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標題: | 血清鐵蛋白與C反應蛋白於全身性紅斑性狼瘡患者感染時之角色 The Role of Serum Ferritin and C-Reactive Protein in Systemic Lupus Erythematosus Patients with Infection |
作者: | 陳仁豪 Jen-Hao Chen |
指導教授: | 謝松洲 Song-Chou Hsieh |
關鍵字: | 紅斑性狼瘡,鐵蛋白,C反應蛋白,感染,非典型感染, Systemic lupus erythematosus,Ferritin,CRP,Infection,Atypical infection, |
出版年 : | 2023 |
學位: | 碩士 |
摘要: | 背景:
全身性紅斑性狼瘡患者死亡率最高之原因為感染(31.1%)。然而在免疫功能低之狀況下,患者臨床許多感染症狀,例如發燒、心跳加快等…不一定會出現,又實驗室的檢查,包括白血球增多症、急性反應蛋白(紅血球沉降速率、 C反應蛋白、前降鈣素…)上升,亦時常無法早期觀察到,因而造成診斷與治療上之延遲,影響到病人存活率。過去研究發現C反應蛋白似乎可以做為全身性紅斑性狼瘡患者早期感染指標,惟僅限於非活動期的狼瘡患者。因此,如何找到合適的指標來提早診斷活動性狼瘡患者的感染事件是臨床醫師極大的挑戰。本論文的實驗目標係如何尋找、分析、驗證可靠的實驗室檢驗指標,以期能達到早期診斷紅斑性狼瘡患者感染症的目的。 實驗方法: 實驗期間為民國109年1月1日至民國112年1月31日,我們蒐集21位免疫疾病患者之資料(紅斑性狼瘡13位,其他免疫疾病8位),其他免疫疾病包含ANCA血管炎3位、原發性乾燥症2位、多發性肌炎2位、全身性硬化症1位;共記錄到25次的感染事件(紅斑性狼瘡15次,其他免疫疾病8次;非典型感染12次,非典型感染13次)。收治醫院為台大醫院與台大雲林分院。急性期檢體的採檢,在首次診斷感染七日內進行。檢測的發炎指標包含血清鐵蛋白[ferritin]與C反應蛋白[CRP]。紅斑性狼瘡患者同時也會使用紅斑性狼瘡活性指標評估,(SLEDAI 2K),指數 ≥7.4代表高活性)。基礎期檢體採檢於疾病恢復期,或採用感染前12周內之檢體,檢測血清鐵蛋白及C反應蛋白。統計分析方式採「無母數配對檢定-魏克生符號檢定」(Wilcoxon signed-rank test),分析感染前後鐵蛋白與C反應蛋白之變化。對於高度懷疑感染的紅斑性狼瘡患者,我們分析「接收者操作特徵曲線」(receiver operating characteristic curve,又稱ROC曲線),以計算出判斷感染的臨界值。 為分析高鐵蛋白血症(hyperferritinemia)之成因,我們使用酵素結合免疫吸附分析法(enzyme-linked immunosorbent assay, ELISA)檢測血清醣化鐵蛋白分率(Glycosylated Ferritin (GF)/Ferritin ratio),正常人分率為50%至80%。若結果明顯高於50%,傾向細胞受損釋放出其內醣化鐵蛋白引起;若結果明顯低於50%,則傾向活化發炎體(inflammasome)路徑引起。 結果: 第一組:活動期紅斑性狼瘡非典型感染(n=6平均活性指標SLEDAI:14.7,屬高活性),基礎平均血清球蛋白值為429ng/mL,感染平均血清球蛋白值為2919ng/mL (p=0.0277)。基礎平均血清C反應蛋白值為0.32mg/dL,感染平均血清C反應蛋白2.68mg/dL(p=0.0277)。 第二組:活動期紅斑性狼瘡細菌感染(n=9平均活性指標SLEDAI:11.1 高活性),基礎平均血清球蛋白值為157ng/mL,感染平均血清球蛋白值為1588ng/mL (p=0.0077)。 基礎平均血清C反應蛋白值為0.18mg/dL,感染平均血清C反應蛋白9.7mg/dL(p=0.0076)。 第三組:其他免疫疾病非典型感染(n=7) 基礎平均血清球蛋白值為293ng/mL,感染平均血清球蛋白值為1130ng/mL (p=0.018). 基礎平均血清C反應蛋白值為0.45mg/dL,感染平均血清C反應蛋白3.28mg/dL(p=0.028)。 第四組: 其他免疫疾病細菌感染(n=3) 基礎平均血清球蛋白值為462ng/mL,感染平均血清球蛋白值為10768ng/mL (p=0.285). 基礎平均血清C反應蛋白值為0.45mg/dL,感染平均血清C反應蛋白15.1mg/dL(p=0.108)。 自體免疫疾病(包含紅斑性狼瘡與其他免疫疾病)預測感染之ROC曲線分析最佳預測值位於400-799 ng/mL區段,其平均值為600ng/mL (敏感度:73% 特異性:95.23%) 。 為分析同一位活動期紅斑性狼瘡患者遭遇細菌與非典型感染時,C反應蛋白與球蛋白上升的情況,我們分析四位病患,使用C反應蛋白差值(ΔCRP: 感染期-基礎期)、血清鐵蛋白差值(ΔFerritin: 感染期-基礎期)、 C反應蛋白差值與血清鐵蛋白差值比值(ΔFerritin/ΔCRP)作為分析指標。 結果顯示兩者ΔCRP皆有顯著統計學差異。平均ΔCRP在非典型感染為2.87mg/dL,在細菌感染為14.89mg/dL, p=0.01738,而Δferritin及ΔFerritin/ΔCRP則明顯無差異,表示活動性紅斑性狼瘡患者C反應蛋白於非典型感染時相較細菌感染血清鐵蛋白無法顯著上升,難以預測感染症;而血清鐵蛋白不論是在非典型或細菌感染皆有顯著差異。 血清醣化鐵蛋白分率結果分為兩群:活動性紅斑性狼瘡腎炎患者遭遇細菌或隱球菌感染時,其平均分率為17.35% (0.54 - 32%;n=4);以及活動性紅斑性狼瘡腎炎患者且無感染者,其平均分率為39.67% (9.9 - 57%;n=3)。此結果顯示活動性紅斑性狼瘡遭遇細菌或隱球菌感染時,血清醣化鐵蛋白分率偏低, 推測為其高鐵蛋白血症較傾向為活化發炎體(inflammasome)路徑之結果。 結論:血清鐵蛋白≥600ng/mL可作為免疫疾病(包含全身性紅斑性狼瘡與其他免疫疾病)之早期感染偵測指標。血清鐵蛋白在活動性紅斑性狼瘡病人感染時仍能穩定升高,不論是對細菌感染或是非典型感染都有極佳的預測性。反觀C反應蛋白,在活動性狼瘡的病人遭遇非典型感染時預測性不佳,在非活動性紅斑性狼瘡或是細菌感染的情況較能明顯上升。而活動性紅斑性狼瘡患者遭遇感染引發之高鐵蛋白血症,傾向是因活化發炎體(inflammasome)路徑所引起。故臨床上當我們難以區分紅斑性狼瘡患者為感染或是疾病活性上升時,同時檢測血清鐵蛋白與C反應蛋白可以幫助我們更精確判斷為何者。 Background: The main cause of mortality in SLE patient is infection (31.1%). Patients with immunocompromised conditions often do not show common signs of infection, such as fever, tachycardia, leukocytosis, and acute phase protein elevation (CRP, erythrocyte sedimentation rate (ESR), procalcitonin [PCT]). In previous studies, CRP (≥60.0mg/L) seems to be a valuable marker for diagnosing infection; however, it is only limited to inactive SLE patients. Therefore, how to recognize infection in active SLE patients imposes a difficult challenge. The aim of our study is to find a reliable laboratory marker for early diagnosis of infection in SLE patients. Methods: Between January 1, 2020 to January, 31, 2023, we gathered data from 21 patients (SLE: n=13, other autoimmune diseases n=8) from NTUH and NTUH-Yunlin and recorded a total of 25 infection incidences (SLE: n=15; Other: n=10). We analyzed the SLE patients’ disease activity, as measured by the SLEDAI 2k score, as well as their inflammation markers (serum ferritin and CRP), within 7 days of their infection or within 12 weeks before the infection and at the time of recovery. The Wilcoxon signed-rank test was used to compare the baseline data. To determine the cut-off level of serum ferritin in SLE patients highly suspected to have infection, we used the Receiver Operating Characteristic (ROC) curve. To clarify the etiology of hyperferritinemia, we analyzed serum glycosylated ferritin/ferritin ratio using an enzyme-linked immunosorbent assay (ELISA) kit. If glycosylated ferritin (GF)/ferritin ratio is low, lupus-related reaction is likely. On the other hand, if glycosylated ferritin/ferritin ratio is high, this could mean cell damage and glycosylated ferritin release from the lysed cells. Result: Group 1 Active SLE with atypical infection (SLEDAI:14.7 High activity): The mean serum ferritin levels were 429ng/mL (baseline) and 2919 ng/mL (infection)(p=0.0277). The mean CRP levels were 0.32mg/dL (baseline) and 2.68mg/dL (infection)(p=0.0277). Group 2 Active SLE with bacterial infection (SLEDAI:11.1, High activity): The mean serum ferritin levels were 157ng/mL (baseline) and 1588ng/mL (infection)(p=0.0077). The mean CRP levels were 0.18mg/dL (baseline) and 9.7mg/dL (infection)(p=0.0076). Group 3 Other autoimmune disease with atypical infection (n=7): The mean serum ferritin levels were 293ng/mL (baseline) and 1130ng/mL (infection)(p=0.018). The mean CRP levels were 0.45mg/dL (baseline) and 3.28mg/dL (infection)(p=0.028). Group 4 Other autoimmune disease with bacterial infection (n=3): The mean serum ferritin levels were 462ng/mL (baseline) and 10768ng/mL (infection)(p=0.285). The mean CRP levels were 0.45mg/dL (baseline) and 15.10mg/dL (infection)(p=0.108). The cut-off value of ferritin level for infection in patients with autoimmune diseases (SLE or others) was 600ng/mL (400-799) (sensitivity: 73% specificity:95.23) as calculated by using the Receiver Operating Characteristic (ROC) curve. The mean ΔCRP(infection-baseline) of the same patient with atypical and bacterial dual infections were(n=4) atypical: 2.87 mg/dL, bacterial:14.89 mg/dL and with a statistically significant difference (p=0.01738). However, the mean ΔFerritin or ΔFerritin/ΔCRP ratio did not show significant difference. The GF/Ferritin ratios were lower in the SLE with infection group than the disease flare group (mean 17.35%, 0.54 – 32.7% vs 39.67%, 9.9 – 57%), which indicated that the result of hyperferritinemia in active SLE patients with infection may be due to overexpression of the inflammasome pathway rather than cell damage/lysis. Conclusion: Serum ferritin increases steadily in patients with active lupus erythematosus contracted with bacterial or atypical infections. Serum ferritin level with a cut-off value of ≥ 600ng/mL can be used as an early infection indicator in patients with autoimmune diseases, including systemic lupus erythematosus and other autoimmune diseases. In contrast, CRP is not predictive of atypical infections in patients with active lupus, but can be seen to increase significantly in patients with inactive lupus erythematosus with bacterial infection. Patients with active lupus erythematosus encounter infection-induced hyperferritinemia, which tends to be caused by activation of the inflammasome pathway. Therefore, clinically when it is difficult to differentiate between SLE patients with infections or disease flare, testing both ferritin and CRP can assist practitioners make a more precise diagnosis. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90226 |
DOI: | 10.6342/NTU202303601 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 臨床醫學研究所 |
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