兒童異位性疾病環境風險因子分析與兒童過敏性氣喘患者之益生菌介入效果

Abstract

背景與目標：兒童異位性疾病之盛行率在世界各國都普遍上升，但背後成因仍未完全明朗化。除了文獻探討之外，本論文第一部分，透過社區收案，嘗試瞭解兒童異位性疾病之盛行率並探討各種可能誘發過敏疾病的環境因素；第二部分則延伸針對兒童氣喘患者以隨機臨床試驗研究設計，評估給予口服乳酸桿菌屬益生菌後，能否改善臨床嚴重度以及對免疫生物標記的影響。 方法：本研究第一部分，從社區收案分析疾病盛行率，並進行「過敏及環境因子問卷」及「皮膚過敏原測試」進一步橫斷性分析。接著，第二部分收案符合資格之160位氣喘學童進行雙盲、隨機分派之臨床試驗，分成四組，在標準治療之外，分別給予安慰劑、Lactobacillus paracasei (LP)、Lactobacillus fermentum (LF)及兩者合併(LP + LF)之介入並持續追蹤三個月，分析氣喘嚴重度及免疫生物標記之前後變化。 結果：本研究第一部份，招募了3,192名社區兒童受測者，其中485名（15.2％）兒童患有異位性皮膚炎（Atopic Dermatitis），1,126名（35.3％）兒童患有過敏性鼻炎（Allergic Rhinitis），552名（17.3％）兒童患有氣喘（Asthma）。在受測的氣喘兒童中大約有42%的兒童氣喘表現型（Phenotype）為異位性（Atopic）。受到環境二手菸暴露的兒童和居家環境中牆壁有長霉菌的兒童患氣喘的風險可能更高，粗勝算比（crude odds ratios）分別為1.25（1.03-1.52）和1.22（1.01-1.47）。我們發現塵?致敏與異位性皮膚炎、過敏性鼻炎和氣喘的風險顯著增加有關，校正後勝算比（adjusted odds ratios）分別為2.15（1.53-3.03）、1.94（1.46-2.58）和2.31（1.63-3.29）。第二部份研究中，以廣義估計方程模型分析，將接受LP、LF和LP + LF組別與安慰劑組相比，介入後氣喘嚴重程度顯著較低（分別為p = 0.024、0.038和0.007），Childhood Asthma Control Test得分則顯著較高（p＝0.005，<0.001和<0.001）。 LP + LF組表現出Peak Expiratory Flow Rate顯著增加（P <0.01）和免疫球蛋白E水準明顯下降（P <0.05）。 結論：環境暴露對兒童異位性疾病的發生有明顯相關，暴露於特定過敏原為異位性疾病之獨立危險因子，臨床隨機試驗顯示口服乳酸菌對氣喘兒童有明顯症狀改善的效果。

Background and Objectives: The prevalence of childhood atopic diseases has been shown to rise worlwide. However, potential risk factors and effective interventions were still inconclusive. The dissertation was composed of two major parts following the detailed background chapter. In the first part, we investigated the association of environmental exposures, allergen sensitizations, and the development of atopic diseases with a survey. In the second part, we evaluated the effects of Lactobacillus paracasei (LP), Lactobacillus fermentum (LF), and their combination (LP + LF) on the clinical severity and immune biomarkers in children with asthma by a randomized control trial (RCT). Methods: We conducted a community-based survey for atopic diseases in kindergartens in the first part. Information about the development of atopic diseases and environmental exposures by standardized questionnaires was collected. We performed skin prick tests to detect allergen sensitizations. A cross-sectional evaluation was conducted for the associations among environmental exposures, allergen sensitizations, and atopic diseases. In the second part, a double-blind, randomized, and placebo-controlled trial was carried out, including 160 children with asthma aged 6–18 years, randomized to receive LP, LF, LP + LF, or a placebo for three months. Their Childhood Asthma Control Test (C-ACT) scores, Pediatric Asthma Severity Scores, peak expiratory flow rates (PEFRs), the levels of immune biomarkers at different visits, and the associated changes were evaluated accordingly. Results: A total of 3,192 children were recruited, among which 485 (15.2%) children had atopic dermatitis (AD), 1,126 (35.3%) had allergic rhinitis (AR), and 552 (17.3%) had asthma. The allergic phenotype of asthma was estimated as 42% in all asthma children in the survey. Children with environmental tobacco smoke exposure and fungi on the house wall had a higher risk of asthma, showing crude ORs (95% CIs) of 1.25 (1.03–1.52) and 1.22 (1.01–1.47), respectively. Mite sensitization was the most common environmental risk factor and associated with significant increases of relative risk for AD, AR, and asthma, with adjusted ORs (95% CIs) of 2.15 (1.53–3.03), 1.94 (1.46–2.58), and 2.31 (1.63–3.29), respectively. In the second part, compared with the placebo group by generalized estimating equation model, children receiving LP, LF, and LP+LF had lower asthma severity (p = 0.024, 0.038, and 0.007, respectively) but higher C-ACT scores (p = 0.005, <0.001, and <0.001, respectively). The LP+LF group demonstrated increased PEFR (p <0.01) and decreased immunoglobulin E levels (P<0.05). Conclusion: Environmental exposures play critical roles in the development of childhood atopic diseases. Our analysis unraveled that specific allergens were independent risk factors for the development of atopic diseases. Also, the RCT revealed that Lactobacillus might be beneficial to children with asthma. Both LP and LF could reduce asthma severity and improve asthma control significantly in school-age children.