謝新寶 朱燕鳳 王曉紅 俞 蕙 曾 玫 陸 怡 沈 軍 楊天嬌,2
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·論著·
兒童播散性隱球菌病8例臨床特征和預(yù)后
謝新寶1,3朱燕鳳1,3王曉紅1俞 蕙1曾 玫1陸 怡1沈 軍1楊天嬌1,2
目的探討兒童播散性隱球菌病的臨床特征和預(yù)后。方法回顧性分析2009年5月至2013年11月復(fù)旦大學(xué)附屬兒科醫(yī)院感染科收治的播散性隱球菌病患兒的臨床資料,總結(jié)臨床特征和預(yù)后。結(jié)果8例播散性隱球菌病連續(xù)病例進(jìn)入分析,男5例,女3例,平均年齡6.1歲。血清HIV抗體均陰性,流式細(xì)胞儀檢測CD4細(xì)胞計數(shù)正常。2例起病前曾口服糖皮質(zhì)激素,余6例否認(rèn)免疫抑制劑服用史及基礎(chǔ)疾病史。8例患兒家長均否認(rèn)鴿子或其他禽類接觸史。8例患兒起病均表現(xiàn)為持續(xù)發(fā)熱,7例有明顯的肝脾腫大,4例有黃疸,2例有咳嗽等呼吸道癥狀,2例服用糖皮質(zhì)激素患兒有皮膚損害,8例均無頭痛、嘔吐或意識改變等神經(jīng)系統(tǒng)癥狀。8例血清隱球菌抗原滴度均>1∶640,6例血培養(yǎng)結(jié)果示新型隱球菌陽性,4例CSF隱球菌抗原升高,5例外周血嗜酸性粒細(xì)胞計數(shù)升高。8例血清IgE均升高,平均3 896.5 KuA·L-1。3例影像學(xué)檢查提示累及膽道,肝內(nèi)膽管擴(kuò)張,胸部CT示7例累及肺部。8例起病至確診2~7周,均接受全身性抗真菌治療(兩性霉素B聯(lián)合5-氟胞嘧啶或氟康唑),其中1例治療后出現(xiàn)隱球菌相關(guān)性免疫重建炎癥綜合征,8例治療反應(yīng)良好。8例誘導(dǎo)治療結(jié)束后外周血嗜酸性粒細(xì)胞計數(shù)和血清IgE水平均恢復(fù)正常,停藥后隨訪3~6個月,均無復(fù)發(fā)。結(jié)論播散性隱球菌病可發(fā)生于無HIV感染的兒童,可累及多系統(tǒng)臟器,以單核-巨噬細(xì)胞系統(tǒng)和肺部受累多見。外周血嗜酸性粒細(xì)胞計數(shù)升高和血清IgE水平升高是本病實驗室檢查的顯著特點。
播散性隱球菌?。?兒童; 臨床特征; 預(yù)后
相對于成人,兒童隱球菌感染較少見[1];即使在HIV感染或AIDS人群中,兒童隱球菌感染率仍<1%,明顯低于成人5%~10%的感染率[2,3]。
越來越多的文獻(xiàn)報道新型隱球菌感染可發(fā)生于免疫功能正常的機(jī)體, 10%~44%的新型隱球菌感染成人患者不存在免疫功能低下的基礎(chǔ)疾病[4];同樣在無HIV感染的兒童中,也有報道發(fā)生隱球菌感染[5~13],以亞洲兒童報道居多,多局限于兒童中樞神經(jīng)系統(tǒng)感染或肺部感染,臨床表現(xiàn)為播散性隱球菌病的報道少見。本文回顧性分析復(fù)旦大學(xué)附屬兒科醫(yī)院(我院)感染科診治的8例無HIV感染播散性隱球菌病患兒的臨床資料,對其臨床特征和預(yù)后進(jìn)行討論和文獻(xiàn)回顧。
1.1 播散性隱球菌病診斷標(biāo)準(zhǔn) 2個或以上不相鄰的部位感染(病灶證據(jù))和血培養(yǎng)陽性和(或)血清隱球菌莢膜抗原高滴度或雙份血清有4倍以上升高[14]。
1.2 納入標(biāo)準(zhǔn) ①我院感染科住院患兒;②符合播散性隱球菌病診斷標(biāo)準(zhǔn)。
1.3 治療方案 參照美國感染病學(xué)會(IDSA)指南[15,16]的治療方案,誘導(dǎo)治療期給予兩性霉素B(或兩性霉素B脂質(zhì)體)聯(lián)合氟胞嘧啶(或氟康唑),療程>4周,待體溫恢復(fù)正常,臨床表現(xiàn)和實驗室指標(biāo)均好轉(zhuǎn)后,給予氟康唑鞏固和維持治療。
1.4 隨訪 要求患兒出院后2周來院隨訪,以后每隔1~2個月隨訪1次,隨訪內(nèi)容包括常規(guī)體檢、復(fù)查曾有異常的實驗室檢查指標(biāo),包括肝功能、血隱球菌抗原滴度等,并調(diào)整藥物劑量。
1.5 資料提取 回顧性翻閱病史,截取以下資料用于本文分析:①一般情況:性別、年齡;②臨床表現(xiàn):癥狀、起病至確診的時間;③既往史:生長發(fā)育、傳染病接觸史、外院診斷和治療情況;④實驗室和輔助檢查:截取入院后的首次檢測指標(biāo),包括血清隱球菌抗原、血液真菌培養(yǎng)、腦脊液檢查、血清轉(zhuǎn)氨酶、血清總膽紅素、血清IgE、外周血嗜酸性粒細(xì)胞計數(shù)、寄生蟲抗體、血清HIV抗體、流式細(xì)胞儀檢測CD4細(xì)胞計數(shù)、肝組織活檢、胸部CT、腹部CT或MRI檢查;⑤治療;⑥隨訪。
2.1 一般情況 2009年5月至2013年11月8例播散性隱球菌病連續(xù)病例進(jìn)入分析,男5例,女3例,年齡3.5~13.5歲,平均6.1歲。體格發(fā)育均正常。入院前4例診斷為發(fā)熱伴肝功能異常原因待查,3例診斷為發(fā)熱伴淋巴結(jié)腫大原因待查,1例診斷為發(fā)熱、皮疹原因待查。2例來我院就診前因皮疹在當(dāng)?shù)蒯t(yī)院就診并用糖皮質(zhì)激素0.3 mg·kg-1·d-11和2個月,余6例既往體健,否認(rèn)基礎(chǔ)性疾病史。8例患兒家長均否認(rèn)鴿子或其他禽類接觸史。
2.2 臨床表現(xiàn) 如表1所示,8例患兒起病均表現(xiàn)為持續(xù)發(fā)熱,從起病至確診2~7周,平均4.5周。例2和3有咳嗽等呼吸道癥狀和皮疹,來我院前應(yīng)用糖皮質(zhì)激素,其中例2皮膚損害明顯,全身可見散在大小不等的皰疹樣皮疹,胸前可見一融合皮膚損害約10 cm×2 cm,后背一融合皮膚潰瘍約10 cm×7 cm,皮疹滲出物涂片墨汁染色提示隱球菌陽性;例3皮疹較輕,為頭面及頸背部的散在斑丘疹。例1、2、6和7入院時以黃疸為主要癥狀,其中例7門診就診時考慮梗阻性黃疸,入住外科剖腹探查除外了腫瘤等梗阻性原因。7例(87.5%)伴有肝臟明顯腫大。8例均無頭痛、聽力缺失、驚厥和意識改變等神經(jīng)系統(tǒng)癥狀。
2.3 實驗室檢查 如表1所示,8例HIV抗體均陰性,血清隱球菌抗原(乳膠凝集法)檢測均陽性,滴度均>1∶640。6例(75.0%)血液真菌培養(yǎng)提示新型隱球菌生長。8例均行腰椎穿刺,4例CSF檢查證實存在隱球菌腦膜炎,CSF隱球菌抗原(乳膠凝集法)檢測陽性,滴度均>1∶640;例2、7和8 CSF墨汁染色陽性,CSF細(xì)菌培養(yǎng)均為陰性。5例血清轉(zhuǎn)氨酶升高,其中4例存在明顯膽汁淤積。例6肝組織活檢病理示肉芽腫炎癥,六胺銀染色陽性提示肝組織存在隱球菌感染(圖1A和B)。
8例血清IgE均高于正常(正常值 100 KuA·L-1),平均3 896.5 KuA·L-1,其中例4和5血清IgE>10 000 KuA·L-1。4例外周血嗜酸性粒細(xì)胞計數(shù)升高(正常值 400·mL-1),平均4 321·mL-1。8例血清均送至上海市中國疾病預(yù)防控制中心寄生蟲病預(yù)防控制所,檢測血清寄生蟲(包括囊蟲、肺吸蟲、華支睪吸蟲、血吸蟲、包蟲、旋毛蟲、弓形蟲、曼氏裂頭蚴、廣州管圓線蟲、絲蟲等)抗體均陰性。
2.4 影像學(xué)檢查 表1所示,7例行胸部CT檢查,均有肺部病變,表現(xiàn)為肺門、縱膈淋巴結(jié)腫大、胸腔積液、肺部滲出、肺部間質(zhì)改變及肺部網(wǎng)格狀影等。7例行腹部CT或MRI檢查,其中6例存在肝臟和(或)脾臟腫大及腹腔淋巴結(jié)腫大。例1、4和7影像學(xué)檢查提示累及膽道,肝內(nèi)膽管擴(kuò)張;例7腹部CT提示肝內(nèi)膽管彌漫性擴(kuò)張(圖1C)。
2.5 治療情況 8例患兒明確診斷后,均給予全身性抗真菌治療,治療約1周,體溫逐漸恢復(fù)正常。例2誘導(dǎo)治療選用兩性霉素B聯(lián)合氟康唑,例8選用兩性霉素B脂質(zhì)體聯(lián)合氟胞嘧啶,余6例誘導(dǎo)治療均為兩性霉素B聯(lián)合氟胞嘧啶(表1),均在靜脈滴注兩性霉素B時,給予地塞米松0.1 mg·kg-1·d-1減輕過敏反應(yīng)。待患兒耐受治療后逐漸減量并停用地塞米松 ,誘導(dǎo)期療程至少4周 。 例4和5在治療第2周因不耐受兩性霉素B改用兩性霉素B脂質(zhì)體,例5在治療第3周出現(xiàn)粒細(xì)胞明顯下降,停用氟胞嘧啶。例2和6誘導(dǎo)治療期間發(fā)生低鉀血癥,給予口服補(bǔ)鉀藥物后血清鉀恢復(fù)正常;誘導(dǎo)治療過程中,所有患兒血清腎功能檢測均正常。
圖1 肝穿刺病理發(fā)現(xiàn)和腹部MRI所見
Fig 1 Percutaneous liver biopsy findings and abdominal MRI scan
Notes A: Case 6 Inflammation and granuloma composed by multi-nuclear giant cells and lymphocytes were observed in the portal area (Hematoxylin-eosin, original magnification×400); B: The arrow showed teardrop budding and chains consisted ofCryptococcusneoformans(Gomori-methenamine sliver, original magnification×400); C: The fat suppressed abdominal MRI scan revealed inhepatic cholangiectasis
例8治療后第4周,再次出現(xiàn)了發(fā)熱、嘔吐和頭痛,抽搐1次,隨訪胸部X線片提示肺部炎癥加重,CSF常規(guī)檢查示W(wǎng)BC較前升高,考慮存在隱球菌相關(guān)性免疫重建炎癥綜合征(IRS),給予地塞米松0.3 mg·kg-1·d-1靜脈滴注,調(diào)整抗真菌藥物為兩性霉素B、氟康唑及氟胞嘧啶聯(lián)用2周,患兒體溫逐漸下降,病情好轉(zhuǎn),于4周后減停地塞米松。
在誘導(dǎo)治療結(jié)束后,8例血清IgE水平均恢復(fù)正常。例2和3皮膚損害患兒聯(lián)合外科清創(chuàng)治療后,皮膚損害好轉(zhuǎn)。例1、2、6和7患兒黃疸逐漸減輕,肝功能恢復(fù)正常,腫大的肝臟和脾臟逐漸回縮,淺表淋巴結(jié)逐漸變小。例1、2、4、6和7外周血嗜酸性粒細(xì)胞計數(shù)逐漸恢復(fù)至正常水平;隨訪胸部X線片或CT顯示肺部炎癥消失,肺部腫大的淋巴結(jié)亦逐漸縮小。
2.6 隨訪 8例均完成了誘導(dǎo)治療,病情改善并穩(wěn)定后出院,均在門診隨訪,給予氟康唑口服鞏固和維持治療,鞏固期10~12 mg·kg-1·d-1,療程8周;維持期6 mg·kg-1·d-1,療程6~12個月。停藥后隨訪3~6個月,均未復(fù)發(fā)。
新型隱球菌在人類無癥狀感染常見,兒童發(fā)生新型隱球菌感染大多為亞臨床型感染或在未察覺的情況下發(fā)生了感染[5]。1999年,美國學(xué)者報道采用ELISA方法,檢測了未感染HIV組(n=27,年齡1.6~15歲)和HIV感染組(n=34,年齡1.5~13歲)患兒的血清新型隱球菌莢膜多糖體抗原的抗體,發(fā)現(xiàn)兩組患兒血清IgG和IgM抗體均呈陽性,提示這些患兒在早期已經(jīng)接觸過新型隱球菌或發(fā)生過亞臨床型感染[17]。隨后有研究發(fā)現(xiàn),2~5歲免疫功能正常的兒童新型隱球菌莢膜多糖抗原抗體的陽性率>56%,>5歲兒童抗體陽性率>70%,表明在免疫功能正常兒童中,特別是>2歲的兒童中,大多數(shù)已經(jīng)感染過新型隱球菌[18]。
Joshi等[8]調(diào)查了2003至2008年美國42家州立兒童醫(yī)院收治的63例年齡<19歲的隱球菌病患兒,發(fā)現(xiàn)20.6%患兒免疫功能正常,63.5%存在基礎(chǔ)性疾病(包括腫瘤、實體器官移植、骨髓移植、囊性纖維化、系統(tǒng)性紅斑狼瘡等),僅15.9%的患兒存在HIV感染,表明在美國兒童隱球菌病大部分發(fā)生于未感染HIV者。類似的情況也見于中國的報道,Yuchong等[19]報道中國大陸地區(qū)1985至2010年8 796例隱球菌病患者中僅15.7%為AIDS或HIV感染者。本文8例患兒均無HIV感染,其中6例免疫功能正常,2例服用糖皮質(zhì)激素存在免疫抑制,與文獻(xiàn)報道的隱球菌病患者多無HIV感染這一情況相符。
除了感染累及肺部、中樞神經(jīng)系統(tǒng)、皮膚外,黃疸是本文患兒較突出的臨床表現(xiàn),4例存在明顯的膽汁淤積和肝功能異常,其中例7臨床表現(xiàn)類似梗阻性黃疸,例6肝組織活檢病理提示存在肝臟隱球菌感染;3例腹部CT或MRI明確存在肝和(或)脾腫大及肝內(nèi)膽管擴(kuò)張。隱球菌感染累及單核-巨噬細(xì)胞系統(tǒng),表現(xiàn)為肝和(或)脾腫大,特別是伴有肝內(nèi)膽管擴(kuò)張,甚至梗阻性黃疸的文獻(xiàn)報道不多,既往兒童報道更少見,僅見4例報道[20~23]。本文患兒在接受有效的抗真菌治療后,黃疸減退,肝功能好轉(zhuǎn),肝脾逐漸回縮,治療效果上亦符合隱球菌病診斷。
血清高IgE水平和明顯升高的外周血嗜酸性粒細(xì)胞計數(shù)是播散性隱球菌病的顯著特點。本文8例患兒均進(jìn)行了血清寄生蟲抗體檢測除外了寄生蟲感染。血液系統(tǒng)疾病(如淋巴瘤、白血病等)也會導(dǎo)致外周血嗜酸性粒細(xì)胞升高,但本文患兒均無這些疾病的特異性臨床表現(xiàn),在接受系統(tǒng)性抗真菌治療后,隨著臨床癥狀的好轉(zhuǎn),血清IgE水平和外周血嗜酸性粒細(xì)胞計數(shù)均恢復(fù)正常,提示血清高IgE水平和升高的嗜酸性粒細(xì)胞計數(shù)由隱球菌感染所致。國外也已有文獻(xiàn)報道HIV陰性的隱球菌病患者外周血嗜酸性粒細(xì)胞計數(shù)升高[24~27]。
目前國內(nèi)外關(guān)于兒童隱球菌病的報道不少,臨床表現(xiàn)多局限于腦膜炎或肺部感染,發(fā)生播散性感染的報道較少。本文6例血培養(yǎng)示新型隱球菌陽性,2例血培養(yǎng)陰性的患兒其血清隱球菌抗原滴度均≥1∶1 280,提示存在高真菌負(fù)荷,且感染累及中樞神經(jīng)系統(tǒng)、肺部、皮膚、肝臟和淋巴結(jié)等系統(tǒng)或器官中的至少2個,因此播散性隱球菌病診斷明確。
IDSA在2000年發(fā)布了隱球菌病的治療指南[15],并在2010年補(bǔ)充了關(guān)于兒童方面的治療[16]。本文播散性隱球菌感染病例根據(jù)2010年IDSA頒布的指南,誘導(dǎo)治療期均給予兩性霉素B(或兩性霉素B脂質(zhì)體)聯(lián)合氟胞嘧啶(或氟康唑),療程均>4周,給予系統(tǒng)性的抗真菌治療后,體溫在治療后1周左右逐漸恢復(fù)正常,誘導(dǎo)治療結(jié)束后臨床表現(xiàn)和實驗室指標(biāo)均明顯好轉(zhuǎn),完成鞏固和維持治療后,門診隨訪3~6個月均未復(fù)發(fā)。
IRS的典型臨床表現(xiàn)為淋巴腺炎、中樞神經(jīng)系統(tǒng)疾病加重, 或出現(xiàn)皮膚軟組織病灶。IRS可發(fā)生于隱球菌病患者合并HIV感染,接受高效抗逆轉(zhuǎn)錄病毒治療后,也可發(fā)生于免疫功能正常隱球菌病患者抗真菌治療過程中[28~31]。目前推薦的診斷標(biāo)準(zhǔn)包括:①在給予適當(dāng)有效治療的情況下,原有臨床表現(xiàn)再現(xiàn)或進(jìn)一步加重,或出現(xiàn)了新的炎癥性表現(xiàn);②出現(xiàn)的臨床表現(xiàn)不能用原有感染、新發(fā)感染以及治療的不良反應(yīng)來解釋[32]。目前,對IRS還沒有明確的治療方案,2000年IDSA發(fā)布的隱球菌病診治指南及病例系列報道推薦IRS經(jīng)驗性治療使用糖皮質(zhì)激素2~6周[16,31,33]。本文例8起初對抗真菌藥物治療反應(yīng)良好,予以兩性霉素B的最初2~3周同時給予小劑量地塞米松減輕藥物過敏反應(yīng);地塞米松停用后1周左右,又出現(xiàn)發(fā)熱、頭痛、抽搐和肺部炎癥加重,CSF細(xì)胞數(shù)增加,考慮存在IRS,在繼續(xù)抗真菌藥物的基礎(chǔ)上又給予4周小劑量地塞米松治療,患兒熱退,未再有頭痛、嘔吐及抽搐,隨訪肺部CT顯示肺部炎癥消失,腦脊液正常;復(fù)習(xí)該患兒的整個治療過程,符合IRS的特點。
本文患兒的臨床表現(xiàn)無特異性,均通過血清隱球菌抗原檢測得到了初步診斷的線索;隱球菌抗原(乳膠凝集法)檢測是一種簡便、快速、特異的實驗室診斷方法,在國內(nèi)外已得到廣泛應(yīng)用,其敏感度和特異度高達(dá)83%和100%[34]。若臨床上遇到發(fā)熱、肝脾和(或)淋巴結(jié)腫大患兒同時伴有升高的外周血嗜酸性粒細(xì)胞計數(shù)及高血清IgE水平時,應(yīng)考慮可能存在隱球菌感染,應(yīng)進(jìn)行隱球菌抗原檢測協(xié)助診斷。
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《中國循證兒科雜志》編輯部
2014年12月1日
Clinical features and prognosis of disseminated cryptococcosis in 8 children
XIEXin-bao1,3,ZHUYan-feng1,3,WANGXiao-hong1,YUHui1,ZENGMei1,LUYi1,SHENJun1,YANGTian-jiao1,2
(1DepartmentofInfectiousDiseases,Children′sHospitalofFudanUniversity,Shanghai201102,China; 2ShanghaiUnitedFamilyHomeHealth,Shanghai200336,China; 3Co-firstauthor)
YANG Tian-jiao,E-mail:tjyang87@fudan.edu.cn
ObjectiveTo investigate the clinical characteristics, treatment and outcome of disseminated cryptococcosis in nonhuman immunodeficiency virus-infected children. MethodsRetrospective study was performed to review the charts of 8 nonhuman immunodeficiency virus-infected children diagnosed as disseminated cryptococcosis in a tertiary care teaching hospital from May 2009 to November 2013.ResultsEight children with the average age of 6.1 years were recruited in the study, including 5 boys and 3 girls. Two children receiving corticosteroids were immunocompromised, other 6 children were immunocompetent. All had fever, 7/8 cases had hepatosplenomegaly, 4 cases had jaundice, 2 cases had cough, and skin lesions were initial and remarkable clinical features of the 2 immunocompromised children. None had symptoms of central nervous system (CNS) involvement. All had high titers of serum cryptococcal antigen with latex agglutination test at initial of admission, which was 1∶640 or higher, 6 cases had positive blood culture ofCryptococcusneoformans. Four cases were identified as CNS involved by cerebrospinal fluid examination. Five cases (62.5%) had notably increased eosinophil counts in peripheral blood, the serum levels of IgE were also elevated at the beginning of admission for all the patients. Three of 8 cases revealed a dilated intrahepatic bile duct by imaging examination, and 7 cases were identified pulmonary involved by chest CT scan. Inductive therapy with combination of amphotericin B (AmB) or lipid formulation of AmB (LFAmB) plus flucytosine or fluconazole was given. One case occurred immune reconstitution inflammatory syndrome after steroid withdrawal. All responded well to systemic antifungal therapy, both eosinophil counts and elevated serum IgE levels decreased after induction therapy. All children were followed up at outpatient clinic to continue consolidation and maintenance therapy with fluconazole. After cessation of therapy, none relapsed.ConclusionThe clinical manifestations of disseminated cryptococcsis in nonhuman immunodeficiency virus-infected pediatric patients are often nonspecific and variable. Reticuloendothelial system and lung are the most common sites of infection in the patients, followed by central nervous system, biliary tract, and skin. Elevated eosinophil counts of the peripheral blood and IgE levels are notable characteristics of the laboratory results.
Disseminated cryptococcosis; Children; Clinical feature; Prognosis
1 復(fù)旦大學(xué)附屬兒科醫(yī)院感染科 上海,201102; 2 現(xiàn)在上海和睦家家庭醫(yī)療工作 上海,200336;3 共同第一作者
楊天嬌,E-mail:tjyang87@fudan.edu.cn
10.3969/j.issn.1673-5501.2015.04.009
2015-04-30
2015-07-15)