摘要
近30年來自體免疫疾病以及過敏性疾病在開發中及已開發國家，悄悄的以驚人的幅度大增，由其是高發展經濟富裕工業化的國家，幾乎成了國家的流行病。這些大幅增加的疫疾中，自體免疫疾病是以Th1免疫反應為主，包括有第一型糖尿病、多發性硬化症、以及克隆式症；過敏性疾病則以Th2免疫反應為主，包括有過敏性鼻炎、氣喘、以及異位性皮膚炎。 對於過敏性疾病大幅增加的現象，學者習慣地將這現象歸因於基因背景不同，空氣污染嚴重、過敏原暴露增加，造成致敏的機會大增。然而，九零年代後對照流行病學的研究，卻顯示了這些理論無法解釋的結果。以基因背景為致病基礎的理論受到了挑戰，流行病學的研究顯示由相同民族背景，但生活在兩種經濟開發程度不同的生活環境下的小孩，會有不同的氣喘發生率。這些研究包括移民美國的巴基斯坦兒童，罹患過敏性疾病的機會是居住在巴基斯坦兒童的數倍；東西德統一後，慕尼黑和柏林兒童相較，慕尼黑兒童罹患氣喘約是東德柏林兒童的1.5倍；同樣的情況也反映在中國大陸的兒童身上。新疆烏魯木齊、北京、香港分別代表三個現代化不同程度的都市，氣喘盛行率分別是2.9﹪、6﹪、9.2﹪。說明環境扮演了比基因背景扮演著更重大的角色。其次空氣污染嚴重，或是過敏原暴露的機會增加雖然有確切的證據會造成氣喘惡化，卻不能解釋這三十年來氣喘發生率大增的現象。柏林的空氣污染較西德慕尼黑嚴重；北京的空氣污染較香港嚴重；澳洲、紐西蘭的城市更是享有世界數一數二的空氣品質，但是氣喘等過敏性疾病最多。對照香港和廣州的兒童大規模血清血清塵螨特異性抗體濃度也無顯著的差異。 在此同時，流行病學的研究卻發現在日間看護所的嬰兒，多兄弟姐妹的家庭，幼時罹患寄生蟲疾病，幼時罹患麻疹相對於富裕清潔的成長環境，是氣喘等過敏性疾病的保護因子。於是英國的Strachan教授，根據這些流行病學調查的資料以及實驗室的發現，於1989年作了「清潔理論」的假設，來解釋這些現象。「清潔理論」的大意是過去三十年來，由於環境衛生的改善，抗生素的普遍使用，以及生育率降低，和疫苗的全面施打，使得感染性疾病例如風濕熱、A型肝炎、肺結核、麻疹大幅下降，造成嬰幼兒免疫系統的刺激減少，而導致過敏性以及自體免疫疾病大幅的增加。 從免疫學的觀點來看，母親在懷孕時為了避免對胎兒產生排斥作用，身體的免疫系統會有許多變化，其中之一便是輔助T細胞由攻擊破壞性為主的TH1免疫反應轉換成保護性過敏性為主的TH2免疫反應變化。胎兒在TH2反應的子宮免疫環境中成長，以胎盤為界面，接受來自母親循環的種種不同抗原的刺激，出生後繼續接受環境抗原的刺激。使免疫系統TH2反應為主矯正為TH1/TH2反應平衡。若此時接受的屬於TH1反應的抗原刺激例如病毒感染、腸內益生菌不足，免疫系統無法從TH2反應為主矯正為TH1/TH2反應平衡，那麼日後的免疫系統發展將趨向TH2反應為主。在此免疫系統發展的關鍵時期遇到的過敏原激發(allergen sensitization)也將趨向TH2反應為主，並藉由記憶T細胞一直記憶到未來，日後若再遇到相同的過敏原，便會產生過敏反應。引發氣喘、過敏性鼻炎、異位性皮膚炎等疾病。 陸續許許多多的研究提出正反雙方的證據，結核菌、乳酸菌、A型肝炎、內毒素、幽門羅旋桿菌的感染和氣喘等過敏性疾病的發生率呈負相關，支持清潔理論的假設；呼吸道病毒、黴漿菌、非典型結核菌則感染和過敏發生率呈正比，不支持清潔理論。於是，儘管研究的證據支持多於反對，清潔理論到目前依然無法解釋所有的現象。而且，許多清潔理論研究所面臨的共同瓶頸便是無法確定感染時期是在嬰兒的前一歲關鍵時期感染，從而證實清潔理論所言「免疫系統發展的關鍵時期」感染對日後免疫系統發展的影響。另一方面也無法厘清感染和氣喘的先後而定因果，再一方面流行病學的研究至目前為止尚未有能證實明確的感染病原為氣喘重要保護因子，其一無法克服的原因便是嬰兒呼吸道病毒的感染症狀和氣喘無法有效分辨。 因為B型肝炎的診斷相對客觀，和氣喘無混淆的可能，且有二分之一到三分之一是垂直感染，可以確定在嬰幼兒的免疫發育關鍵時期感染，二者時序性相對明確。因此，本研究嘗試以B型肝炎的感染和氣喘的相關來驗證清潔理論的假說。 問卷的方式是以回溯性研究方式探討母親和本人B型肝炎帶原和氣喘的相關，研究方法是B型肝炎帶原情形由本人問卷自我報告，氣喘的確定由ISAAC氣喘問卷或二位醫師診斷為標準，統計兩者的相關。並針對家族氣喘史、兄弟人數、幼年是否鄉居生活、幼年寵物飼養、身高、性別、體重、母乳餵食、家庭二手煙等因子控制進行統計。在已回收的有效2931分問卷中，經控制上述危險及保護因子，我們發現，母親的B型肝炎帶原，和子代氣喘累積發生率呈負相關，為保護因子，相對危險性為母親無B型肝炎帶原之對照組的0.71 (OR 0.71, 95% CI 0.51 to 0.98)。本人B型肝炎帶原在控制母親B型肝炎保護因子的情況下，和本人氣喘累積發生率呈正相關，為危險因子，相對危險性為本人無B型肝炎帶原之對照組的1.48 (OR 1.48, 95% CI 1.01 to 2.16)。這樣的發現證實了清潔理論關鍵時期感染的影響，也有助於了解臺灣兒童氣喘增加的部分因素。除此之外，也是流行病學上第一次發現母親的明確感染病原為子代氣喘保護因子，並也指出母親慢性感染對於幼兒氣喘的影響，為日後的研究開啟新的方向。
並列摘要
Asthma is the most common chronic disease in childhood and accounts for substantial morbidity and health care costs. During the last thirty years, an increase in the prevalence of asthma as been documented in many countries. As the human genotype would not have changed drastically over a relatively short time period, these phenomena are not easily ascribed to genetic changes in populations. Hence, environmental factors has become the focus of medical research. For a long time, allergen exposure early in life was considered to be a major risk factor for the development of asthma and other allergic diseases. No intervention studies, however, showed that reduced exposure to allergens has a significant impact on the development of asthma and allergic disease. Because of the consistent observations of an inverse association between family size and risk of atopy, allergic rhinitis, and eczema., the so-called “hygiene hypothesis” was proposed, suggesting changes in the type and degree of stimulation from the microbial environment associated with improvements in public health and hygiene may increase the predisposition to chronic allergic conditions during childhood. This hypothesis is explained by shifts in the pattern of infectious diseases in early life, affecting the maturation of the immune system. Thus, at birth the immune system is skewed towards a Th2 cytokine profile which is characteristic of allergic individuals, but during infancy and early childhood this profile is normally shifted towards a non-allergic Th1 profile, perhaps through exposure to infections and other environmental stimuli. Some epidemiological studies support the hypothesis by showing that exposure to measles, rubella, varicella, mumps, and environmental endotoxin in childhood may protect against the development of allergy, while for mycobacteria, measles and respiratory viruses, there are studies that demonstrate an enhancement rather than prevention of allergic disease. The available epidemiological evidence in supportive of hygiene hypothesis is thus controversial. Recently, it is increasingly apparent that asthma phenotype could probably programmed before birth. The interactions between mother, placenta and fetus in influencing the development of fetal and infant immune responses to allergens during gestation have emerged as a focus of intense research. Despite the laboratory work, few clinical studies on the effect of maternal infection on the development of childhood atopy have been inconsistent. Positive association between maternal use of antibiotics during pregnancy and childhood asthma and negative association between probiotics use during pregnancy advocate the hygiene hypothesis, while inverse relation between maternal vaginitis and febrile infection episodes during pregnancy defied the hypothesis. In this study, we retrospectively investigated the relationship between maternal and personal chronic hepatitis B virus (HBV) infection and its subsequent influence on the development of asthma of the child, because HBV is the most prevalent chronic maternal and neonatal infection in Taiwan before the implementation of universal neonatal HBV vaccination program. An estimated 15 to 20% of child-bearing age women are affected and approximately 40% to 50% of their children were infected perinatally. Besides, we hypothesized that chronic infection rather than episodic infection might play more roles in the maturation of the immune system. The carriage status between mother and child was also analyzed to see if there is any synergistic role on the development of asthma in later life. The study population consisted of randomly selected 2931 1980~1982 birth cohort in northern Taiwan, who participated in the national survey of asthma prevalence in 1995~1996. Asthma was defined by using International Study of Asthma and Allergies in Childhood (ISSAC) self-reported and video questionnaires and physician diagnosis. Detailed information on history of wheezing episodes, early age rural life and nursing status, pet-keeping, sibship size, and family history of allergy were acquired with standardized questionnaires. Maternal and personal Hepatitis B virus carrier status was obtained from self-reported questionnaires or telephone interview records and secondarily confirmed by reported hospital health records. An individual with a mother of HBV carrier was associated with a decreased cumulative incidence of asthma in the 20th ~21st year than with a mother of non-HBV carrier (OR 0.71, 95% CI 0.51 to 0.98). There was no association between asthma and personal HBV carrier status in the first 20th ~21st years of life, regardless of maternal carrier status. When maternal HBV carrier status was controlled, postnatally acquired HBV carrier was associated with an increased cumulative incidence of asthma at the age of 20 to 21 (OR 1.48, 95% CI 1.01 to 2.16). Our results showed that maternal carriage of HBV served as protective factors against the development of childhood asthma, and post-natally acquired HBV infection was positively associated with the incidence of asthma. The results may lend support to the view that that immune deviation as a critical factor against atopic disease may start before birth. Post-natally chronic HBV carrier state may reflect the Th2 nature of immunity and the propensity of asthma development. Further studies are required to clarify the underlying immunological mechanism. Studies on relationship between other maternal chronic infections on the risk of childhood atopy are also required.