系統(tǒng)性紅斑狼瘡合并彌漫性肺泡出血一例并文獻復(fù)習(xí)

張利 竇艷娜 馬爽 肖靜 程根陽 劉棟 趙占正

·論著·

系統(tǒng)性紅斑狼瘡合并彌漫性肺泡出血一例并文獻復(fù)習(xí)

張利 竇艷娜 馬爽 肖靜 程根陽 劉棟 趙占正

目的 分析系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus，SLE)合并彌漫性肺泡出血(diffuse alveolar hemorrhage,DAH)的臨床特點，觀察血漿置換聯(lián)合激素救治該類患者的臨床療效，以提高對罕見病例的診療水平，避免誤診及延誤治療。方法 回顧性分析2015年8月12日鄭州大學(xué)第一附屬醫(yī)院收治的1例SLE合并DAH患者的臨床表現(xiàn)，觀察血漿置換聯(lián)合激素沖擊治療該患者的臨床療效，同時綜合分析國內(nèi)報道的101例SLE合并DAH患者的臨床表現(xiàn)、治療方案及其臨床效果。結(jié)果 本例20歲女性患者，臨床表現(xiàn)主要為發(fā)熱，痰中帶血，面頰部紅斑，伴陰道出血；實驗室檢查結(jié)果提示抗核抗體(antinuclear antibodies ,ANA)1∶1000，抗雙鏈DNA(anti double stranded DNA,ds-DNA)抗體陽性，抗Smith抗體陽性；貧血，血紅蛋白進行性下降；胸部CT示兩肺野見多發(fā)條片狀，斑點狀，結(jié)節(jié)狀密度增高影,邊緣模糊。診斷考慮SLE合并DAH，給予血漿置換聯(lián)合激素沖擊，同時給予人免疫丙種球蛋白應(yīng)用，患者咯血停止，面頰部紅斑消失，貧血較前明顯改善，目前口服糖皮質(zhì)激素并規(guī)律減量。我國文獻報道類似病例101例，具體描述患者臨床表現(xiàn)的有83例，這些患者中ANA均為陽性，抗ds-DNA抗體陽性者58例，咯血67例，發(fā)熱61例，腎臟受累71例，血紅蛋白下降74例，呼吸困難80例，低氧血癥70例。影像學(xué)均顯示肺部浸潤影。通過血漿置換、激素沖擊，免疫抑制劑等藥物的應(yīng)用，10例行血漿置換，7例有效；29例給予丙種球蛋白，21例有效；74例接受了大劑量激素沖擊，47例有效；21例使用了機械通氣，8例有效；49例給予免疫抑制劑，36例有效；12例使用了支氣管肺泡灌洗，10例有效。結(jié)論 DAH是SLE罕見且威脅生命的并發(fā)癥，盡早明確診斷，及時血漿置換聯(lián)合激素沖擊等對癥支持治療，積極防治并發(fā)癥，可有效改善患者的臨床表現(xiàn)及其預(yù)后。

系統(tǒng)性紅斑狼瘡; 彌漫性肺泡出血; 文獻復(fù)習(xí)

彌漫性肺泡出血(diffuse alveolar hemorrhage,DAH)是系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus，SLE)罕見而又威脅生命的并發(fā)癥，此病病情進展迅速，病死率高，但其臨床表現(xiàn)并不具有特異性，容易被誤診或漏診。我們收治了1例SLE合并DAH的患者，本文通過分析此病的臨床表現(xiàn)及診療經(jīng)過，并復(fù)習(xí)了相關(guān)文獻，討論了此類疾病的臨床表現(xiàn)及治療措施，以提高對此類疾病的認識，及早有效地搶救患者的生命及改善預(yù)后。

病 例 資 料

患者，女，20歲，因“間斷發(fā)熱1個月，不規(guī)則陰道出血4 d”于2015年8月12日入院。患者1個月前無明顯誘因出現(xiàn)發(fā)熱，體溫最高達40 ℃，無明顯咳嗽、咳痰，無口腔潰瘍、脫發(fā)、面部皮疹等癥狀,于當(dāng)?shù)卦\所給予退熱藥物應(yīng)用,體溫降至正常。4 d前無明顯誘因出現(xiàn)輕度頭痛，咳嗽，咳痰，痰中帶血, 為鮮紅色, 伴陰道出血，出血量大于月經(jīng)量，色鮮紅，伴血塊及乏力。體檢：體溫39℃，血壓78/38～102/67 mmHg，心率84次/min，雙側(cè)面部及鼻梁處可見散在紅斑，心臟各瓣膜聽診區(qū)未聞及明顯雜音，雙肺聽診可聞及散在濕啰音,雙腎區(qū)叩擊痛陰性，陰道持續(xù)出血，色鮮紅，如月經(jīng)量。血常規(guī)：白細胞計數(shù)(white blood cell,WBC)7.3×109/L，紅細胞計數(shù)(red blood cell,RBC) 3.97×1012/L,血紅蛋白113 g/L,血小板計數(shù)33×109/L。1 d后RBC 2.69×1012/L,血紅蛋白76 g/L(陰道出血量明顯減少)，11 h后血紅蛋白降至54 g/L。尿常規(guī):尿蛋白陰性，尿紅細胞0.66/μl，尿白細胞8.58/μl，24 h尿蛋白定量為0.03 g，丙氨酸氨基轉(zhuǎn)移酶175 U/L，天門冬氨酸氨基轉(zhuǎn)移酶>1 333 U/L，血白蛋白22.7 g/L，血尿素氮10.16 mmol/L，血肌酐51 μmol/L,活化部分凝血活酶時間(activated partial thromboplastin time,APTT)78.1 s,凝血酶原時間(prothrombin time,PT) 11.6 s (5 d后APTT 34.8 s, PT 9.10 s),CD4為120，CD4/CD8為0.81，補體C3為0.25 g/L，補體C4為0.02 g/L，Ⅶ因子活性202.8%(50%～129%), 紅細胞沉降率9.9 mm/h,C反應(yīng)蛋白95.12 mg/L，降鈣素原1.528 μg/L?？购丝贵w(antinuclear antibodies，ANA)1∶1000, 抗雙鏈DNA(anti double stranded DNA,ds-DNA)抗體, 抗Smith抗體陽性, ENA譜中其余抗體陰性?？怪行粤＜毎|(zhì)抗體、髓過氧化物酶、抗腎小球基底膜抗體、抗心磷脂抗體均陰性。影像學(xué)檢查：腹部彩超示肝輕度彌漫性回聲改變。心電圖：竇性心動過速，ST-T改變。子宮彩超：宮頸處不均質(zhì)稍高回聲(考慮積血)。胸部CT示：兩肺野見多發(fā)條片狀,斑點狀,結(jié)節(jié)狀密度增高影,邊緣模糊(見圖1A)。系統(tǒng)性紅斑狼瘡疾病活動度評分(systemic lupus erythematosus disease activity index,SLEDAI)為20分。診斷為：①系統(tǒng)性紅斑狼瘡合并彌漫性肺泡出血；②功能失調(diào)性子宮出血；③失血性低血壓。給予3次血漿置換，血漿置換量為2 600 ml每次(根據(jù)體質(zhì)量45 kg和紅細胞比容0.17計算)，同時給予隔天應(yīng)用甲潑尼龍0.5 g，3次，期間給予甲潑尼龍40 mg,每天2次,靜脈滴注；人免疫球蛋白針20 g，連用3 d；同時給予輸注紅細胞、縮宮素、比阿培南(后根據(jù)血培養(yǎng)結(jié)果改為莫西沙星)。患者咯血量較前減少，血紅蛋白趨于正常。入院2 d后患者陰道出血量減少并逐漸停止，但仍有間斷痰中帶血癥狀，遂于入院后第13天再次給予甲潑尼龍0.5 g，隔天應(yīng)用，連用3次；人免疫球蛋白針12.5 g，連用3 d。同時行氣管鏡檢查，未見出血點，氣管活檢提示真菌感染。

出院后患者規(guī)律服用潑尼松60 mg/d(3個月后減為50 mg/d，之后每1周減10 mg?，F(xiàn)為60 mg，隔天1次)，以及伏立康唑片0.2 g，口服，每天2次，共服1周。復(fù)查結(jié)果如表1及圖1B、圖1C、圖1D。

表1 患者隨訪結(jié)果

注:A:治療前;B:治療第4天;C:治療第7天;D:治療第28天圖1 患者胸部CT變化情況

討 論

DAH是SLE患者罕見卻威脅生命的并發(fā)癥，最早于1904年由Osler[1]報道。在SLE患者中的發(fā)病率為0.52%～5.7%[2-5]，其發(fā)病機制目前尚不明確，可能與免疫復(fù)合物導(dǎo)致肺泡毛細血管基底膜損傷和血管炎有關(guān)，還可能與繼發(fā)感染﹑充血性心力衰竭﹑神經(jīng)源性肺水腫﹑腎衰竭和顱內(nèi)高壓有關(guān)[6]。

SLE患者符合以下4條標(biāo)準中的至少3條即可診斷為SLE合并DAH：①肺部癥狀：咯血，呼吸困難，低氧血癥；②肺部影像學(xué)：新出現(xiàn)的肺部浸潤影；③原因不明情況下的血紅蛋白快速下降，24～48 h內(nèi)下降>15 g/L，且與咯血量不匹配；④支氣管鏡或支氣管肺泡灌洗液顯示出血或有含鐵血黃素巨噬細胞。本例患者臨床表現(xiàn)有發(fā)熱，面頰部紅斑，實驗室檢查示ANA 1∶1000，ds-DNA 抗體陽性,貧血等，符合SLE診斷，另患者痰中持續(xù)帶血，低氧血癥，胸部CT示兩肺野多發(fā)條狀、斑片狀﹑結(jié)節(jié)狀密度增高影?；颊哐t蛋白在12 h內(nèi)下降23 g/L。臨床排除了心力衰竭，肺栓塞及出凝血障礙，符合SLE合并DAH的診斷。

回顧性分析1996年至2012年我國文獻報道的101例SLE合并DAH，其中38例行支氣管鏡或支氣管肺泡灌洗，提示肺泡出血或含鐵血黃素巨噬細胞。研究表明SLEDAI大于10分可作為SLE合并DAH的獨立危險因素[5]，本例患者SLEDAI評分為20分。

根據(jù)既往的文獻報道，SLE合并DAH的發(fā)病年齡為11～62歲，平均年齡(29±14)歲，以青年女性多見，男女發(fā)病比例為4∶13[7]?；仡櫺苑治錾鲜?01例SLE并DAH患者，其中男性23例,女性78例，男女比例約為3∶10，其中年齡最小者為12歲男孩。本例患者為女性，發(fā)病年齡21歲，較平均年齡明顯提前。

SLE合并DAH的臨床表現(xiàn)多種多樣，其中文獻中具體描述患者臨床表現(xiàn)的有83例，這些患者中ANA均為陽性，抗ds-DNA抗體陽性者58例，咯血67例，發(fā)熱61例，腎臟受累71例，血紅蛋白下降74例，呼吸困難80例，低氧血癥70例。影像學(xué)均顯示肺部浸潤影。本例患者有咯血，發(fā)熱，ANA陽性，抗ds-DNA抗體陽性，并有頭痛，低氧血癥，血紅蛋白在24 h內(nèi)下降超過15 g/L。

SLE合并DAH患者的治療主要是激素聯(lián)合免疫抑制劑，多數(shù)專家推薦大劑量激素沖擊療法，接著是逐漸減量至維持口服激素劑量。免疫抑制劑首選環(huán)磷酰胺，推薦劑量為2 mg·kg-1·d-1，可維持使用數(shù)周，但應(yīng)注意其不良反應(yīng)[8]，嗎替麥考酚酯在維持疾病緩解中有一定作用[9]。有報道提出使用利妥昔單抗治療對常規(guī)免疫抑制劑耐藥的患者有效[10-14]。大劑量免疫球蛋白靜脈注射療法可作為一種強有力的輔助治療措施，其原理目前尚未明確，多與激素﹑免疫抑制劑及血漿置換等聯(lián)用有關(guān)[15-16]。 對于有持續(xù)性肺泡出血的患者可采用血漿置換術(shù)，其原理為清除其特異性自身抗體﹑可溶性免疫復(fù)合物以及參與組織損傷的非特異性炎癥介質(zhì)和免疫活性物質(zhì)，阻止上述物質(zhì)所導(dǎo)致的疾病進程,但Badsha等[17]指出血漿置換并不能提高SLE并DAH的生存率。表2為我們搜集的此類患者治療措施與預(yù)后的關(guān)系。

表2 不同治療方法對SLE合并DAH的治療效果

注：101例SLE合并DAH患者中，有些病例接受了以上6種治療方法中的幾種治療措施

SLE合并DAH的預(yù)后不良，可能與機械通氣，合并感染，激素及免疫抑制劑等藥物及SLEDAI有關(guān)[18]。另外，Claridge等[19]指出液體負荷量過多會使DAH加重，此時，應(yīng)謹慎增加液體負荷，以免使病情惡化。

總之,SLE合并DAH病情兇險,早期診斷、早期治療極為重要。對于不明原因發(fā)熱、出血的患者,進行免疫學(xué)血清指標(biāo)檢查排除SLE,有助于早期明確診斷,病情危重者使用血漿置換可以改善患者的預(yù)后。

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A case report and literature review of systemic lupus erythematosus with diffuse alveolar hemorrhage

ZHANGLi,DOUYan-na,MAShuang,XIAOJing,CHENGGen-yang,LIUDong,ZHAOZhan-zheng.

TheNephrologyCenteroftheFirstAffiliatedHospitalofZhengzhouUniversity,Zhengzhou450052,China

LIUDong,E-mail:liudong030@163.com

Objective To analyze the clinical characteristics of systemic lupus erythematosus (SLE) with diffuse alveolar hemorrhage (DAH), and to study the efficacy of plasmapheresis combined with hormone in SLE with DA in order to improve the level of diagnosis and treatment of rare cases, and avoid misdiagnosis and delayed treatment. Methods The clinical manifestations of 1 case of SLE with DAH in our hospital were reported, and the clinical effect of plasma exchange combined with corticosteroid for treatment of the patients was observed at the same time. A comprehensive analysis was done on DAH clinical manifestations, treatment and clinical effects of 101 Chinese SLE patients. Results This patient was a 20-year old female, and the main clinical manifestations were fever, bloody sputum, facial erythema, accompanied by vaginal bleeding. The laboratory test showed that the titer of anti-nuclear antibody (ANA) was 1:1000, anti-double stranded DNA (ds-DNA) antibody and anti-Smith antibody were both positive, and hemoglobin was progressively reduced. The chest CT showed two lung fields displayed more spiral shape and spot shape, nodule density increased shadow, and edge was blur. A diagnosis of SLE combined with DAH was made. She was given plasmapheresis combined with glucocorticoid, while giving the human normal immunoglobulin. Thereafter, hemoptysis stopped, facial erythema disappeared, anemia was significantly improved, and now she was given glucocorticoids and got reduction regularly. In our country, 101 cases were reported, and the specific clinical manifestations were described in 83 cases. These patient's ANA was all positive, 58 cases were positive for anti ds-DNA antibody, 67 cases presented with hemoptysis, 61 cases presented with fever, 71 cases presented with renal involvement, hemoglobin decreased in 74 cases, there were 80 cases of dyspnea, and 70 cases of hypoxemia. The imaging examination showed pulmonary infiltration. Through the treatment with plasmapheresis, hormone shock, immune inhibitors and other drugs, 10 patients underwent plasma exchange, 7 cases were effective; 29 cases were treated with gamma globulin, 21 cases were effective; 74 patients received high-dose corticosteroid, 47 cases were effective; 21 cases were given mechanical ventilation, 8 cases were effective; 49 cases were treated with immunosuppressive drugs, 36 cases were effective; 12 cases received the bronchoalveolar lavage, 10 cases were effective. Conclusions DAH is a rare and life-threatening complications of SLE. Early diagnosis, the use of plasmapheresis combined with hormone shock and other supportive treatment, preventing and treating the complications actively, will improve the patient’s clinical manifestations and prognosis effectively.

Systemic lupus erythematosus; Diffuse alveolar hemorrhage; Literature review

10.3969/j.issn.1671-2390.2017.03.006

河南省科技計劃項目(No.142300410232)

450052 鄭州，鄭州大學(xué)第一附屬醫(yī)院腎臟病中心 鄭州大學(xué)腎臟病研究所

劉棟，E-mail：liudong030@163.com

2016-04-09

2016-11-07)