IFN-α/γ在24～72h內(nèi)對上呼吸道感染兒童中性粒細胞的影響

張開京，曾工博，呂曉娟

IFN-α/γ在24～72h內(nèi)對上呼吸道感染兒童中性粒細胞的影響

張開京1，曾工博2，呂曉娟1

1.杭州市兒童醫(yī)院血液科，浙江杭州 310005；2.杭州市兒童醫(yī)院檢驗科，浙江杭州 310005

探討上呼吸道感染時干擾素（interferon，IFN）-α和IFN-γ對24～72h血液中性粒細胞的影響。選取2020年1月至2022年8月于杭州市兒童醫(yī)院診治的上呼吸道感染患兒92例，根據(jù)24～72h內(nèi)中性粒細胞水平將其分為ANC組（中性粒細胞<1000×106/L，49例）和NT組（中性粒細胞≥1000×106/L，43例）。收集患兒的臨床資料，采用多因素Logistic回歸分析影響患兒中性粒細胞的危險因素，對最終篩選出的因素進行受試者操作特征曲線（receiver operating characteristic curve，ROC曲線）分析。NT組患兒的年齡大于ANC組，IFN-α、IFN-γ水平低于ANC組（<0.05）。多因素Logistic回歸分析結(jié)果顯示IFN-α和IFN-γ升高均是24～72h血液中性粒細胞減少的獨立危險因素（<0.05）。ROC曲線顯示，IFN-α、IFN-γ預測中性粒細胞減少的曲線下面積分別為0.734和0.719，兩者均有較高的預測價值。IFN-α和IFN-γ可預測上呼吸道感染患兒的中性粒細胞水平，且均是患兒中性粒細胞減少的獨立危險因素。

干擾素-α；干擾素-γ；中性粒細胞減少

干擾素（interferon，IFN）是糖蛋白家族成員之一，分為Ⅰ型、Ⅱ型和Ⅲ型。Ⅰ型主要為IFN-α、IFN-β，Ⅱ型主要為IFN-γ[1]。既往研究發(fā)現(xiàn)Ⅰ型和Ⅱ型IFN對腫瘤、病毒、微生物均有一定的對抗作用[2-5]。然而最近的研究發(fā)現(xiàn)當IFN-γ過度表達時對人體的骨髓造血有抑制作用[6]。IFN表達升高刺激下游的信號轉(zhuǎn)導及轉(zhuǎn)錄活化因子1（signal transducer and activator of transcription 1，STAT1）磷酸化，適量的STAT1磷酸化可促進中性粒細胞分化，但STAT1過度磷酸化對髓系祖細胞有抑制作用[7-9]。IFN-α和IFN-γ擁有共同的STAT1信號通路[10]，當人體受到病原體感染導致IFN-α、IFN-γ升高時，可抑制造血功能從而導致血液中中性粒細胞減少。中性粒細胞在人體循環(huán)中的半衰期為5～10h，因此，當IFN-α、IFN-γ升高抑制骨髓造血繼而影響血液循環(huán)中的中性粒細胞至少需要5h以上的時間[11]。本文回顧性分析上呼吸道感染時IFN-α、IFN-γ水平對血液中中性粒細胞數(shù)量的影響，現(xiàn)將結(jié)果報道如下。

1 資料與方法

1.1 研究對象

收集2020年1月至2022年8月于杭州市兒童醫(yī)院診治的上呼吸道感染患兒92例，患兒入院后未使用抗生素（如青霉素類、頭孢類藥物等）和抗病毒藥物（如阿昔洛韋、奧司他韋、IFN等），未應用免疫球蛋白、糖皮質(zhì)激素藥物；排除白血病、造血功能障礙、先天性中性粒細胞缺乏等骨髓造血功能異常疾病。本研究經(jīng)杭州市兒童醫(yī)院醫(yī)學倫理委員會審核通過[倫理審批號：（2019）年倫審（臨研）第（1）號]，所有患兒家屬均簽署知情同意書。

1.2 方法

收集患兒的臨床資料，采用乳膠增強免疫透射比濁法測定C反應蛋白（C-reactive protein，CRP）水平；采用流式細胞儀阻抗法測定白細胞計數(shù)（white blood cell count，WBC）。在NAVIO流式細胞儀（Beckman Coulter）中使用細胞因子12項試劑盒（Raisecare）檢測細胞因子水平。收集患兒入院當天白細胞介素（interleukin，IL）-1β、IL-6、IL-8、腫瘤壞死因子-α（tumor necrosis factor，TNF-α）、IFN-α、IFN-γ、CRP及隨后24～72h內(nèi)檢測的中性粒細胞。將中性粒細胞<1000×106/L者納入ANC組（49例），中性粒細胞≥1000×106/L者納入NT組（43例）。

1.3 統(tǒng)計學方法

采用SPSS 26.0軟件對數(shù)據(jù)進行統(tǒng)計學分析。計量資料數(shù)據(jù)不符合正態(tài)分布，采用中位數(shù)（四分位數(shù)間距）[（1，3）]表示，比較采用非參數(shù)檢驗；計數(shù)資料采用例數(shù)（百分率）[（%）]表示，比較采用2檢驗。將ANC組定義為0，NT組定義為1，分別對IL-1β、IL-6、IL-8、TNF-α、IFN-α、IFN-γ進行單因素分析，根據(jù)是否<0.2對數(shù)據(jù)進行篩選；對篩選后的數(shù)據(jù)進行多因素Logistic回歸分析，以<0.05確定獨立危險因素。對最終篩選出的獨立危險因素進行受試者操作特征曲線（receiver operating characteristic curve，ROC曲線）分析。

2 結(jié)果

2.1 兩組患兒的臨床資料比較

NT組患兒的年齡大于ANC組，IFN-α、IFN-γ水平低于ANC組（<0.05），見表1。

2.2 多因素Logistic回歸分析

結(jié)果顯示IFN-α和IFN-γ升高均是24～72h血液中中性粒細胞減少的獨立危險因素（<0.05），見表2。

表2 多因素Logistic回歸分析

2.3 IFN-α、IFN-γ預測中性粒細胞減少的效能

ROC曲線顯示，IFN-α、IFN-γ預測中性粒細胞減少的曲線下面積（area under the curve，AUC）分別為0.734和0.719，兩者均有較高的預測價值，見表3。

表1 兩組患兒的臨床資料比較

表3 IFN-α、IFN-γ預測中性粒細胞減少的ROC曲線

3 討論

中性粒細胞是人體的第一道防線，在病原體入侵時可非特異性殺滅包括細菌、真菌和病毒在內(nèi)的病原微生物[12-14]。中性粒細胞減少時機體處于易感狀態(tài)，兒童的免疫功能尚未發(fā)育成熟，因此更容易出現(xiàn)嚴重感染[15]。

當上呼吸道受到病原微生物感染時，上皮細胞、樹突狀細胞、巨噬細胞、肥大細胞等產(chǎn)生IL-1、IL-6、IL-8、TNF-α激活中性粒細胞[16]。研究發(fā)現(xiàn)IFN-γ具有正向和負向調(diào)節(jié)作用[6,17-18]。負向調(diào)節(jié)主要通過IFN-γ-STAT1信號通路的異常激活，使STAT1過度磷酸化所致[19]。在STAT1基因突變導致磷酸化明顯受抑制的細胞中，病毒感染時IFN-α和IFN-γ的功能也嚴重受損，提示IFN-α、IFN-γ可通過STAT1磷酸化來調(diào)控造血功能[20-21]。說明IFN-α和IFN-γ在受到感染時可通過共同的STAT1信號通路影響血液中中性粒細胞水平。本研究發(fā)現(xiàn)，IFN-α、IFN-γ升高均是影響血液中中性粒細胞水平的獨立危險因素，且IFN-α、IFN-γ預測上呼吸道感染患兒24～72h內(nèi)中性粒細胞減少的效能相當。

多項研究證實IFN-α和IFN-γ對中性粒細胞的影響[22-24]。人體在受到病原體感染時會通過多種方式干預疾病病程，因此很少在人體中觀察IFN-α、IFN-γ對中性粒細胞的影響，本研究通過排除抗生素、抗病毒藥物、免疫球蛋白及糖皮質(zhì)激素等對病程的影響，再根據(jù)中性粒細胞在血液循環(huán)中的半衰期判斷IFN-α和IFN-γ對隨后24～72h內(nèi)血液中中性粒細胞的影響，發(fā)現(xiàn)IFN-α、IFN-γ可在一定程度上預測未來24～72h內(nèi)中性粒細胞水平，對指導臨床治療有一定意義。

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Effects of IFN-α/γ in children with upper respiratory tract infection on neutrophils within 24-72 hours

ZHANG Kaijing, ZENG Gongbo, LYU Xiaojuan

1.Department of Hematology, Hangzhou Children’s Hospital, Hangzhou 310005, Zhejiang, China; 2.Department of Clinical Laboratory, Hangzhou Children’s Hospital, Hangzhou 310005, Zhejiang, China

To investigate the effects of interferon (IFN) -α and IFN-γ on blood neutrophils during 24-72 hours of upper respiratory tract infection.Ninety-two children with upper respiratory tract infection diagnosed and treated in Hangzhou Children’s Hospital from January 2020 to August 2022 were selected and divided into ANC group (49 cases with neutrophils < 1000×106/L) and NT group (43 cases with neutrophils ≥1000×106/L) according to the levels of neutrophils within 24-72 hours. The clinical data of the children were collected, and the risk factors affecting neutrophils in the children were analyzed by multivariate Logistic regression, and the receiver operating characteristic (ROC) curve was analyzed for the factors finally selected.The age of children in NT group was higher than that in ANC group, and the levels of IFN-α and IFN-γ were lower than those in ANC group (<0.05). Multivariate Logistic regression analysis showed that IFN-α and IFN-γ were independent risk factors for blood neutropenia within 24-72 hours (<0.05). ROC curve showed that area under the curve of IFN-α and IFN-γ predicted neutropenia were 0.734 and 0.719, respectively, both of which had high predictive value.IFN-α and IFN-γ predict the level of neutrophils in blood of children with upper respiratory tract infection, and are independent risk factors for neutropenia in children.

Interferon-α; Interferon-γ; Neutropenia

R725.6

A

10.3969/j.issn.1673-9701.2023.28.018

呂曉娟，電子信箱：zjxslxj@qq.com

（2022–12–28）

（2023–09–19）