑制者，包括获得性免疫缺陷综合征、糖尿病、恶性肿瘤患者等，需高度警惕军团菌肺炎发生[15,19,20]。此外，随着免疫治疗兴起，肿瘤坏死因子拮抗剂、皮质类固醇及器官移植排斥剂等免疫抑制药物[17,21]对军团菌肺炎发病率的影响也不容小觑。
军团菌肺炎以散发、急性起病为主，污染水源或土壤的聚集地可形成暴发或流行。临床症状通常在感染后2～14天出现[22]，主要包括寒战、发热、干咳、呼吸困难等非特异性呼吸道症状及头痛、肌痛、呼吸困难、腹泻、谵妄在内的肺外器官受累症状等[23, 24]。
部分实验室指标的异常可能提示军团菌肺炎的发生，如电解质紊乱、肝酶及磷酸激酶水平升高等，其中电解质紊乱以低钠血症常见，低磷血症、低钾血症也时有发生[3,25]。此外，在CAP中，C反应蛋白水平的升高在军团菌肺炎中较为常见，但具体机制仍尚未明确[26]。
影像学方面，军团菌肺炎表现多样且具有非特异性，以单肺叶斑片状浸润影最常见，可进展为实变[27, 28]。相较其他非典型病原体肺炎，军团菌肺炎影像学常呈磨玻璃影间混杂边界分明实变区的特征性改变[29]，且实变范围主要集中于肺门周围而非周边区域[23]。此外，其影像学改变与临床症状具有非同步性，临床症状改善后，影像学在数日内仍可能有所进展，肺部浸润影持续数周甚至数月后才可完全吸收[22,30]。
诊断
军团菌肺炎的延迟诊断及缺乏易于获得的检测技术往往与其高病死率相关[18]，然而其临床特征缺乏特异性、现有检测技术较为局限，落实临床快速精准诊断仍具有一定挑战性。对此，不同病原学检测技术及临床评分系统应运而生，为实现军团菌肺炎的快速精准诊断带来机遇。
2016年中国成人社区获得性肺炎诊断和治疗指南[30]推荐在以下特定情况下积极进行军团菌筛查：①群聚性发病；②发病前2周有外出旅居史；③免疫缺陷者；④重症CAP；⑤影像学提示双侧胸腔积液、双肺多叶病灶；⑥初始经验性治疗效果欠佳。此外，美国感染病学会（Infectious Diseases Society of America，IDSA）及美国胸科学会（American Thoracic Society，ATS）均推荐对具有特定危险因素或流行病学暴露的非重症CAP患者，以及重症或需要住院治疗的CAP患者进行军团菌肺炎检测[16,31]。
军团菌肺炎精准快速诊断的关键在于对疑似或高危患者进行恰当病原学检测，避免漏诊的同时，及时启动针对性治疗以改善患者临床结局。常用军团菌检测技术包括分离培养、抗原抗体检测及以宏基因组下一代测序（metagenomic next-generation sequencing，mNGS）为代表的核酸扩增技术等。
从痰液、胸腔积液、支气管抽吸物、支气管肺泡灌洗液（bronchoalveolar lavage fluid，BALF）等下呼吸道标本中分离培养出病原体仍是军团菌肺炎病原学诊断的金标准[3]。其中，BALF培养阳性率最高。必要情况下，肺活检组织，甚至肺外组织，如血液、软组织、关节液等也可作为培养标本，但并不常用[3, 24]。通过分离培养，可识别所有已知军团菌种及血清型，敏感性达60%～80%，特异性接近100%[32]。然而，军团菌培养条件苛刻，培养周期相对较长，对检测人员技术水平要求高，往往需在pH为6.5～7.3 且含L-半胱氨酸条件下，于活性炭-酵母浸出液琼脂培养基中培养3～5天甚至2周才可得到结果[33, 34]。此外，研究显示约16%的军团菌患者就诊时无咳嗽症状，约38%的患者仅有干咳，仅不足50%的患者可获取痰标本[26]，而BALF需通过有创支气管镜检查获取，对无痰和（或）无法耐受/不愿行支气管镜检查者来说很难实现。
针对军团菌免疫球蛋白G（IgG）及免疫球蛋白M（IgM）抗体的血清学检测是1980年代早期用于诊断军团菌肺炎的主要方法之一[35]。截至目前，包括间接免疫荧光测定法（IFA）、酶免疫测定法（EIA）、微凝集检测法等多种血清学检测技术均被用于军团菌病原体测定，有效缩短了检测时间、提高了检测敏感性（78%～90%）[24]。然而，血清学诊断中所识别的抗体在不同血清群或不同种军团菌感染中可能是共有的，因此很难可靠鉴别导致感染的血清群或军团菌种类[36]；此外，血清学检测往往需急性期与恢复期双份血清标本呈现4倍及以上变化才有临床价值，而大多数军团菌感染者在感染后数周才产生相应抗体，且抗体产生受宿主免疫状态影响，约25%的军团菌肺炎患者在全病程中均未产生血清抗体[37]；同时，抗体的升高并不一定特异性指向军团菌感染，已证实脆弱拟杆菌、鹦鹉热梭菌等感染可能造成假阳性结果[24]。因此，从1995年至2021年，使用血清学检测诊断军团菌肺炎的比例下降近60%，并逐步被尿抗原检测法取代[38,39]，目前多用于回顾性研究及流行病学调查。
UAT特异性高，主要靶向嗜肺军团菌细胞壁中的脂多糖，可用于急性期检测[3, 40]。通过免疫层析法（immunochromatographic test，ICT）对尿液中抗原进行检测，可实现15 min内快速床旁检测，敏感性和特异性分别可达80%和100%[41]。然而，UAT仅能检测出嗜肺军团菌血清组1的感染[42]。完全依赖该检测技术可能会造成漏诊，且在不同严重程度军团菌肺炎患者中的检测阳性率波动较大[43]。
随着分子检测技术的发展，核酸扩增技术广泛应用于军团菌的检测。聚合酶链反应（polymerase chain reaction，PCR）的应用打破了对病原体活性及种属的限制，实现了对受损或死亡病原体DNA的检测及对不同种军团菌的鉴别，特异性可达95%～100%，在军团菌肺炎暴发或流行病学调查中具有较好的应用价值[32, 44, 45]。部分军团菌肺炎患者无法提供足够的痰标本是该检测技术的主要限制因素，尝试获取诱导痰或可进一步提高诊断率[46]。环介导等温扩增技术（loop-mediated isothermal amplification，LAMP）优化了PCR检测的DNA提取及热循环过程，提高了检测敏感性，但其技术要求高，目前尚未在临床推广应用[47]。此外，既往病例已报道mNGS技术在军团菌肺炎病原学检测中的价值，其不仅可识别军团菌感染，还可同时实现对合并感染病原体的鉴定，尤其对极易合并多重病原体感染的免疫抑制患者抗感染治疗起到关键性指导作用[48,49]。然而其价格昂贵，目前仍未作为临床常规检测技术手段。
19-kU寡聚糖相关脂蛋白（peptidoglycan associated lipoprotein，PAL）是一种通过尿液排泄的可溶性抗原，Min等[50]研究提出对尿液中PAL进行检测似乎可协助军团菌肺炎诊断，通过浓缩尿液标本进行检测甚至可达100%检测敏感性。同样地，核糖体L7/L12[51]、白介素-17A（IL-17A）[52]等作为军团菌检测新兴标志物的研究也正在进行中。
为实现临床快速精准诊断，研究者们致力于探索较完备的军团菌肺炎临床诊断模型及评分系统，以指导临床实践。Cunha教授提出的WUH评分系统包含6个主要因素[53, 54]：①体温＞38.9℃伴相对缓脉；②血沉＞90 mm/h或C反应蛋白＞180 mg/L；③铁蛋白＞2倍正常值；④低磷血症；⑤磷酸激酶升高＞2倍；⑥入院时镜下血尿。当患者符合其中3项及以上，且对β-内酰胺类抗生素无效时，应高度怀疑军团菌肺炎，以此指导临床快速识别军团菌肺炎患者。
治疗
及时启动治疗对降低军团菌肺炎患者病死率、改善预后尤为重要。其救治成功的关键在于抗感染治疗的及时、恰当启动，呼吸衰竭、肾衰竭、中枢神经受累等并发症的防治，以及潜在合并症和风险因素的管理等方面[17]。
对于疑似军团菌肺炎者，在获得确切病原学依据前，应适时启动经验性抗感染治疗。ATS/IDSA指南推荐CAP经验性治疗时选择可覆盖非典型病原体，包括嗜肺军团菌的抗生素，如氟喹诺酮类（如左氧氟沙星、环丙沙星）或大环内酯类抗生素（如阿奇霉素、克拉霉素）[16]。目前尚无随机对照试验对比评估氟喹诺酮类与大环内酯类抗生素治疗军团菌肺炎的效果[3]，但Kato等[55]的一项meta分析发现相较于大环内酯类抗生素，氟喹诺酮类抗生素可显著缩短军团菌肺炎患者的住院时间，且似乎具有缩短发热时间、降低不良事件风险甚至病死率的趋势。因此，在无禁忌证的前提下，建议首选氟喹诺酮类抗生素（左氧氟沙星、环丙沙星）进行经验性治疗。
军团菌主要感染人类肺泡巨噬细胞，因此，针对军团菌选用的抗生素必须具有足够的体外杀菌活性、细胞内渗透性和对嗜肺军团菌的体内活性[22, 24]。目前已知常用于军团菌肺炎治疗的抗生素包括喹诺酮类、大环内酯类、多西环素、利福平和复方磺胺甲噁唑等[56]。其中，轻中度患者建议首选口服大环内酯类（阿奇霉素）或氟喹诺酮类抗生素（环丙沙星、左氧氟沙星或莫西沙星）；重症患者、免疫抑制患者或医院获得性军团菌肺炎患者，静脉应用氟喹诺酮类抗生素为首选[41, 57]。
随着大环内酯类和氟喹诺酮类抗生素耐药率的增加[58, 59]，新型抗生素不断被开发。甲苯磺酸奥玛环素（Omadacycline）是一种衍生自四环素的半合成氨基甲基环素抗生素[60]，对多种革兰氏阳性及阴性病原体均具有体外活性，且克服了传统四环素“外排泵”及“核糖体保护”两大耐药机制[61]。2018年美国食品药品监督管理局已批准其用于军团菌在内的非典型病原体肺炎的治疗[62]，未来甚至可能成为疑诊军团菌肺炎患者经验性治疗的潜在选择。
目前尚无氟喹诺酮类抗生素与大环内酯类抗生素联用可改善患者临床结局的证据[63, 64]，但有研究者推荐在克拉霉素基础上联用利福平，或在多西环素或氟喹诺酮单药治疗基础上联用复方磺胺甲噁唑或利福平[56, 65]。
中重度军团菌肺炎患者建议使用左氧氟沙星或阿奇霉素7～10天，免疫功能低下宿主则建议延长至21天[3]，直至患者临床稳定且无发热48小时以上可考虑停止治疗。
糖皮质激素作为军团菌肺炎的辅助治疗仍存在争议。ATS/IDSA并不建议常规启动激素治疗[31]。现有关于糖皮质激素的应用多局限于合并免疫缺陷疾病或急性呼吸衰竭、急性肾衰竭等危重并发症的军团菌肺炎患者[66, 67]。
ECMO是重症急性呼吸衰竭患者的潜在选择。在军团菌肺炎患者中，联合使用ECMO治疗的存活率可能高达80%以上[68, 69]。
大多数军团肺炎患者对治疗反应迅速，2～5天后退热[70, 71]。影像学吸收往往滞后于临床症状改善，通常持续数周甚至数月后才可完全吸收[22, 30]。当治疗效果欠佳时，需警惕多重菌感染或耐药性的产生，及时调整治疗方案。
军团菌肺炎是一种罕见但高病死率的肺部感染类型，精准识别疑似患者，及时进行病原学检测以采取恰当诊治，是降低病死率、改善远期预后的关键。
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作者简介
李园园
中南大学湘雅医院
副教授、副主任医师，医学博士，硕士生导师
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