重症流感病毒性肺炎合并侵袭性肺曲霉病15例临床特征分析

The clinical characteristics of severe influenza virus pneumonia complicated with invasive pulmonary aspergillosis:a retrospective study of 15 cases

目的探讨重症流感病毒性肺炎合并侵袭性肺曲霉病(IPA)的临床特点、影像学、实验室检查及危险因素。方法应用病例对照研究的方法,纳入自2017年11月1日至2018年3月31日入住中日友好医院呼吸重症监护室(RICU)的重症流感病毒性肺炎患者64例,其中男33例,女31例,平均(55±14)岁。根据是否符合IPA确诊及临床诊断标准,将所有患者分为IPA组及对照组。其中IPA组15例,确诊IPA者1例,临床诊断IPA者14例,男11例,女4例,平均(53±16)岁。对照组49例,均为不合并IPA的重症流感病毒性肺炎患者,男22例,女27例,平均(57±18)岁。比较两组的临床特点、实验室检查、影像学及气管镜下表现,并通过多元logistic回归分析重症流感病毒性肺炎合并IPA的危险因素。比较两组患者血浆炎症因子水平的差异及合并IPA患者的炎症因子与疾病严重程度的相关性。组间比较采用t检验或方差分析。结果15例IPA者中死亡7例。IPA组出现喘鸣音的患者(13/15)明显高于对照组(25/49),两组比较差异有统计学意义(P<0.05)。IPA组的白细胞计数[(11.0±2.7)×109/L]、血半乳甘露聚糖[(2.46±0.80)μg/L]及BALF的半乳甘露聚糖[(5.30±0.98)μg/L]明显高于对照组的(6.1±3.3)×109/L、(0.33±0.07)μg/L和(0.73±0.17)μg/L(均P<0.01),而降钙素原[0.50(0.30~40.60)μg/L]低于对照组的1.9(0.60~42.70)μg/L(P<0.01)。与对照组相比,IPA组胸部CT出现沿支气管血管束分布的结节影(11例)、大片实变影(9例)、晕征(3例)、空洞或空气新月征(5例)的患者多于对照组(8、11、0和4例),两组比较差异有统计学意义(均P<0.05)。IPA组12例气管镜下出现气道黏膜假膜形成,气道狭窄10例,对照组分别为2例和17例(均P<0.05)。多元logistic回归分析结果提示入住RICU后糖皮质激素应用史、降钙素原水平、CT出现多发结节影及晕征、气管镜下假膜形为重症流感病毒性肺炎合并IPA的危险因素。与对照组相比,IPA组血浆促炎因子IFN-γ[34.9(20.6~64.0)μg/L]及IL-2[16.2(8.9~20.7)μg/L]明显低于对照组的65.2(43.8~124.5)μg/L和20.4(14.6~28.8)μg/L(均P<0.05),而抑炎因子IL-4[51.6(32.7~69.7)μg/L]及IL-10[15.7(11.8~92.5)μg/L]高于对照组的8.9(6.1~15.0)μg/L和7.8(3.6~21.8)μg/L(均P<0.05)。Spearman相关性分析结果提示,IFN-γ(r=-0.658,P=0.02)及IL-6(r=-0.602,P=0.038)与疾病严重程度呈负相关,IL-10(r=0.641,P=0.025)与疾病严重程度呈正相关。结论重症流感病毒性肺炎患者如果有糖皮质激素应用史、治疗过程中出现白细胞增高而降钙素原无明显增高、影像学出现沿气道分布的多发结节影及气管镜下表现为特征性假膜形成时,应高度怀疑合并IPA。

Objective To explore the clinical characteristics,risk factors and possible inflammatory response mechanisms in critically ill patients with influenza and invasive pulmonary aspergillosis co-infection.Methods Sixty-four patients with severe influenza virus pneumonia were included in the RICU of the China-Japanese Friendship Hospital from November 1st,2017 to March 31th,2018.There were 33 males and 31 females,with an average age of(55±14)years.T-tests orχ2 test were applied for comparisons between the two groups.Fifteen patients were complicated with IPA and were classified as the IPA group,while the other 49 served as the control group.The clinical characteristics,laboratory examinations,and endoscopic manifestations were compared between the two groups and the risk factors for severe influenza virus pneumonia with IPA were analyzed by multivariate logistic regression.The possible mechanisms of inflammatory response were explored by comparing the differences of plasma inflammatory factors between the two groups.Results Seven patients(7/15,47.7%)in the IPA group died.The percentage of wheezing in the IPA group(n=13)was significantly higher than that in the control group(n=25)(P<0.05).The values of WBC[(11.0±2.7)×109/L],and the levels of blood GM[(2.46±0.80)μg/L]and BALF GM[(5.30±0.98)μg/L]in the IPA group were significantly higher than those in the control group,while PCT was lower than that in the control group[(6.1±3.3)×109/L,(0.33±0.07)μg/L and(0.73±0.17)μg/L,respectively](P<0.01).Compared with the control group,the chest CT of the IPA group showed more nodules along the bronchial bundle(n=11),massive consolidation shadow(n=9),halo sign(n=3)and cavity/air crescent sign(n=5)(control group:8,11,0 and 4,respectively)(P<0.05).Airway mucosal pseudomembrane formation(n=12)and airway stenosis(n=10)were significantly higher in the IPA group than in the control group(2 and 17)(P<0.05).Multivariate logistic regression analysis suggested that the history of glucocorticoid use after ICU admission,normal PCT,multiple nodules,halo signs and pseudomembrane formation under endoscopy were risk factors for severe influenza virus pneumonia with IPA.The plasma pro-inflammatory factors IFN-γ[IPA group:34.9(20.6-64.0)μg/L]and IL-2[16.2(8.9-20.7)μg/L]were significantly lower than in patients without IPA[control group:65.2(43.8-124.5)μg/L and 20.4(14.6-28.8)μg/L,respectively](P<0.05);while the inflammatory inhibitors IL-4[51.6(32.7-69.7)μg/L)and IL-10[15.7(11.8-92.5)μg/L]were higher in IPA group[control group 8.9(6.1-15.0)μg/L and 7.8(3.6-21.8)μg/L](P<0.05).SOFA scores showed a negative correlation with IFN-γ(r=-0.658,P=0.02)and IL-6(r=-0.602,P=0.038),but a positive correlation with IL-10(r=0.641,P=0.025)by Spearman correlation analysis.Conclusions Some relatively specific clinical characteristics could be found in severe influenza pneumonia complicated with IPA.IPA should be highly suspected when a patient had a history of glucocorticoid use after ICU admission,high WBCs in the course of treatment without significant increase of PCT,multiple nodules along the airway distribution and the characteristic pseudomembrane formation under bronchoscopy.Influenza virus caused imbalance of immune responses,leading to a weakened pro-inflammatory response and a strengthened inflammatory suppression,which might be a possible mechanism for IPA development.