2019, Vol. 46
2. 美国科罗拉多大学医学院病理系 阿罗拉市 80046
2. Department of Pathology, University of Colorado School of Medicine, Aurora 80046, USA
感染是导致皮肌炎/多肌炎(dermatomyositis/polymyositis, DM/PM)患者死亡的主要原因[2-5], 死亡率达27.7%, 其中半数死于真菌感染[6]。
侵袭性肺部真菌感染(invasive pulmonary fungal infections, IPFI)的临床表现常不典型, 早期缺乏特异性的诊断指标, 因此早期确诊十分困难, 许多患者因延误治疗而死亡。2009年ECIL专家问卷调查结果显示, 97%的专家认为经验性抗真菌治疗是有效的治疗方法[7]。因此, “2009年欧洲对白血病和造血干细胞移植受体的抗真菌治疗指南”中提出经验性抗真菌治疗的观点[8]。然而, 对皮肌炎合并IPFI患者进行经验性治疗是否能提高生存率的相关研究非常少, 亦无相关指南。我们对近年来复旦大学附属华山医院风湿免疫科经验性抗真菌治疗的皮肌炎合并IPFI患者进行临床分析, 以期为经验性治疗提供临床证据。
资料和方法一般资料 收集2011年11月至2017年6月我院风湿免疫科收治的皮肌炎合并IPFI患者15例, 其中男性患者4例, 女性患者11例, 平均年龄51.3岁。
诊断标准
皮肌炎的诊断标准 采纳1975年Bohan标准[9]。根据起病时临床资料, 15例患者中确诊14例, 其中13例具备典型的皮肌炎皮疹+对称性四肢近端肌无力+肌酶升高+肌电图示肌源性损害改变, 1例患者在上述基础上肌活检证实有活动性肌炎改变; 拟诊1例, 具备典型的皮肌炎皮疹+对称性四肢近端肌无力+肌酶升高。
侵袭性肺部真菌感染诊断标准 采用分级诊断模式, 诊断依据有宿主因素、临床证据、微生物学证据和组织病理学证据4部分组成, 分为确诊、临床诊断和拟诊[1]。
治疗方法
真菌治疗方案 所有患者达到IPFI拟诊或临床诊断标准均给予经验性抗真菌治疗。抗真菌治疗方案:4例患者痰真菌培养结果为念珠菌感染, 单用氟康唑治疗; 2例患者肝酶升高, 改用卡泊芬净; 1例患者影像学怀疑曲霉菌感染, 单用伏立康唑; 5例患者怀疑合并肺孢子菌感染, 合用SMZco治疗; 5例患者病情较重, 合用抗曲霉真菌药物治疗, 其中4例患者影像学检查怀疑为曲霉菌感染, 1例患者痰培养曲霉菌。
真菌治疗用法和用量 氟康唑:400 mg (ivgtt qd); 卡泊芬净:第1天70 mg (ivgtt qd), 第2天起50 mg (ivgtt qd); 伏立康唑:第1天200 mg (ivgtt), 每12 h 1次, 第2天起200 mg (ivgtt qd); 伊曲康唑:第1天200 mg (ivgtt), 每12 h 1次, 第2天起200 mg (ivgtt qd); 两性霉素B:25 mg (ivgtt qd); 泊沙康唑:10 mL (400 mg) bid口服。疗程:6~55天。
合并感染治疗 15例患者抗真菌感染均同时合用抗生素治疗, 5例患者合用抗病毒治疗。
支持治疗 14例患者用大剂量丙种球蛋白治疗, 15例病例有低白蛋白血症, 输注白蛋白以缓解低白蛋白血症。
观察指标 治疗开始时每日观察并记录患者的体温、咳嗽、咳痰等症状及体征, 定期监测血常规、肝肾功能、电解质、血气分析、痰涂片和培养、G试验和GM试验等指标, 并随访胸部CT。
疗效评判标准[10] 痊愈:侵袭性真菌感染的症状和体征完全消失及完全或近完全影像学表现消失; 显效:绝大部分侵袭性真菌感染的症状和体征改善或消失及至少50%影像学表现改善或消失; 进步:侵袭性真菌感染的症状和体征得到改善, 但低于50%影像学表现改善或消失; 无效:用药72 h后侵袭性真菌感染的症状和体征无好转或加重及影像学表现无吸收甚至扩大。以治愈率和显效率之和计算有效率。
结果一般情况 15例患者中临床诊断2例, 拟诊13例, 2例临床诊断患者符合宿主因素+临床依据+微生物学依据; 13例拟诊患者符合宿主因素+临床依据。
15例患者IPFI的各自诊断依据可简要概括为表 1。15例患者都有宿主因素:诊断之前30天内曾经或正在接受免疫抑制剂治疗, 持续应用类固醇激素3周以上(最少4周, 最长524周); 15例患者均有IPFI的临床特征:1项主要临床特征或2项次要临床特征; 12例患者符合IPFI影像学依据, 10例有靠近胸膜的新发浸润病灶, 符合次要影像学表现, 2例符合主要影像学表现。15例患者均有活动胸闷、气促, 血气分析显示7例患者有Ⅰ型呼衰, 8例患者有低氧血症。2例患者临床诊断有微生物学依据:1例2次G试验阳性; 1例2次直接镜检发现菌丝, 2次真菌培养阳性。
| Cases | Clinical diagnosis/suspect | Host factors | Pulmonary infection-related presentations | Microbiology testing | Treatment regimens | |
| Primary features | Secondary features | |||||
| 1 | Suspect | Yes | Subpleural nodule with cavity | Cough and expectoration, double lung rale, Ⅰ-type respiratory failure | G test positive once Sputum culture candida twice | Caspofungin, 19 d; amphotericin B, 19 d; posaconazole, 19 d |
| 2 | Suspect | Yes | Ground-glass attenuation, hypoxemia | High density shadow under the pleura | G test positive once | SMZ 3#tid 6 d, fluconazole, 6 d |
| 3 | Suspect | Yes | Ⅰ-type respiratory failure | Fever for 96 hours with no response to antibiotic therapy, cough and expectoration, double lung rale, high density shadow under the pleura | Caspofungin, 19 d; Posaconazole, 9 d | |
| 4 | Suspect | Yes | Ground-glass attenuation, Ⅰ-type respiratory failure | Fever for 96 h with no response to antibiotics, cough and expectoration, double lung rale, two lung plaques shadow | G test positive once, Sputum fungal smear positive once, Sputum culture candida once | Fluconazole, 17 d; SMZ2#, bid, 7 d |
| 5 | Diagnosis | Yes | Ground-glass attenuation, Ⅰ-type respiratory failure, pulmonary nodules with cavity | Cough and expectoration, double lung rale | Spores observed in sputum fungal smear twice Sputum culture candida twice | SMZ 3#, qid, 5 d; 3#, tid, 2 d; fluconazole, caspofungin, and voriconazole |
| 6 | Suspect | Yes | Ground-glass attenuation, hypoxemia | Double lung subpleural plaque, fever for 96 h with no response to antibiotics | Fluconazole, 15 d | |
| 7 | Suspect | Yes | Ⅰ-type respiratory failure | Fever for 96 hours with no response to antibiotic therapy, cough and expectoration, double lung rale | Sputum culture candida once | Fluconazole, 12 d |
| 8 | Suspect | Yes | Diffuse Ground-glass attenuation, hypoxemia | Fever for 96 h with no response to antibiotics, cough and expectoration, double lung rale | Sputum culture candida once | SMZ 3#, tid 6 d, itraconazole, 19 d; voriconazole, 36 d |
| 9 | Suspect | Yes | Ⅰ-type respiratory failure | Double lung subpleural plaque, fever for 96 h with no response to antibiotic therapy, cough, Sputum drawing, dyspnea | G test positive once | SMZ 1#, tid, 3 d, itraconazole, 19 d |
| 10 | Diagnosis | Yes | Ground-glass attenuation, hypoxemia | Cough, sputum drawing, dyspnea, high density shadow under the pleura | G test positive twice | Voriconazole, 11 d |
| 11 | Suspect | Yes | Ground-glass attenuation, Ⅰ-type respiratory failure | Cough and expectoration, double lung rale, 2 high-density nodular infiltrates in the right lung | G test positive once sputum culture candida once | Caspofungin, 15 d |
| 12 | Suspect | Yes | Ground-glass attenuation, hypoxemia | Right subpleural high-density nodule infiltration, cough, sputum drawing, dyspnea | G test positive once spores observed in sputum fungal smear twice GM positive once | Itraconazole, 5 d; voriconazole, 29 d; caspofungin, 14 d |
| 13 | Suspect | yes | Hypoxemia | Near the left pleural high-density nodules infiltrate shadow, cough and expectoration, double lung rale | Spores observed in sputum fungal smear twice sputum culture candida once | Fluconazole, 19 d |
| 14 | Suspect | Yes | Hypoxemia | Fever for 96 h with no response to antibiotics, right pleural infiltration shadow, cough and expectoration | G test positive once aspergillus flavus in sputum culture once | Caspofungin, 17 d |
| 15 | Suspect | Yes | Hypoxemia | Fever for 96 h with no response to antibiotics, cough and expectoration, chest tightness, dyspnea | G test positive once | Fluconazole, 13 d |
3例根据痰培养结果临床诊断肺部感染, 7例合并巨细胞病毒感染, 巨细胞病毒感染诊断标准为CMV-DNA>103拷贝。
抗真菌治疗时15例患者均有新发的皮肌炎皮疹伴肌酶升高, 8例患者肌电图有肌源性受损害表现, 6例未查肌电图, 15例患者均合并间质性肺炎, 其中13例为活动性间质性肺炎。抗真菌治疗时皮肌炎的活动情况和治疗情况见表 2。所有患者皮肌炎病程为1个月至10年余。
| Cases | Lung lesions detected by imaging | CPK (38-174U/L) |
LDH 106-211U/L) |
Myogenic injury by electromyogram | New skin rash | Hormone dosage | Immunosuppressant, biologics | Gamma globulin impact therapy |
| 1 | Multi strip patch shadow | 530 | 672 | No | Heliotrope rash, Gottron rash | 40 mg | No | Yes |
| 2 | Multiple interstitial changes | 14 | 239 | Yes | Heliotrope rash, gottron rash, shawl rash, mechanic’s hand | 60 mg | Hydroxychloroquine, tacrolimus | Yes |
| 3 | Ground glass shadow | 38 | 552 | N/A | Heliotrope rash, gottron rash | 40 mg | Hydroxychloroquine, ciclosporin | Yes |
| 4 | Gridding and grinding glass | 6 594 | 795 | Active | Heliotrope rash, v-shaped rash, gottron rash | 40 mg | Hydroxychloroquine, Azathioprine | Yes |
| 5 | Diffuse glass shadow | 23 | 433 | Yes | Heliotrope rash, v-shaped rash, gottron rash | 40 mg | MabThera 500 mg, cellcept | Yes |
| 6 | Scattered in the grind glass shadow | 131 | 294 | N/A | Heliotrope rash, gottron rash | 24 mg | Tacrolimus | No |
| 7 | Multiple grid, honeycomb, fiber strip shadow | 43 | 397 | Yes | Heliotrope rash, gottron rash | 40 mg | Methotrexate, hydroxychloroquine | Yes |
| 8 | Grind glass | 661 | 279 | N/A | Mechanic’s hand, gottron rash | 40 mg | Tacrolimus | Yes |
| 9 | Mesh, patch shadow | 29 | 294 | Yes | Heliotrope rash, shawl rash, gottron rash | 40 mg | Hydroxychloroquine, tacrolimus | Yes |
| 10 | Multiple grind glass shadow, patch shadow | 180 | 283 | N/A | Heliotrope rash, gottron rash | 60mg | Ciclosporin | Yes |
| 11 | Mild interstitial changes | 100 | 251 | N/A | Heliotrope rash, gottron rash | 40 mg | No | Yes |
| 12 | Multiple grind glass shadow, patch shadow | 82 | 359 | Yes | Heliotrope rash, gottron rash, v-shaped rash | 80 mg | Hydroxychloroquine, cellcept | Yes |
| 13 | Scatter in fibrous cord | 29 | 250 | N/A | shawl rash | 24 mg | No | Yes |
| 14 | Diffuse grid shadow | 1 234 | 1 069 | Mild | Mechanic’s hand, gottron rash | 40 mg | No | Yes |
| 15 | Fibrous cord | 171 | 386 | Yes | Shawl rash, v-shaped rash | 60 mg | No | Yes |
临床疗效 经治疗, 出院前15例IPFI患者的临床症状、体征及血气指标都得到明显改善(表 3):8例发热患者出院前体温都达到正常, 13例咳嗽、咳痰、肺部啰音患者症状体征明显缓解, 15例胸闷气促患者症状明显缓解, 7例Ⅰ型呼衰得到纠正, 8例低氧血症得到明显改善; 8例侵袭性肺部真菌感染影像学病灶吸收大于50%, 4例影像学病灶吸收小于50%;根据疗效评判标准:11例患者显效, 4例患者进步, 有效率为73%。
| Clinical features | Cases with features (n) | Cases with complete recover (n) | Cases with significant improvement (n) | Cases with mild improvement (n) |
| Fever | 8 | 8 | ||
| Cough and expectoration, double lungrale | 13 | 13 | ||
| Chest distress, inhalation | 15 | 15 | ||
| IPFI imaging lesions | 10 | 6 (50% improvement) | 4 | |
| Hypoxemia/I-type respiratory failure | 8/7 | 7 (correcting Ⅰ-type respiratory failure) | 8 (improvement in hypoxemia) | |
| Positive sputum fungus smear twice | 1 | 1 | ||
| Sputum fungal smear positive twice | 1 | 1 | ||
| Neutropenia | 1 | 1 |
文献报道[11], 102例DM/PM ICU住院患者急性呼吸衰竭的发生率为80.4%, 死亡率为79.4%, 其中皮肌炎患者的死亡率高于多肌炎患者。包括IPFI在内的机会感染以及快速进展的间质性肺炎是皮肌炎患者死亡的主要原因。
国内的研究资料显示[12], 15 407例DM/PM住院患者感染的相对危险度OR=3.4 (95%CI:2.9~4.0), 细菌感染的相对危险度OR=3.5 (95%CI:3.0~4.1), 真菌感染的相对危险度OR=2.5 (95% CI:1.5~4.0)。
根据IPFI的诊断标准[1], 早期诊断依据是临床依据(包括影像学)和微生物学依据(痰真菌涂片和培养、G试验和GM试验)。然而, 皮肌炎合并IPFI早期缺乏特异性的诊断指标, 痰涂片和培养阳性率不高, 且有污染可能; G试验敏感度高, 但特异度低; GM试验虽然特异度高但阳性率不高, 尤其是合并间质性肺炎时, 影像学上很难与间质性肺炎加重相鉴别。本研究15例患者均合并间质性肺炎, 其中13例合并活动性间质性肺炎。皮肌炎间质性肺炎合并IPFI起病急、进展快, 许多患者的因延误治疗在起病1周内死亡。因此, 为提高皮肌炎间质性肺炎患者的生存率, 需要掌握皮肌炎合并IPFI的早期临床特征和危险因素, 做到早防、早治。
本研究的全部病例早期均有胸闷、气促症状, 血气分析都有低氧或Ⅰ型呼衰依据, 提示除发热、咳嗽及痰拉丝外, 持续性低氧血症或Ⅰ型呼衰是皮肌炎合并IPFI早期识别的依据; 根据文献[1], 侵袭性真菌感染临床特征包括主要特征:(1)胸部CT影像学特征为:早期出现胸膜下密度增高的结节实变影, 数天后病灶周围可出现晕轮征, 10~15天后肺实变区液化、坏死, 出现空腔阴影或新月征(图 1A), 皮肌炎间质性肺炎也会出现胸膜下高密度影, 鉴别要点在于皮肌炎间质性肺炎是双侧对称的胸膜下高密度影, 不会有晕轮、空腔影和新月征。(2)肺孢子菌肺炎的胸部CT影像学特征为两肺出现毛玻璃样肺间质病变征象, 伴有低氧血症, 与皮肌炎间质性肺炎的鉴别要点在于前者是弥漫毛玻璃改变, 部分患者可见散在薄壁圆形囊腔(图 1B)。本研究10例患者出现单侧新发胸膜下高密度浸润影或结节影, 提示单侧新发胸膜下高密度浸润影或结节影是皮肌炎合并IPFI另一早期识别依据。
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| A:That the left lung subpleural high-density shadow had a cavity of cases 1;B:Thin-walled circular capsule space showed on the two lungs filled with ground-glass opacity of case 5. 图 1 2例皮肌炎合并IPFI患者的胸部CT Fig 1 Chest CT images of two cases of dermatomyositis combined with IPFI |
本研究的全部患者在达到早期诊断标准(临床诊断和拟诊)情况下即给予经验性抗真菌治疗, 其中大部分因为只有1次G试验和或GM试验阳性、1次痰真菌涂片和或培养阳性而只能诊断为拟诊患者, 在没有充分微生物学依据情况下, 根据肺部感染的症状和体征、持续性低氧血症或Ⅰ型呼衰、影像学依据即给予抢先治疗, 全部患者的症状、体征、氧分压、血氧饱和度均得到明显好转, 一半以上患者影像学好转大于50%, 根据疗效评判标准有效率达到73%。
因此, 皮肌炎合并IPFI诊治要及时, 可以参照侵袭性肺部真菌感染的诊断标准与治疗原则[1], 对临床诊断和拟诊患者进行经验性治疗, 尤其是尚无微生物学依据的拟诊患者, 这样可以大大提高皮肌炎合并感染患者的生存率; 抗真菌治疗的剂量要充足, 疗程要长; 念珠菌感染首选氟康唑; 曲霉菌感染首选伏立康唑; 肝肾功能不全患者可用卡泊芬净; 严重感染可以合用多种抗真菌药; 皮肌炎合并IPFI往往合并细菌和病毒感染, 需要联合应用抗生素和抗病毒治疗。本研究中所有患者均有新发的皮肌炎皮疹、肌酶增高、合并有间质性肺炎, 提示原发病活动, 11例患者用大剂量激素控制原发病, 2例患者由于皮肌炎重度活动给予激素冲击治疗, 2例患者由于皮肌炎轻度活动给予中等剂量激素, 抗真菌治疗时激素剂量调整到0.5~1 mg/kg, 控制原发病有利于控制感染, 大剂量丙种球蛋白能够同时帮助控制原发病和感染, 加强支持治疗纠正低白蛋白血症能帮助控制感染。
文献证实[13]侵袭性真菌感染的易感因素包括:基础疾病, 长期应用广谱抗生素和糖皮质激素, 免疫抑制剂, 侵入性操作, 环境因素如空调污染、密切接触鸽类。回顾性分析研究[6]显示:每天使用30 mg以上强的松超过3个月、抗生素治疗以及间质性肺炎是结缔组织病肺部侵袭性真菌感染的危险因素。因此, 避免空调机污染、避免接触鸽类; 漱口保持口腔清洁, 制霉菌素甘油涂抹口腔黏膜能预防侵袭性真菌感染。
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