任芳萍，劉玲莉，楊娟利，吳昌歸

成人哮喘患者血清25(OH)D3水平與哮喘控制程度的關(guān)系

任芳萍，劉玲莉，楊娟利，吳昌歸

目的 了解成人哮喘患者血清25-羥維生素D3[25(OH)D3]水平與治療前后肺功能改善程度的相關(guān)性，為哮喘控制提供新思路。方法 收集門(mén)診確診中度哮喘患者95例，入組后測(cè)定血清25(OH)D3濃度，給予沙美特羅替卡松(50 μg/250 μg)，1吸/次，1次/12 h，規(guī)范治療3個(gè)月。測(cè)定治療前后患者基礎(chǔ)肺功能，如第1秒用力呼氣容積占預(yù)計(jì)值百分比(FEV1% pred)和呼氣中段流速(FEF25%～75%)，并記錄治療前后哮喘控制測(cè)試(ACT)評(píng)分。對(duì)25(OH)D3濃度與治療前后FEV1% pred、FEF25%～75%以及ACT評(píng)分的改善情況進(jìn)行相關(guān)性分析。結(jié)果 入組患者95例，未按規(guī)定時(shí)間隨訪(fǎng)32例，未按醫(yī)囑規(guī)范治療23例，有效隨訪(fǎng)患者40例?；颊哐?5(OH)D3濃度與治療后FEV1% pred、FEF25%～75%和ACT評(píng)分的增加值均呈正相關(guān)(P<0.01)。結(jié)論 成人哮喘患者血清25(OH)D3濃度與哮喘治療反應(yīng)呈正相關(guān)。

哮喘；25-羥維生素D3；肺功能；ACT評(píng)分；相關(guān)性

支氣管哮喘(以下簡(jiǎn)稱(chēng)“哮喘”)是我國(guó)乃至全世界范圍內(nèi)最普遍的疾病之一，是特殊變應(yīng)原引發(fā)的以氣道炎癥、氣道高反應(yīng)(AHR)和氣道可逆性阻塞為特征的慢性疾病。雖然哮喘發(fā)病機(jī)制還不十分清楚，但既往的研究顯示其與免疫功能紊亂有關(guān)[1]，特別是Th1/Th2細(xì)胞平衡失調(diào)理論得到了廣泛認(rèn)可[2]。哮喘作為一種危害較大的氣道可逆性疾病，目前還無(wú)根治性辦法，其治療重點(diǎn)在于達(dá)到并維持臨床控制。臨床中我們發(fā)現(xiàn)，分級(jí)相同的哮喘患者對(duì)藥物的治療反應(yīng)也存在明顯差異，這種差異尚未得到合理解釋。

維生素D3是一類(lèi)脂溶性類(lèi)固醇化合物，主要參與鈣、磷吸收的調(diào)節(jié)。最近發(fā)現(xiàn)維生素D3也可對(duì)免疫細(xì)胞發(fā)揮調(diào)節(jié)作用，進(jìn)而影響哮喘發(fā)病過(guò)程[3-4]，初步的臨床研究發(fā)現(xiàn)其與哮喘的呼吸道癥狀相關(guān)[5-7]。然而，目前的研究主要集中于兒童人群，且主要關(guān)注維生素D3與哮喘發(fā)病的相關(guān)性，對(duì)于哮喘控制程度是否與維生素D3相關(guān)，尚未見(jiàn)相關(guān)報(bào)道。因此，本研究觀(guān)察了成人哮喘患者血清維生素D水平與治療前后哮喘控制程度之間的相關(guān)性。

1 對(duì)象與方法

1.1 研究對(duì)象 選擇2012年1月～2012年6月我科初診的慢性中度持續(xù)性哮喘患者95例。病例入選標(biāo)準(zhǔn)：年齡18～80歲；入選前4 w內(nèi)無(wú)使用全身糖皮質(zhì)激素；試驗(yàn)前1 w內(nèi)未口服或吸入長(zhǎng)效β2受體激動(dòng)劑，未應(yīng)用白三烯受體拮抗劑；能夠正確掌握藥物吸入方法；診斷符合中華醫(yī)學(xué)會(huì)呼吸病學(xué)分會(huì)哮喘學(xué)組2008年支氣管哮喘防治指南中哮喘中度持續(xù)的診斷標(biāo)準(zhǔn)[8]。排除標(biāo)準(zhǔn)：用藥依從性不佳者；未按規(guī)定時(shí)間隨訪(fǎng)；合并慢性疾病或嚴(yán)重的心、肝、腎疾病及其他臟器功能衰竭；有心理疾病或社會(huì)心理問(wèn)題，包括使用鎮(zhèn)靜劑。

1.2 治療方案 所有患者均給予吸入沙美特羅替卡松(50 μg/250 μg)，1吸/次，1次/12 h；并按需吸入短效β2-受體激動(dòng)劑沙丁胺醇?xì)忪F劑。連續(xù)治療3個(gè)月。

1.3 觀(guān)察指標(biāo)

1.3.1 血清25-羥維生素D3[25(OH)D3]水平的測(cè)定 所有受試者入組后即取晨起空腹靜脈血5 ml，以3000 r/min離心10 min，用電化學(xué)發(fā)光法(Cobas E411分析儀，羅氏)測(cè)定血清25(OH)D3濃度[25(OH)D3檢測(cè)試劑盒，羅氏]。與我院正常值標(biāo)準(zhǔn)(>30 ng/ml)進(jìn)行比對(duì)，分為不足(20～30 ng/ml)和缺乏(<20 ng/ml)。

1.3.2 肺功能測(cè)定 分別于患者治療前和治療后3個(gè)月測(cè)定肺功能。采用德國(guó)JAEGER MasterScreen肺功能儀測(cè)定：用力肺活量(FVC)、第1秒用力呼氣容積占預(yù)計(jì)值百分比(FEV1% pred)、呼氣中段流速(FEF25%～75%)等指標(biāo)。

1.3.3 哮喘控制測(cè)試評(píng)分(ACT) 分別于患者治療前和治療后3個(gè)月進(jìn)行ACT評(píng)分(表1)，通過(guò)回憶過(guò)去4 w內(nèi)有關(guān)自身哮喘病癥的相關(guān)情況，回答5個(gè)問(wèn)題，選擇每個(gè)問(wèn)題的得分，將分?jǐn)?shù)相加，計(jì)算出哮喘控制測(cè)試的總得分，并與說(shuō)明對(duì)照，就可獲得哮喘控制情況的評(píng)估結(jié)果。

1.4 隨訪(fǎng) 對(duì)所有患者進(jìn)行電話(huà)隨訪(fǎng)，1次/2 w，隨訪(fǎng)內(nèi)容為用藥依從性及飲食有無(wú)添加維生素D；治療滿(mǎn)3個(gè)月時(shí)門(mén)診隨訪(fǎng)，進(jìn)行肺功能檢測(cè)及ACT評(píng)分。

1.5 統(tǒng)計(jì)學(xué)方法 數(shù)據(jù)用SPSS 13.0統(tǒng)計(jì)軟件進(jìn)行統(tǒng)計(jì)處理，計(jì)量資料以均數(shù)±標(biāo)準(zhǔn)差表示，兩樣本均數(shù)比較采用t檢驗(yàn)；相關(guān)性檢驗(yàn)采用雙變量相關(guān)分析，P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 一般情況 入組患者95例，試驗(yàn)期間，未按規(guī)定時(shí)間隨訪(fǎng)32例，未按醫(yī)囑規(guī)范治療23例，有效隨訪(fǎng)患者40例。治療后FEV1% pred、FEF25%～75%、ACT分別增加(20.92±8.92)%、(0.64±0.60)L/s和11.20±3.16，與治療前相比均具有明顯差異(P<0.05)。

2.2 血清25(OH)D3水平與治療后FEV1% pred等指標(biāo)增加值的相關(guān)性分析 血清25(OH)D3與治療后FEV1% pred和FEF25%～75%增加值及ACT變化值呈正相關(guān)(r=0.445，r=0.477，r=0.557，P<0.01)。

3 討論

細(xì)胞學(xué)研究提示，維生素D3可調(diào)節(jié)免疫細(xì)胞、氣道上皮和平滑肌細(xì)胞的功能。在佝僂病患者中，低血清維生素D3水平與吞噬細(xì)胞活性降低有關(guān)[9]，并且可通過(guò)補(bǔ)充1,25-(OH)2D3而逆轉(zhuǎn)[10]。1,25-(OH)2D3可通過(guò)抑制活化B細(xì)胞的增殖并誘導(dǎo)其凋亡，穩(wěn)定B細(xì)胞[11]，也可抑制輔助T淋巴細(xì)胞的增殖[12]。氣道上皮細(xì)胞可將骨化二醇活化為骨化三醇，后者能夠抑制病毒感染后多聚免疫復(fù)合物誘導(dǎo)的趨化因子和細(xì)胞因子的產(chǎn)生，并維持抗病毒活性，對(duì)炎癥反應(yīng)起重要調(diào)節(jié)作用[13-14]。骨化三醇可以增加氣道平滑肌24-羥化酶的表達(dá)，還可抑制血小板衍生生長(zhǎng)因子誘導(dǎo)的氣道平滑肌DNA合成，且呈劑量依賴(lài)性[15]。引用美國(guó)全國(guó)健康和營(yíng)養(yǎng)調(diào)查數(shù)據(jù)，Keet等[16]發(fā)現(xiàn)維生素D3濃度與喘息癥狀和發(fā)生哮喘的風(fēng)險(xiǎn)呈負(fù)相關(guān)，維生素D3濃度每下降10 ng/ml，發(fā)生喘息的機(jī)會(huì)增加20%，發(fā)生哮喘的機(jī)會(huì)增加8%。研究還發(fā)現(xiàn)血清維生素D3濃度下降與肺功能下降、氣道對(duì)乙酰甲膽堿反應(yīng)性增加和激素治療的反應(yīng)性差相關(guān)[17-19]。

表1 哮喘控制測(cè)試評(píng)分

注：各題的分?jǐn)?shù)相加得總分。25分：完全控制；20～24分：部分控制；<20分：未控制

本研究結(jié)果顯示，給予沙美特羅替卡松(50 μg/250 μg)治療3個(gè)月后，患者肺功能和ACT評(píng)分均得到改善，且改善程度在血清維生素D3濃度較高患者中更加明顯。維生素D3對(duì)沙美特羅替卡松治療的增效機(jī)制尚未明確。有研究表明，補(bǔ)充維生素D3可以通過(guò)抑制肺內(nèi)炎性細(xì)胞因子，增加T細(xì)胞和樹(shù)突細(xì)胞分泌白介素-10，減輕免疫反應(yīng)性炎癥[19-21]。動(dòng)物實(shí)驗(yàn)顯示，維生素D3可以改善哮喘大鼠氣道高反應(yīng)性，降低血清IgE水平，減少支氣管肺泡灌洗液中嗜酸性粒細(xì)胞的浸潤(rùn)[22]。另有研究發(fā)現(xiàn)，維生素D3與地塞米松協(xié)同抑制哮喘大鼠氣道炎癥反應(yīng)，其機(jī)制可能與降低哮喘大鼠血清中IgE水平、減少局部IL-4和IL-5等細(xì)胞因子有關(guān)[23]。補(bǔ)充活性形式的維生素D3，可以增強(qiáng)地塞米松對(duì)T細(xì)胞表達(dá)IL-10的刺激作用，并誘導(dǎo)調(diào)節(jié)性T細(xì)胞，以抑制Th2細(xì)胞因子的過(guò)多釋放；在激素抵抗性患者，維生素D3可逆轉(zhuǎn)調(diào)節(jié)性T細(xì)胞的分化障礙[24]。有學(xué)者還證實(shí)，氟替卡松和骨化三醇聯(lián)合運(yùn)用較任一單用能更明顯抑制TNF-α和IFN-γ所致的RANTES分泌，骨化三醇可抑制氟替卡松誘導(dǎo)的趨化因子FKN的釋放[25]。

綜上，維生素D3水平與哮喘控制程度相關(guān)，補(bǔ)充維生素D3可能對(duì)提高哮喘控制水平有益。然而仍需要隨機(jī)、對(duì)照、干預(yù)性臨床試驗(yàn)來(lái)說(shuō)明維生素D3與哮喘發(fā)病的因果關(guān)系，為哮喘治療提供依據(jù)。

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Correlation between serum 25(OH)D3level and asthma control degree in adult patients with asthma

Ren Fangping,Liu Lingli,Yang Juanli,Wu Changgui

Department of Respiratory Disease,Xijing Hospital of the Fourth Military Medical University,Xi'an,Shanxi,710032,China

Objective To explore the correlation between serum 25(OH)D3level and improvement degrees of pulmonary function before and after the treatment in adult patients with asthma.Methods 95 patients diagnosed as moderate asthma were selected.Their concentration of serum 25(OH)D3was detected.They

inhalation with salmeterolticasone(50 μg /250 μg)(1 inhalation every 12 hours)for 3 months.Their basic pulmonary functions before and after the treatment were detected,such as the percentage of the forced expiratory volume at the first second in the predicted value(FEV1% pred)and the forced vital capacity(FEF25%-75%).The asthma control test(ACT)scores before and after the treatment were recorded.The correlations between serum 25(OH)D3concentration and the improvements in FEV1%pred,FEF25%-75%,and ACT sores were analyzed.Results Among the 95 cases,32 ones did not receive the follow-up on time;23 ones did not receive the treatment according to the physician's order;and 40 ones received the follow-up to the end of the study.There was positive correlation between serum 25(OH)D3concentration and the increases of FEV1% pred,FEF25%-75%,and ACT scores(P<0.01).Conclusion There is a positive correlation between serum 25(OH)D3concentration and the therapeutic reaction in adult patients with asthma.

asthma;25-hydroxyvitamin D3;pulmonary function;ACT score;correlation

710032 西安，第四軍醫(yī)大學(xué)西京醫(yī)院呼吸內(nèi)科

吳昌歸，E-mail：changgui@fmmu.edu.cn

R 562.25

A

1004-0188(2014)02-0138-03

10.3969/j.issn.1004-0188.2014.02.008

2013-12-20)