Therapeutic potential of Calotropis gigantea extract against invasive pulmonary aspergillosis:In vitro and in vivo study

Objective:To characterize the antifungal activity of methanolic leaf extract of Calotropis gigantea alone or in combination with amphotericin B against invasive pulmonary aspergillosis in mice.Methods:GC/MS was used for analysis of active constituents of Calotropis gigantea extract.Spore germination assay and broth micro-dilution method were used to determine antifungal potential of Calotropis gigantea/amphotericin B against Aspergillus fumigatus.Neutropenic mice were randomly assigned into 5 groups:group 1 was neutropenic(control);group 2 was infected with Aspergillus fumigatus;group 3 was infected with Aspergillus fumigatus,and treated with Calotropis gigantea extract;group 4 was infected with Aspergillus fumigatus and treated with amphotericin B;group 5 was infected with Aspergillus fumigatus and treated with both Calotropis gigantea extract and amphotericin B.Fresh lung tissues were histopathologically examined.Fungal burden and gliotoxin concentration were evaluated in lung tissues.Catalase,superoxide dismutase,and malondialdehyde content were determined in lung tissues.Myeloperoxidase,tumor necrosis factor-alpha,interleukin-1,and interleukin-17 were also estimated by the sandwich enzyme-linked immuno-sorbent assay.Results:Calotropis gigantea/amphotericin B had a minimum inhibitory concentration and minimum fungicidal concentration of 80 and 160μg/mL,respectively,for Aspergillus fumigatus.Additionally,Calotropis gigantea/amphotericin B significantly reduced lung fungal burden by 72.95%and inhibited production of gliotoxin in lung tissues from 6320 to 1350μg/g lung.Calotropis gigantea/amphotericin B reduced the oxidative stress of the lung via elevating the activity of antioxidant enzymes and decreasing the levels of lipid peroxidation.Myeloperoxidase activity and the production of pro-inflammatory cytokines were also significantly reduced.Scanning electron microscopy revealed deteriorations in the hyphae ultrastructure in Calotropis gigantea/amphotericin B treated Aspergillus fumigatus and leak of cellular components after damage of the cell wall.In vivo study revealed the suppression of lung tissue damage in mice of invasive pulmonary aspergillosis,which was improved with Calotropis gigantea/amphotericin B compared to the control group.Conclusions:Calotropis gigantea/amphotericin B is a promising treatment to reduce lung fungal burden and to improve the drugs’therapeutic effect against invasive pulmonary aspergillosis.

The Effect Analysis of Different Experimental Methods for the Diagnosis of Invasive Pulmonary Aspergillosis in a Rat Model

Background: Consensus on the most reliable assays to detect invasive aspergillosis from minimally or noninvasive samples has not been reached. In this study, we compared the efficacy of an enzyme-linked immunosorbent assay (ELISA) for galactomannan (GM) detection and quantitative real-time PCR assay (qRT-PCR) for the diagnosis of invasive pulmonary aspergillosis in a rat model. Methods: Neutropenic, male Sprague-Dawley rats (specific pathogen free;8 weeks old;weight, 200 ± 20 g) were immunosuppressed with cyclophosphamide and infected with Aspergillus fumigatus intratracheally. Tissue and whole blood samples were harvested on days 1, 3, 5, and 7 post-infection and examined with GM ELISA and qRT-PCR. Results: On day 7, A. fumigatus DNA was amplified from 14 of 48 whole blood samples from immunosuppressed infected rats: day 1 (0/12), day 3 (0/12), day 5 (6/12), day 7 (8/12) post infection. The sensitivity and specificity of the qRT-PCR assay were 29.2% and 100%, respectively. Receiver operating characteristic curve (ROC) analysis indicated a Ct cut-off value of 15.35, and the area under the curve (AUC) was 0.627. The GM assay detected antigen in sera obtained on day 1 (5/12), day 3 (9/12), day 5 (12/12), and day 7 (12/12) post-infection, and thus had a sensitivity of 79.2% and a specificity of 100%. The ROC of the GM assay indicated that the optimal cut-off value was 1.40 (specificity, 100%;AUC, 0.919). Conclusions: The GM assay was more sensitive than qRT-PCR assay in diagnosing invasive pulmonary aspergillosis in rats.

A Case of Invasive Pulmonary Aspergillosis Resulted from the Treatment of Chronic Eczema

This was an advanced male(87-year-old)with refractory chronic eczema for over 40 years,based on his allergic constitution,accompanied with chronic kidney disease due to primary hypertension(CKD,phase 3).It was so difficult to tolerate the severe itching that the glucocorticoids(GC)had to be applied to it,but some new-onset respiratory symptoms,such as cough,dyspnea after exertion etc.,occurred to this patient.Some classical IPA images were found on his pulmonary CT scanning,which were further comfirmed by the positive findings of GM-test,and then a final diagno­sis of IPA was accordingly established.Unfortunately,a persistent fever emerged after starting an antifungal therapy to the patient,and his IL-2 level was detected to be superhigh.As a response to allergic fever,GC was carefully given intravenously again to treat it,and it turned out to be totally improved since then;suggesting that systemic thinking(integrated with the other clinical evidences)is essential to diagnose IPA,and GC can also be used to improve its symptoms with the existence of antifungal therapy.

111例侵袭性肺曲霉病(IPA)的临床特征及预后风险因素

目的探讨侵袭性肺曲霉病(IPA)的临床特征、实验室检查及预后风险因素。方法回顾性分析2020年9月—2023年6月某院IPA患者的临床资料,分析其临床特征及预后风险因素。结果共纳入111例IPA患者,年龄为(68.8±12.5)岁,以男性为主(63.1%),主要分布于呼吸科、重症监护病房(ICU)、血液科及感染科,共占75.6%。IPA常见的曲霉为烟曲霉、黄曲霉及黑曲霉,分别占67.6%、19.8%、4.5%。支气管肺泡灌洗液的(1,3)-β-D-葡聚糖抗原检测(G试验)、半乳甘露聚糖抗原检测(GM试验)阳性率分别为73.7%、68.0%。111例IPA患者中,32例(28.8%)随访发现预后不良,25例(22.5%)合并病毒感染。logistic多因素回归分析显示,合并病毒感染[OR(95%CI):4.535(1.385~14.846),P=0.012]、连续3周使用糖皮质激素史[OR(95%CI):9.128(2.293~36.341),P=0.002]、机械通气[OR(95%CI):4.690(1.100~19.990),P=0.037]及留置导尿管[OR(95%CI):7.144(1.345~37.950),P=0.021]是IPA患者预后不良的独立危险因素。结论多种因素与IPA预后不良有关,应联合多种检测手段早期识别并尽早给予合理治疗,以改善患者预后,同时需采取相应预防措施,避免出现医院感染。

重症患者侵袭性肺曲霉病的抗真菌治疗用药方案对比研究

目的对比分析不同抗真菌药物治疗方案用于ICU侵袭性肺曲霉病(Invasive pulmonary aspergillosis,IPA)患者的疗效和安全性。方法应用HIS系统回顾性收集2020年1月至2022年1月入住陕西省人民医院ICU并确诊为IPA患者的相关临床资料,比较伏立康唑单药、卡泊芬净单药或伏立康唑+卡泊芬净联合治疗等不同抗真菌治疗之间的临床疗效、ADR发生率和出院时的全因死亡率。结果共纳入40例患者,其中单药治疗组34例(伏立康唑组22例,卡泊芬净组12例),伏立康唑+卡泊芬净组6例。烟曲霉菌是IPA患者最常见的致病菌,其次为黄曲霉菌。临床疗效方面,单药治疗组与联合治疗组有效率差异无统计学意义(P=0.564),单用伏立康唑或卡泊芬净与伏立康唑联合卡泊芬净有效率比较,差异亦无统计学意义(P=0.280)。安全性方面,联合用药组的总ADR发生率略高于单药治疗组,但差异无统计学意义(P>0.05),联合用药组肾功能异常、肝功能异常、视觉异常及低钾血症例数与单药治疗组比较,差异无统计学意义,但联合用药组全血细胞减少的发生率高于单药治疗组(P<0.01)。全因死亡率方面,联合用药组高于两个单药治疗组(P<0.05)。结论伏立康唑仍是危重症IPA患者的首选治疗药物,卡泊芬净具有较好的临床疗效和安全性,可有效替代伏立康唑用于该类患者,而伏立康唑与卡泊芬净的联合治疗不会改善危重症IPA患者全因死亡率,并不推荐作为该类患者的初始治疗方案。

Significance of Aspergillus spp. isolation from lower respiratory tract samples for the diagnosis and prognosis of invasive pulmonary aspergillosis in chronic obstructive pulmonary disease

Background Chronic obstructive pulmonary diseases （COPD） is an emerging population at risk for invasive infection of Aspergillus. Isolation of Aspergillus from lower respiratory tract （LRT） samples is important for the diagnosis of invasive pulmonary aspergillosis （IPA）. The purpose of this study was to investigate the value of Aspergillus isolation from LRT samples for the diagnosis and prognosis of IPA in COPD population. Methods Clinical record with Aspergillus spp. isolation in COPD and immunocompromised patients was reviewed in a retrospective study. Patients were categorized and compared according to their severity of illness （admitted to general ward or ICU） and immunological function （COPD or immunocompromised）. Results Multivariate statistical analysis showed that, combined with Aspergillus spp. isolation, APACHE II scores 〉18, high cumulative doses of corticosteroids （〉350 mg prednisone or equivalent dose） and more than four kinds of broad-spectrum antibiotics received in hospital may be predictors of IPA in COPD （0R=9.076, P=0.001; 0R=4.073, P=-0.026; OR=4.448, P=-0.021, respectively）. The incidence of IPA, overall mortality, mortality of patients with IPA and mortality of patients with Aspergillus spp. colonization were higher in COPD patients in ICU than in general ward, but were similar between COPD and immunocompromised patients. Conclusions Aspergillus spp. isolation from LRT in COPD may be of similar importance as in immunocompromised patients, and may indicate an increased diagnosis possibility of IPA and worse prognosis when these patients received corticosteroids, antibiotics, and need to admit to ICU. Aspergillus spp. isolation from LRT samples combined with certain risk factors mav be useful in differentiating colonization from IPA and evaluating the prognosis of IPA in COPD patients.

Role of Triggering Receptor Expressed on Myeloid Cell-1 Expression in Mammalian Target of Rapamycin Modulation of CD8＋ T-cell Differentiation during the Immune Response to Invasive Pulmonary Aspergillosis

Background： Triggering receptor expressed on myeloid cell- 1 （TREM- 1） may play a vital role in mammalian target ofrapamycin （mTOR） modulation ofCD8＋ T-cell differentiation through the transcription factors T-box expressed in T-cells and eomesodermin during the immune response to invasive pulmonary aspergillosis （IPA）. This study aimed to investigate whether the roTOR signaling pathway modulates the proliferation and differentiation of CD8＋ T-cells during the immune response to I PA and the role TREM-1 plays in this process. Methods： Cyclophosphamide （CTX） was injected intraperitoneally, and Asl？e;gillus.[mnigams spore suspension was inoculated intranasally to establish the immunosuppressed IPA mouse model. After inoculation, rapamycin （2 mg-kg ·d -1） or interleukin （IL）-12 （5 μg/kg every other day） was given for 7 days. The number of CD8＋ effector memory T-cells （Tern）, expression of interferon （IFN）-y, roTOR, and ribosomal protein $6 kinase （S6K）, and the levels of IL-6, IL- 10, galactomannan （GM）, and soluble TREM- 1 （sTREM-I） were measured. Results： Viable A. fumigatus was cultured from the lung tissue of the inoculated mice. Histological examination indicated greater inflammation, hemorrhage, and lung tissue injury in both IPA and CTX ＋ IPA mice groups. The expression of mTOR and S6K was significantly increased in the CTX ＋ IPA ＋ I L- 12 group compared with the control, I PA （P = 0.01 ; P - 0.001 ）, and CTX ＋ 1PA （P = 0.034; P = 0.032） groups, but significantly decreased in the CTX ＋ IPA ＋ RAPA group （P 〈 0.001 ）. Compared with the CTX ＋ IPA group, the proportion of Tern, expression of IFN-y, and the level ofsTREM-I were significantly higher after IL-12 treatment （P = 0.024, P = 0.032, and P = 0.017, respectively）, and the opposite results were observed when the roTOR pathway was blocked by rapamycin （P 〈 0.001）. Compared with the CTX ＋ I PA and CTX ＋ I PA ＋ RAPA groups, IL-12 treatment increased IL-6 and downregulated IL- 10 as well as G M, which strengthened the immune response to the IPA infection. Conclusions： mTOR modulates CD8＋ T-cell differentiation during the immune response to IPA. TREM-1 may play a vital role in signal transduction between mTOR and the downstream immune response.

Initial computed tomography findings of invasive pulmonary aspergillosis in non-hematological patients

Background The computed tomography （CT） findings of invasive pulmonary aspergillosis （IPA） are unclear in non- hematological patients. The present study was a retrospective evaluation of CT images in non-hematological patients with IPA. Methods All adult patients who met the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group （EORTC/MSG） criteria for proven or probable IPA were included during a 5-year study at our institutions. Initial CT findings in our cohort were retrospectively reviewed by two independent thoracic radiologists blinded to patient demographics and clinical outcomes. The presence, pattern, and distribution of abnormalities were recorded. Results Twenty-three non-hematological patients with pathologically confirmed IPA were included in our study. Areas of ground-glass opacities were present in 14 patients （61%）, which were bilateral in 10 patients and unilateral in four. This pattern mainly involved the middle and upper lung zones. Air-space consolidation was identified in 12 patients （52%）, and the areas were distributed along the bronchus or subpleura in most cases. Other findings, including five small nodules （22%）, three macronodules （13%）, and one halo sign （4%）, were less common. Conclusions CT findings of IPA in non-hematological patients frequently manifested as acute bronchopneumonia, and ground-glass opacities and air-space consolidations were the most common CT findings of IPA in these patients.

Prognostic value of serum galactomannan index in critically ill patients with chronic obstructive pulmonary disease at risk of invasive pulmonary aspergillosis

Background Critically ill chronic obstructive pulmonary disease （COPD） patients admitted to an intensive care unit （ICU） due to respiratory failure are at particularly high risk of Aspergillus infection.The serum galactomannan index （GMI） has proven to be one of the prognostic criteria for invasive pulmonary aspergillosis （IPA） in classical immunocompromised patients.However,the prognostic value of serum GMI in critically ill COPD patients needs evaluation.The purpose of this study is to investigate the prognostic value of serum GMI in patients with severe COPD.Methods In this single-center prospective cohort study,serum samples for GMI assay were collected twice a week from the first day of ICU admission to the day of the patients＇ discharge or death.Patients were divided into two groups according to their clinical outcome on the 28th day of their ICU admission.Univariate analysis and survival analysis were tested in these two groups.Results One hundred and fifty-three critically ill COPD patients were included and were divided into survival group （106 cases） and non-survival group （47 cases） according to their outcome.Univariate analysis showed that the highest GMI level during the first week after admission （GMI-high 1st week） was statistically different between the two groups.Independent prognostic factors for poor outcome in severe COPD patients were：GMI-high 1st week ＞0.5 （RR：4.04,95％ CI：2.17-7.51） combined with accumulative dosage of corticosteroids ＞216 mg before the RICU admission （RR：2.25,95％ CI：1.11-4.56） and clearance of creatinine （Ccr） ＜64.31 ml/min （RR：2.48,95％ CI：1.22-5.07）.Conclusions The positive GMI-high 1st week （＞0.5） combined with an accumulative dosage of corticosteroids ＞216 mg before the ICU admission and a low Ccr may predicate a poor outcome of critically ill COPD patients.

Altered CD8＋ T-cell counts as an early predictor of prognosis in critically ill immunocompromised patients with invasive pulmonary aspergillosis

Background The number of critically ill immunocompromised （CIIC） patients has increased dramatically in recent years,and they represent a high risk population for invasive pulmonary aspergillosis （IPA） infection.Host immunity should play a major role in determining the outcome and recovery of these patients.The purpose of this study was to evaluate the dynamic changes in host immune status and its potential influence on prognosis in CIIC patients with IPA.Methods We monitored the evolution of a number of key cellular and humoral parameters on days 1,3,and 10 （D1,D3 and D10） following ICU admission in sixty-two CIIC patients with microbiological evidence of IPA.We included immunoglobulins IgG,IgA and IgM,complement factors C3 and C4,and lymphocyte subgroups CD3＋,CD4＋,CD8＋,CD28＋CD4＋,and CD28＋CD8＋ T cells,CD19＋B cells,and CD3-CD16＋CD56＋ natural killer cells （NK）.Results The primary outcome was 28-day mortality.Thirty-eight （61.3％） patients died within the 28 days following ICU admission.Compared to patients who died,CD3＋,CD8＋,CD28＋CD8＋ T-cell counts on D1,D3,and D10,CD28＋CD4＋ T-cell counts on D3 and D10,and NK counts on D3 and D10 were significantly higher in survivors.Receiver operating characteristic （ROC） analysis of immune parameters predicting 28-day mortality revealed area under the curve （AUC） values of 0.82 （95％ CI 0.71-0.92）,0.94 （95％ CI 0.87-0.99）,and 0.94 （95％ CI 0.85-0.99） for CD8＋ T-cell counts for D1,D3,and D10 respectively,and 0.84 （95％ CI 0.75-0.94）,0.92 （95％ CI 0.85-0.99）,and 0.90 （95％ CI 0.79-0.99） for CD28＋CD8＋ T-cell counts for D1,D3,and D10 respectively.Kaplan-Meier survival analysis showed that CD8＋ T-cell counts ＜149.5×106 cells/L and CD28＋CD8＋ T-cell counts ＜75×106 cells/L at ICU admission were associated with lower survival probabilities in CIIC patients with IPA （both Log rank：P＜0.001）.Conclusions Low CD8＋ and CD28＋CD8＋ T-cell counts were associated with high mortality in CIIC patients with IPA.Early counts of CD8＋ and CD28＋CD8＋ T cells in CIIC patients with IPA may be valuable for predicting outcome.

Th17 cells are involved in mouse chronic obstructive pulmonary disease complicated with invasive pulmonary aspergillosis

Background:The incidence of chronic obstructive pulmonary disease(COPD)complicated with invasive pulmonary aspergillosis(IPA)has increased in the last two decades.The mechanism underpinning susceptibility to and high mortality of COPD complicated with IPA is unclear,and the role of T helper cells 17(Th17 cells)in the compound disease remains unknown.Therefore,this study aimed to assess the function of Th17 cells in COPD combined with IPA.Methods:COPD,IPA,and COPD+IPA mouse models were established in male wild type C57/BL6 mice.The amounts of Th17 cells and retinoic acid-related orphan receptorsγt(RORyt)were tested by flow cytometry.Then,serum interleukin(IL)-17 and IL-23.levels were detected by enzyme-linked immunosorbent assay(ELISA)in the control,COPD,IPA and COPD+IPA groups.In addition,COPD+IPA was induced in IL-17 knockout(KO)mice,for determining the role of Th17 cells in COPD+IPA.Results:Compared with the COPD group,the COPD+IPA group showed higher amounts of blood RORyt([35.09±16.12]%vs.[17.92±4.91]%,P=0.02)and serum IL-17(17.96±9.59 pg/mL vs.8.05±4.44 pg/mL,P=0.02),but blood([5.18±1.09]%vs.[4.15±0.87]%,P=0.28)and lung levels of Th17 cells(1.98±0.83]%vs.[2.03±0.98]%,P=0.91),lung levels of RORyt([9.58±6.93]%vs.[9.63±5.98]%,P=0.49)and serum IL-23(51.55±27.82 pg/mL us.68.70±15.20 pg/mL,P=0.15)showed no significant differences.Compared with the IPA group,the COPD+IPA group displayed lower amounts of blood([5.18±1.09]%vs.[9.21±3.56]%,P=0.01)and lung Th17 cells([1.98±0.83]%vs.[6.29±1.11]%,P=0.01)and serum IL-23(51.55±27.82 pg/mL vs.154.90±64.60 pg/mL,P=0.01)and IL-17(17.96±9.59 pg/mL uUs.39.81±2.37 pg/mL,P=0.02),while comparable blood([35.09±16.12]%Vs.[29.86±15.42]%,P=0.25)and lung levels of RORγt(9.58±6.93]%VUS,[15.10±2.95]%,P=0.18)were found in these two groups.Finally,Aspergillus load in IL-17 KO COPD+IPA mice was almost 2 times that of COPD+IPA mice(1,851,687.69±944,480.43"vs.892,958.10±686,808.80,t=2.32,P=0.02).Conclusion:These findings indicate that Th17 cells might be involved in the pathogenesis of COPD combined with IPA,with L-17 likely playing an antifungal role.

非粒细胞缺乏的慢阻肺合并侵袭性肺曲霉菌病诊断及预后分析

目的 探究非粒细胞缺乏的COPD患侵袭性肺曲霉菌病的危险因素及实验室检查相关指标对其的诊断预测价值。方法 根据欧洲癌症/真菌病研究组织的标准收集了108例非粒细胞缺乏的COPD患者,并将他们分为非IPA组(n=76)、IPA组(n=32),其中临床诊断IPA组(n=14)和确诊IPA组(n=18),将IPA组分为存活组(n=22),死亡组(n=10),并进行回顾性分析。结果 IPA组和非IPA组年龄、性别方面没有显著差异。与非IPA组相比,IPA组糖尿病发生率更高,差异存在统计学意义(P<0.05)。IPA组的肺功能分级更高,差异存在统计学意义(P<0.05)。IPA组外周血淋巴细胞计数、白蛋白水平显著低于非IPA组,差异有统计学意义(P<0.05)。与非IPA组相比,IPA组血清IL-8、BALF IL-8和BALF半乳甘露聚糖水平显著升高(P<0.05),而两组间血清半乳甘露聚糖水平无明显差异(P>0.05)。单因素Cox回归分析示存活组与死亡组在淋巴细胞计数、白蛋白水平、血红蛋白、C-反应蛋白、降钙素原、白蛋白、血IL-8、BALF IL-8水平之间存在统计学差异(P<0.05),多因素Cox回归分析提示存活组与死亡组白蛋白水平存在统计学差异(P<0.05)。结论 当患者同时存在外周血淋巴细胞计数下降、BALF IL-8及BALF GM试验水平升高时更加提示COPD可能合并IPA。低白蛋白水平可能是非粒细胞缺乏的COPD患IPA的不良预后的独立危险因素。

气道侵袭性肺曲霉病21例CT征象分析

目的探讨气道侵袭性曲霉病(invasive pulmonary aspergillosis,IPA)的计算机断层扫描(computed tomography,CT)表现特点,旨在加强医师对气道IPA的认识并提高诊断水平。方法选取2018年8月—2023年6月在我院就诊的21例气道IPA,根据CT征象,分为3型,Ⅰ型累及小叶及段支气管,表现为支气管壁增厚;Ⅱ型病灶进一步发展,表现为小叶及段支气管扩张及周围实变;Ⅲ型累及细支气管及肺实质,细支气管壁增厚、周围树芽征及腺泡结节。详细分析3种类型的CT征象及鉴别诊断。结果21例气道IPA患者,Ⅰ型3例(14.3%),表现为段及小叶支气管管壁增厚,部分有树芽征及腺泡结节;Ⅱ型11例(52.4%),表现为段及小叶支气管扩张、周围实变;Ⅲ型7例(33.3%),表现为细支气管管壁增厚,周围树芽征、腺泡结节及斑片状模糊影。结论气道IPA具有特定的CT表现,掌握其CT分型及特征性征象,有助于临床早期诊断及治疗。

大鼠侵袭性肺曲霉菌病模型的建立

目的探讨正常SD大鼠侵袭性肺曲霉菌病(IPA)模型的建立方法。方法选择9只正常SD大鼠随机分为3组,A、B组经气管内滴注不同量曲霉菌孢子悬液,C组滴注生理盐水。结果A组接种后体重较接种前显著下降(P<0.05),B组接种后体重呈下降趋势但无差异显著性(P>0.05),C组接种后体重较接种前显著增加(P<0.05)。A组接种后第5、8天外周血白细胞数较接种前显著升高(P<0.05),B组白细胞数呈升高趋势但差异无显著性(P>0.05),C组白细胞数变化无显著性(P>0.05)。A、B组肺组织培养烟曲霉阳性且病理学表现为强烈的急性炎症反应,C组肺组织培养阴性且病理无急性炎症反应和曲霉菌丝及孢子。结论单次气道内滴注烟曲霉分生孢子悬液(浓度1×10^(9)cfu/mL,孢子量2×10^(8)/个)的方式可在正常免疫大鼠中稳定建立IPA模型。

血清IL-17联合血清GM试验和BALF-GM试验对ICU侵袭性肺曲霉菌病的诊断价值

目的通过监测ICU内具有真菌侵袭高风险的肺部感染患者血清IL-17水平、血清半乳甘露聚糖(GM)试验及肺泡灌洗液(BALF)-GM试验变化,探索联合检测对于早期诊断ICU侵袭性肺曲霉病(IPA)的价值。方法选择60例肺部感染且具有真菌感染相关危险因素的患者,将其分为2组,试验组为确诊+临床诊断IPA组(30例);对照组为拟诊IPA组(30例)。分别进行年龄、危重度评分、血常规(淋巴细胞绝对值)、血清IL-17水平、血清GM试验、BALF-GM试验、BALF真菌培养鉴定和细胞学检测以及肺部影像学检查,并采集数据。应用电化学发光法检测各组血清IL-17水平,采用酶联免疫吸附试验进行GM试验检测。应用logistic回归分析及绘制受试者工作特征曲线(ROC),分析血清IL-17水平、血清GM试验以及BALF-GM试验诊断IPA的效能;进一步评估3种指标联合检测对早期诊断IPA的效能。两两指标联合为血清GM试验联合BALF-GM试验、血清IL-17联合血清GM试验、血清IL-17联合BALF-GM试验。结果试验组患者血清IL-17、血清GM试验以及BALF-GM试验水平均明显高于对照组(P<0.05);logistic回归分析及ROC曲线分析结果显示,血清IL-17联合BALF-GM试验对IPA诊断的灵敏度为86.7%,特异度为80.0%,曲线下面积为0.852,高于血清IL-17联合血清GM及血清GM联合BALF-GM检测。结论IPA患者血清IL-17高表达,且与BALF-GM试验联合检测,能提升IPA的早期诊断价值。

CYP2C19 Genotyping Plus Therapeutic Drug Monitoring Dependent Voriconazole Treatment for Invasive Pulmonary Aspergillosis in a Patient with Liver Failure

Invasive pulmonary aspergillosis(IPA)is a lethal infectious disease with high mortality in patients with liver failure.Early recognition of the risk factors prompting earlier diagnosis and treatment may improve the outcomes.Voriconazole is recommended as the first-line drug for IPA,but hepatotoxicity limits its use in the context of liver diseases.We report a case of a 63-year-old female who was admitted to the Third Affiliated Hospital of Hebei Medical University due to IPA after glucocorticoid therapy for liver failure.The polymorphism of cytochrome P450(CYP)isoenzymes showed CYP2C19∗1/∗2 genotype associated with intermediate metabolism of voriconazole.However,the patient developed side effects such as skin rash,vomiting,hyperbilirubinemia,and alteration of consciousness,even if she received half of the recommended dosage for voriconazole.Therapeutic drug monitoring(TDM)was applied to guide the dosage adjustment of voriconazole in this patient,and consequently,the patient presented a favorable outcome.In conclusion,genotyping screening plus TDM dependent individualized treatment of voriconazole may improve the survival of liver failure patient with IPA.

The Diagnostic performance of galactomannan detection for invasive pulmonary aspergillosis in non-nentropenic hosts

Objective To evaluate the diagnostic performance of galactomannan(GM)detection in serum and BALF for invasive pulmonary aspergillosis(IPA)in non-neutropenic hosts.Methods A prospective study was performed for 1 356 non-neutropenic hosts admitted to the Department of Pulmonary and Critical Care Medicine of

卡泊芬净治疗恶性血液病合并IPA感染临床分析

目的:评估卡泊芬净治疗恶性血液病合并侵袭性肺曲霉菌(IPA)感染的临床疗效和安全性。方法:2008年1月-2012年12月恶性血液病合并IPA感染患者49例,所有患者均经CT检查和GM试验临床诊断;采用注射用醋酸卡泊芬净进行治疗,根据临床疗效标准,评价卡泊芬净治疗的疗效和安全性。结果:49例患者的治疗总有效率为91.84%(45/49)。卡泊芬净治疗过程中9例发生不良反应,不良反应发生率为18.37%。结论:卡泊芬净有很好的抗真菌活性,是治疗恶性血液病合并肺曲霉菌感染安全有效的药物。

狼疮性肾炎继发侵袭性肺曲霉病的临床特征及预后

目的:回顾性分析狼疮性肾炎(LN)患者合并侵袭性肺曲霉病(IPA)的临床特征及预后。方法:选取2008年9月至2022年1月国家肾脏疾病临床医学研究中心收治的LN合并IPA的22例患者,分析其临床资料及预后。结果:22例LN患者发病年龄35.6±15.6岁,LN病程4.5(3,51)月,诊断IPA前6月内平均接受3种免疫抑制剂。IPA首发症状多为发热、咳嗽、咳痰(72.7%),以烟曲霉最为常见。7例(31.8%)患者在IPA起病3月内死亡,死亡组患者IPA起病前6月内24 h尿蛋白定量、IPA感染时乳酸脱氢酶及狼疮活动性指标显著高于存活组,CD20+B细胞计数显著低于存活组,治疗期间出现混合感染、入住ICU、需要丙种球蛋白/升白细胞药物、气管插管机械通气、连续性肾脏替代治疗(CRRT)的比例更高(P<0.05)。5例患者在随访中进入终末期肾病。结论:LN患者继发IPA的危险因素复杂,狼疮活动及免疫功能低下者预后更差。

COVID-19相关性肺曲霉病41例临床分析

目的探讨COVID-19相关性肺曲霉病(CAPA)的危险因素、临床特点,以提高对该病的认识。方法收集2022年12月至2023年5月间在东营市人民医院呼吸与危重症医学科住院治疗的41例CAPA患者作为CAPA组,随机选取同期住院的COVID-19但未继发肺曲霉病的41例患者为对照组。比较两组患者的临床资料,采用单因素和多因素的条件Logistic回归分析CAPA的危险因素。结果CAPA组患者的住院天数为20(12,27)d,明显长于对照组的12(9,14)d,新冠重症患者占比48.8%,明显高于对照组的22.0%,死亡率为19.5%,明显高于对照组的4.9%,差异均有统计学意义(P<0.05);COVID-19合并结构性肺病、糖尿病、心血管疾病、呼吸衰竭、低蛋白血症患者更易继发曲霉菌感染;与对照组比较,CAPA组患者咳嗽咳痰、气短、体质量减轻更多见,差异均有统计学意义(P<0.05);与对照组比较,CAPA组患者的淋巴细胞计数、白蛋白、氧合指数更低,C-反应蛋白、白介素-6、乳酸脱氢酶水平更高,差异均有统计学意义(P<0.05);CAPA患者的影像学表现以气道侵袭为主,表现为结节(41.5%)、斑片影(78.5%)、实变(70.7%);CAPA组患者以烟曲霉感染(90.2%)为主,其次为黑曲霉、黄曲霉;CAPA组患者BALF GM试验阳性率为63.6%,明显高于血清的22.0%,差异有显著统计学意义(P<0.01);CAPA组患者在应用全身糖皮质激素(85.4%)、托珠单抗(39.0%)、广谱抗生素(85.4%)、抗生素使用超过2周(70.7%)的比例明显高于对照组,差异均有统计学意义(P<0.05);多因素条件Logistic分析结果显示,新型冠状病毒感染重型、呼吸衰竭、低蛋白血症、应用糖皮质激素、应用托珠单抗、应用广谱抗生素、抗生素使用超过两周均是CAPA的独立危险因素(P<0.05)。结论COVID-19患者合并结构性肺病、糖尿病、心血管疾病时易继发肺曲霉病;CAPA临床表现无特异性,胸部CT以气道侵袭的非特异性征象为主,低蛋白血症、呼吸衰竭及应用激素、托珠单抗、广谱抗生素、抗生素使用超过两周会增加发病风险。