Interaction of allergic airway inflammation and innate immunity: hygiene and beyond

The lung is constantly exposed to the environment and its microbial components. Infections of the respiratory tract are amongst the most common diseases. Several concepts describe how this microbial exposure interacts with allergic airway disease as it is found in patients with asthma. Infections are classical triggers of asthma exacerbations. In contrast, the hygiene hypothesis offers an explanation for the increase in allergic diseases by establishing a connection between microbial exposure during childhood and the risk of developing asthma. This premise states that the microbial environment interacts with the innate immune system and that this interrelation is needed for the fine-tuning of the overall immune response. Based on the observed protective effect of farming environments against asthma, animal models have been developed to determine the effect of specific bacterial stimuli on the development of allergic inflammation. A variety of studies have shown a protective effect of bacterial products in allergen-induced lung inflammation. Conversely, recent studies have also shown that allergic inflammation inhibits antimicrobial host defense and renders animals more susceptible to bacterial infections. This paper focuses on examples of animal models of allergic disease that deal with the complex interactions of the innate and adaptive immune system and microbial stressors.     

Asthma and allergic diseases: is there a downside to cleanliness and can we exploit it?

When hay fever was first described in the early 19th century it was an uncommon disorder. Since then asthma, allergic rhinitis and eczema, have become common conditions particularly in industrialised western economies. International prevalence studies reveal wide variation in the prevalence of asthma, and allergic disease, but confirm this view although the studies also show these diseases to be by no means rare in most countries. The reasons remain unclear but the "hygiene hypthesis" postulating an inverse relationship between hygiene, in its broadest sense, and allergic disease, fits some of the epidemiology of these diseases and has an associated immunological hypthesis to support it. Recent studies suggest that many hygiene related factors may influence immune development in favour of an allergic phenotype. Antibiotics in the first of life have been associated with increased risks of allergic disease in later childgood, and farming exposures to protection. Interest in hte role of bowel flora in modifying immune development has been suggested as an explanation for the risk associated with antibiotic exposure and has led to studies exploring the effects of modifying bowel flora with probiotics both to influence established allergic disease and to prevent it. The challenge is to continue to reap the enormous benefits that accrued from modifying infectious disease by both public and individual health strategies but at the same time convincing the immune system that it has been exposed to them.     

Diverse microbial exposure - consequences for vaccine development

Numerous epidemiological studies suggest that there is an inverse relationship between "immunologically mediated diseases of affluence", such as allergy, diabetes and inflammatory bowel disease on one hand and few infections encountered in early childhood, on the other hand. Careful analysis of the epidemiological, clinical and animal studies taken together, however, suggests that the protection is mediated by broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life, rather than by infections. Microbial exposure has little relationship with "hygiene" in the usual meaning of the word and the term "hygiene hypothesis" is therefore misleading. A better term would be "microbial deprivation hypothesis". The suggestion that childhood infections would protect against allergic disease led to unfortunate speculations that vaccinations would increase the risk for allergies and diabetes. Numerous epidemiological studies have therefore been conducted, searching for a possible relationship between various childhood vaccinations on one hand and allergy on the other hand. It is reasonable from these studies to conclude that vaccinations against infectious agents neither significantly increase, nor reduce the likelihood of immunologically mediated diseases. It is established that the postnatal maturation of immune regulation is largely driven by exposure to microbes. Germ free animals manifest excessive immune responses when immunised and they do not develop normal immune regulatory function. The gut is by far the largest source of microbial exposure, as the human gut microbiome contains up to 1014 bacteria, i.e. ten times the number of cells in the human body. Several studies in recent years have shown differences in the composition of the gut microbiota between allergic and non-allergic individuals and between infants living in countries with a low and a high prevalence of immune mediated diseases. The administration of probiotic bacteria to pregnant mothers and postnatal to their infants has immune modulatory effects. So far, however, probiotic bacteria do not seem to significantly enhance immune responses to vaccines. The potential to improve vaccine responses by modifying the gut microbiota in infants and the possibility to employ probiotic bacteria as adjuvants and/or delivery vehicles, is currently explored in several laboratories. Although to date few clinical results have been reported, experimental studies have shown some encouraging results.     

Examining the hygiene hypothesis: the Trial of Infant Probiotic Supplementation

The hygiene hypothesis suggests that the absence of infectious exposure at a critical point in immune system development leads to a greater risk for the later development of atopic disease. As a result, it may be possible to devise strategies that can block the onset of atopic diseases such as asthma. This paper outlines the rationale, background and design for the Trial of Infant Probiotic Supplementation study, which is designed to test the effectiveness of a daily infant probiotic supplement in the first 6 months of life in preventing the development of early markers of asthma.     

No epidemiological evidence for infant vaccinations to cause allergic disease

CONTEXT: The prevalence of allergic diseases has increased considerably over the last decades. The hygiene hypothesis has emerged, linking reduced microbial exposure and infections early in life with the development of allergic diseases. Especially some of currently available non-replicating infant vaccines are unlikely to mimic a natural infection-mediated immune response that protects against the development of allergic diseases. Moreover, several studies suggested infant vaccinations to increase the risk of allergic diseases. OBJECTIVE: To determine whether infant vaccinations increase the risk of developing allergic disease. DATA SOURCES: We searched MEDLINE from 1966 to March 2003 and bibliography lists from retrieved articles, and consulted experts in the field to identify all articles relating vaccination to allergy. STUDY SELECTION AND DATA EXTRACTION: We selected epidemiological studies with original data on the correlation between vaccination with diphtheria, pertussis, tetanus (DPT), measles, mumps, rubella (MMR) and Bacillus Calmette-Guérin (BCG) vaccine in infancy and the development of allergic diseases, and assessed their quality and validity. DATA SYNTHESIS: Methodological design and quality varied considerably between the studies we reviewed. Many studies did not address possible confounders, such as the presence of lifestyle factors, leaving them prone to bias. The studies that offer the stronger evidence, including the only randomized controlled trial at issue published to date, indicate that the infant vaccinations we investigated do not increase the risk of developing allergic disease. Furthermore, BCG does not seem to reduce the risk of allergies. CONCLUSIONS: The reviewed epidemiological evidence indicates that, although possibly not contributing to optimal stimulation of the immune system in infancy, current infant vaccines do not cause allergic diseases.     

Long-Chain Polyunsaturated Fatty Acids (LCPUFAs) and the Developing Immune System: A Narrative Review

The immune system is complex: it involves many cell types and numerous chemical mediators. An immature immune response increases susceptibility to infection, whilst imbalances amongst immune components leading to loss of tolerance can result in immune-mediated diseases including food allergies. Babies are born with an immature immune response. The immune system develops in early life and breast feeding promotes immune maturation and protects against infections and may protect against allergies. The long-chain polyunsaturated fatty acids (LCPUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA) are considered to be important components of breast milk. AA, eicosapentaenoic acid (EPA) and DHA are also present in the membranes of cells of the immune system and act through multiple interacting mechanisms to influence immune function. The effects of AA and of mediators derived from AA are often different from the effects of the n-3 LCPUFAs (i.e., EPA and DHA) and of mediators derived from them. Studies of supplemental n-3 LCPUFAs in pregnant women show some effects on cord blood immune cells and their responses. These studies also demonstrate reduced sensitisation of infants to egg, reduced risk and severity of atopic dermatitis in the first year of life, and reduced persistent wheeze and asthma at ages 3 to 5 years, especially in children of mothers with low habitual intake of n-3 LCPUFAs. Immune markers in preterm and term infants fed formula with AA and DHA were similar to those in infants fed human milk, whereas those in infants fed formula without LCPUFAs were not. Infants who received formula plus LCPUFAs (both AA and DHA) showed a reduced risk of allergic disease and respiratory illness than infants who received standard formula. Studies in which infants received n-3 LCPUFAs report immune differences from controls that suggest better immune maturation and they show lower risk of allergic disease and respiratory illness over the first years of life. Taken together, these findings suggest that LCPUFAs play a role in immune development that is of clinical significance, particularly with regard to allergic sensitisation and allergic manifestations including wheeze and asthma.     

N-3 polyunsaturated fatty acids and allergic disease

PURPOSE OF REVIEW: With escalating rates of allergic disease, it is vital to explore novel causal pathways. This review examines the evidence for a potential role of changing dietary intake of omega-3 polyunsaturated fatty acids in the development, treatment and prevention of allergic diseases. RECENT FINDINGS: Although it is difficult to determine the contribution of altered (decreased) dietary intake of omega-3 polyunsaturated fatty acids to the recent rise in the incidence of allergic disease, there is growing evidence that these nutrients have antiinflammatory properties and may modulate immune responses. These fatty acids have few side effects, and may be of some benefit in established allergic diseases (such as asthma and atopic dermatitis), although these effects are not strong. Because of this limited efficacy in established disease, the focus has shifted to the potential benefits of these immune modulators in earlier life for disease prevention. Two recent preliminary reports in infants suggest that dietary omega-3 polyunsaturated fatty acid supplements in pregnancy or in the early postnatal period could have immunomodulatory properties and associated clinical effects, although more studies are now needed. Novel synthetic polyunsaturated fatty acids with more potent and selective antiinflammatory effects may also provide safe therapeutic and preventive strategies in the future. SUMMARY: Dietary factors are important but still under-explored candidates in the search for environmental strategies to reduce the enormous impact of allergic diseases in modernized societies. There is an ongoing need for further research into the role of omega-3 polyunsaturated fatty acids in allergic disease, particularly in early life before atopy is established.     

孕期营养对儿童期哮喘及遗传性过敏性体质发生的影响

20世纪90年代 Barker DJ提出健康与疾病发育起源的学说,越来越多的流行病学调查及动物实验提示母亲孕期营养对其子代成年以后非感染性疾病(代谢性综合征及心肺疾病等)的发生有着重要的联系。而也有一些调查研究发现母亲孕期营养可能引起子代成年时期非感染性疾病,还可能影响子代儿童时期非感染性疾病的发生,如儿童哮喘,喘息,遗传性过敏体质等。这些疾病带给患儿心理负担,严重影响患儿生长发育、生活质量并伴有生命危险。然而大量的研究提示孕期合理营养,科学膳食可以降低子代这些疾病的发病风险。我国目前生活质量提高,现如今多数孕妇营养摄入不平衡,或处饱和甚至过剩状态,而儿童过敏性疾病的发生逐年增加。本文就孕期营养对子代儿童期哮喘,喘息及遗传性过敏性体质发生的影响做一简要的综述。     

Fermented Food in Asthma and Respiratory Allergies—Chance or Failure?

In the last few decades, a dramatic increase in the global prevalence of allergic diseases and asthma was observed. It was hypothesized that diet may be an important immunomodulatory factor influencing susceptibility to allergic diseases. Fermented food, a natural source of living microorganisms and bioactive compounds, has been demonstrated to possess health-promoting potentials and seems to be a promising strategy to reduce the risk of various immune-related diseases, such as allergic diseases and asthma. The exact mechanisms by which allergic diseases and asthma can be alleviated or prevented by fermented food are not well understood; however, its potential to exert an effect through modulating the immune response and influencing the gut microbiota has been recently studied. In this review, we provide the current knowledge on the role of diet, including fermented foods, in preventing or treating allergic diseases and asthma.     

Environment and infant immunity

Pregnancy is associated with a skewing towards T-helper (Th)2-like cell populations. During the first years of life, the neonatal immune responses towards allergens deviate towards a balanced Th1 and Th2-like immunity. The difference between atopic and nonatopic individuals may be how readily the immune deviation takes place. The high prevalence of allergies in industrialized countries is in contrast with the low prevalence of allergies in Eastern Europe, with a life style similar to that prevailing in Western Europe 40 years ago. The discussion on the impact of environmental changes on the incidence of asthma and other allergies has been limited mostly to the possible effects of a deteriorating air quality, poorly ventilated houses and an increased exposure to certain allergens, notably house dust mites. None of these factors can more than marginally explain the observed regional differences in the prevalence of allergic diseases. The concept of 'life style' should therefore be expanded considerably. The mother is a significant 'environmental factor' in early infancy. Human milk contains components that enhance the maturation of the immune system of the newborn infant. However, there are considerable individual variations in the composition of human milk. Recent studies indicate an imbalance in the gut flora of allergic, compared with non allergic infants, and in Swedish children compared with Estonian children. As the microbial flora drives the maturation of the immune system, changes in its composition may play a role for the higher prevalence of allergy. The future search for significant environmental factors should be directed towards other areas that have not yet been explored. The intestinal microflora is one of these factors that deserve a closer analysis.     

Is the global rise of asthma an early impact of anthropogenic climate change?

The increase in asthma incidence, prevalence, and morbidity over recent decades presents a significant challenge to public health. Pollen is an important trigger of some types of asthma, and both pollen quantity and season depend on climatic and meteorologic variables. Over the same period as the global rise in asthma, there have been considerable increases in atmospheric carbon dioxide concentration and global average surface temperature. We hypothesize anthropogenic climate change as a plausible contributor to the rise in asthma. Greater concentrations of carbon dioxide and higher temperatures may increase pollen quantity and induce longer pollen seasons. Pollen allergenicity can also increase as a result of these changes in climate. Exposure in early life to a more allergenic environment may also provoke the development of other atopic conditions, such as eczema and allergic rhinitis. Although the etiology of asthma is complex, the recent global rise in asthma could be an early health effect of anthropogenic climate change.     

中国1990-2019年儿童青少年哮喘疾病负担变化趋势

目的 探索1990-2019年中国儿童青少年哮喘疾病负担变化趋势,为开展防控工作提供参考.方法 基于2019年全球疾病负担研究,利用Joinpoint回归分析性别和年龄别哮喘疾病负担动态变化,与各级社会人口指数(SDI)国家平均水平比较;并分析归因哮喘疾病负担的变化.结果 标化1～19岁哮喘伤残调整寿命年(DALYs)...     

Primary Prevention of Pediatric Asthma through Nutritional Interventions

Asthma is the most common chronic non-communicable disease in children, the pathogenesis of which involves several factors. The increasing burden of asthma worldwide has emphasized the need to identify the modifiable factors associated with the development of the disease. Recent research has focused on the relationship between dietary factors during the first 1000 days of life (including pregnancy)—when the immune system is particularly vulnerable to exogenous interferences—and allergic outcomes in children. Specific nutrients have been analyzed as potential targets for the prevention of childhood wheeze and asthma. Recent randomized controlled trials show that vitamin D supplementation during pregnancy, using higher doses than currently recommended, may be protective against early childhood wheezing but not school-age asthma. Omega-3 fatty acid supplementation during pregnancy and infancy may be associated with a reduced risk of childhood wheeze, although the evidence is conflicting. Data from observational studies suggest that some dietary patterns during pregnancy and infancy might also influence the risk of childhood asthma. However, the quality of the available evidence is insufficient to allow recommendations regarding dietary changes for the prevention of pediatric asthma. This review outlines the available high-quality evidence on the role of prenatal and perinatal nutritional interventions for the primary prevention of asthma in children and attempts to address unmet areas for future research in pediatric asthma prevention.     

Sibship characteristics and risk of allergic rhinitis and asthma

Studying associations between sibship characteristics and allergic diseases in detail may contribute clues to their etiology. The authors studied associations between sibship characteristics and risk of self-reported allergic rhinitis and asthma among 31,145 pregnant women participating in a nationwide study in Denmark during 1997-2000. Increasing sibship size was associated with a decreased risk of allergic rhinitis and asthma with allergic rhinitis but not with asthma without allergic rhinitis. The protective effect of having older siblings was stronger than the protective effect of having younger siblings for both allergic rhinitis and asthma with allergic rhinitis. There was no association between interval to closest older or younger sibling and risk of allergic rhinitis or asthma with allergic rhinitis, while the risk of asthma without allergic rhinitis increased with intervals of 2 or more years compared with less than 2 years to the nearest older sibling. The protective effect of having siblings on the risk of asthma with allergic rhinitis could be explained by a protective effect of siblings on the risk of allergic rhinitis alone. In conclusion, our findings suggest that different etiologic mechanisms are involved for allergic rhinitis and asthma with respect to the effect of sibship characteristics. Furthermore, the findings that allergic rhinitis was associated with the number of younger siblings but not with the age interval to younger siblings support the hypothesis of an influence of postnatal mechanisms and suggest that these mechanisms may not necessarily be operating only in early life.     

Vitamin D and Allergy Susceptibility during Gestation and Early Life

Worldwide, the prevalence of allergies in young children, but also vitamin D deficiency during pregnancy and in newborns is rising. Vitamin D modulates the development and activity of the immune system and a low vitamin D status during pregnancy and in early life might be associated with an increased risk to develop an allergy during early childhood. This review studies the effects of vitamin D during gestation and early life, on allergy susceptibility in infants. The bioactive form of vitamin D, 1,25(OH)2D, inhibits maturation and results in immature dendritic cells that cause a decreased differentiation of naive T cells into effector T cells. Nevertheless, the development of regulatory T cells and the production of interleukin-10 was increased. Consequently, a more tolerogenic immune response developed against antigens. Secondly, binding of 1,25(OH)2D to epithelial cells induces the expression of tight junction proteins resulting in enhanced epithelial barrier function. Thirdly, 1,25(OH)2D increased the expression of anti-microbial peptides by epithelial cells that also promoted the defense mechanism against pathogens, by preventing an invasive penetration of pathogens. Immune intervention by vitamin D supplementation can mitigate the disease burden from asthma and allergy. In conclusion, our review indicates that a sufficient vitamin D status during gestation and early life can lower the susceptibility to develop an allergy in infants although there remains a need for more causal evidence.     

Dietary Fibers: Effects,Underlying Mechanisms and Possible Role in Allergic Asthma Management

The prevalence of asthma is increasing, but the cause remains under debate. Research currently focuses on environmental and dietary factors that may impact the gut-lung axis. Dietary fibers are considered to play a crucial role in supporting diversity and activity of the microbiome, as well as immune homeostasis in the gut and lung. This review discusses the current state of knowledge on how dietary fibers and their bacterial fermentation products may affect the pathophysiology of allergic asthma. Moreover, the impact of dietary fibers on early type 2 asthma management, as shown in both pre-clinical and clinical studies, is described. Short-chain fatty acids, fiber metabolites, modulate host immunity and might reduce the risk of allergic asthma development. Underlying mechanisms include G protein-coupled receptor activation and histone deacetylase inhibition. These results are supported by studies in mice, children and adults with allergic asthma. Fibers might also exert direct effects on the immune system via yet to be elucidated mechanisms. However, the effects of specific types of fiber, dosages, duration of treatment, and combination with probiotics, need to be explored. There is an urgent need to further valorize the potential of specific dietary fibers in prevention and treatment of allergic asthma by conducting more large-scale dietary intervention trials.     

Associations between socioeconomic position and asthma: findings from a historical cohort

Understanding the association between asthma and socioeconomic position (SEP) is key to identify preventable exposures to prevent inequalities and lessen overall disease burden. We aim to assess the variation in asthma across SEP groups in a historical cohort before the rise in asthma prevalence. Male students participating in a health survey at Glasgow University from 1948 to 1968 (n?=?11,274) completed medical history of bronchitis, asthma, hay fever, eczema/urticaria, and reported father's occupation. A subsample responded to postal follow-up in adulthood (n?=?4,101) that collected data on respiratory diseases, early life and adult SEP. Lower father's occupational class was associated with higher odds of asthma only (asthma without eczema/urticaria or hay fever) (trend adjusted multinomial odds ratio (aMOR)?=?1.23, 95?% CI 1.03-1.47) but with lower odds of asthma with atopy (asthma with eczema/urticaria or hay fever) (trend aMOR?=?0.66, 95?% CI 0.52-0.83) and atopy alone (trend aMOR?=?0.84, 95?% CI 0.75-0.93). Household amenities (<3), in early life was associated with higher odds of adult-onset asthma (onset?>?30?years) (OR?=?1.48, 95?% CI 1.07-2.05) though this association attenuated after adjusting for age. Adult SEP (household crowding, occupation, income and car ownership) was not associated with adult-onset asthma. Lower father's occupational class in early life was associated with higher odds of asthma alone but lower odds of asthma with atopy in a cohort that preceded the 1960s rise in asthma prevalence. Different environmental exposures and/or disease awareness may explain this opposed socioeconomic patterning, but it is important to highlight that such patterning was already present before rises in the prevalence of asthma and atopy.     

2010—2017年柳州市恶性肿瘤疾病负担的研究

  目的  了解柳州市恶性肿瘤疾病负担,探索其流行病学特征,为有针对性制定肿瘤综合防控策略提供依据。  方法  对2010-2017年柳州市区恶性肿瘤死亡病例进行收集,采用伤残调整寿命年计算恶性肿瘤疾病负担。  结果  2010-2017年柳州市恶性肿瘤疾病负担为200 939.13人年,其中男性占62.00%,女性占37.99%;每千人损失DALY为21.59人年/1 000,DALY率男性大于女性;2010-2017年柳州市恶性肿瘤疾病负担呈现上升的趋势。恶性肿瘤疾病负担随着年龄的增长而增长,在30岁之后疾病负担增加。  结论  柳州恶性肿瘤疾病负担高于广西和全国平均水平,需进一步加强恶性肿瘤防治和干预措施。     

Prevalence of symptoms of severe asthma and allergies in Irish school children: an ISAAC protocol study, 1995-2007

Childhood asthma is a recurring health burden and symptoms of severe asthma in children are also emerging as a health and economic issue. This study examined changing patterns in symptoms of severe asthma and allergies (ever eczema and hay fever), using the Irish International Study of Asthma and Allergies in Childhood (ISAAC) protocol. ISAAC is a cross-sectional self-administered questionnaire survey of randomly selected representative post-primary schools. Children aged 13-14 years were studied: 2,670 (in 1995), 2,273 (in 1998), 2,892 (in 2002-2003), and 2,805 (in 2007). Generalized linear modelling using Poisson distribution was employed to compute adjusted prevalence ratios (PR). A 39% significant increase in symptoms of severe asthma was estimated in 2007 relative to the baseline year 1995 (adjusted PR: 1.39 [95% CI: 1.14-1.69]) increasing from 12% in 1995 to 15.3% in 2007. Opposite trends were observed for allergies, showing a decline in 2007, with an initial rise. The potential explanations for such a complex disease pattern whose aetiological hypothesis is still evolving are speculative. Changing environmental factors may be a factor, for instance, an improvement in both outdoor and indoor air quality further reinforcing the hygiene hypothesis but obesity as a disease modifier must also be considered.     

过敏性鼻炎儿童发生支气管哮喘的影响因素分析

  目的  探讨过敏性鼻炎患儿发生支气管哮喘的危险因素,为鼻炎患儿发生哮喘的早期诊断、治疗和预防提供依据。  方法  纳入2019年11月至2020年10月在首都儿科研究所变态反应科门诊就诊的单纯过敏性鼻炎患儿(117例)和过敏性鼻炎继发哮喘患儿(111例),采集病史,检测过敏原,对其临床特征、过敏原种类及危险因素等进行统计分析。  结果  单因素分析显示,鼻炎病程、鼻炎严重度、鼻炎类型、季节特征、宠物接触史、过敏性疾病家族史、霉菌、豚草、粉尘螨和户尘螨致敏与过敏性鼻炎患儿哮喘的发生相关(χ2值分别为6.15,8.79,3.99,9.44,5.17,4.43,8.48,10.38,6.18,5.31,P值均 < 0.05)。多因素Logistic回归分析显示,鼻炎严重度(OR=7.03)、过敏性疾病家族史(OR=8.24)、霉菌(OR=5.19)、粉尘螨(OR=25.25)与过敏性鼻炎患儿哮喘的发生呈正相关(P值均 < 0.05),粉尘螨致敏患儿的风险最高。  结论  儿童过敏性鼻炎继发哮喘受多种因素影响,其中鼻炎严重度、过敏性疾病家族史、尘螨致敏是最主要的因素。