Do risk factors for childhood infections and malnutrition protect against asthma? A study of Brazilian male adolescents

OBJECTIVES: We studied the association between early life conditions and asthma in adolescence. METHODS: We conducted a population-based birth cohort study involving 2250 male 18-year-olds residing in Brazil. RESULTS: Approximately 18% of the adolescents reported having asthma. Several childhood factors were found to be significantly associated with increased asthma risk: being of high socioeconomic status, living in an uncrowded household, and children being breastfed for 9 months or longer. CONCLUSIONS: The present results are consistent with the "hygiene hypothesis," according to which early exposure to infections provides protection against asthma. The policy implications of our findings are unclear given that risk factors for asthma protect against serious childhood diseases in developing countries.     

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.     

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.     

Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults: The Adverse Childhood Experiences (ACE) Study

Background: The relationship of health risk behavior and disease in adulthood to the breadth of exposure to childhood emotional, physical, or sexual abuse, and household dysfunction during childhood has not previously been described.Methods: A questionnaire about adverse childhood experiences was mailed to 13,494 adults who had completed a standardized medical evaluation at a large HMO; 9,508 (70.5%) responded. Seven categories of adverse childhood experiences were studied: psychological, physical, or sexual abuse; violence against mother; or living with household members who were substance abusers, mentally ill or suicidal, or ever imprisoned. The number of categories of these adverse childhood experiences was then compared to measures of adult risk behavior, health status, and disease. Logistic regression was used to adjust for effects of demographic factors on the association between the cumulative number of categories of childhood exposures (range: 0–7) and risk factors for the leading causes of death in adult life.Results: More than half of respondents reported at least one, and one-fourth reported ≥2 categories of childhood exposures. We found a graded relationship between the number of categories of childhood exposure and each of the adult health risk behaviors and diseases that were studied (P < .001). Persons who had experienced four or more categories of childhood exposure, compared to those who had experienced none, had 4- to 12-fold increased health risks for alcoholism, drug abuse, depression, and suicide attempt; a 2- to 4-fold increase in smoking, poor self-rated health, ≥50 sexual intercourse partners, and sexually transmitted disease; and a 1.4- to 1.6-fold increase in physical inactivity and severe obesity. The number of categories of adverse childhood exposures showed a graded relationship to the presence of adult diseases including ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease. The seven categories of adverse childhood experiences were strongly interrelated and persons with multiple categories of childhood exposure were likely to have multiple health risk factors later in life.Conclusions: We found a strong graded relationship between the breadth of exposure to abuse or household dysfunction during childhood and multiple risk factors for several of the leading causes of death in adults.     

Determinants of stimulated peripheral blood cytokine production among farming women

Farming environment and environmental exposure to microbial agents have been suggested to promote favorable development of immune system in children and protect against allergic diseases. However, effects of farm exposure on adult immune responses are less clear. Aim of the present study was to examine associations of farm related factors and measured microbial exposure with stimulated production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) in peripheral blood samples among farming women. Whole peripheral blood samples were obtained from 112 women living on farms and stimulated with phorbol myristate acetate/ionomycin, lipopolysaccharide and staphylococcal enterotoxin B. Following 24h stimulation, protein levels of IFN-γ and IL-4 in the supernatants were measured by ELISA. From house dust, concentrations of 3-hydroxy fatty acids (C10:0-C14:0, marker for Gram-negative bacteria), muramic acid (Gram-positive bacteria) and ergosterol (fungal biomass) were analyzed with GC-MS/MS and viable microbes by culturing. Information on farm related factors and allergic diseases were collected from self-administered questionnaires. We found that household pets or other current or childhood farm-related factors had only few associations with stimulated cytokine production among studied farming women. Similarly, no strong associations were observed between markers of microbial exposure measured in house dust and cytokine levels. Atopic sensitization, allergic rhinitis and recent respiratory infections were, however, associated with reduced IFN-γ production. Our results suggest that the capacity of the studied environmental factors to modulate immune system is relatively weak in adulthood.     

Nutritionally mediated programming of the developing immune system

A growing body of evidence highlights the importance of a mother's nutrition from preconception through lactation in programming the emerging organ systems and homeostatic pathways of her offspring. The developing immune system may be particularly vulnerable. Indeed, examples of nutrition-mediated immune programming can be found in the literature on intra-uterine growth retardation, maternal micronutrient deficiencies, and infant feeding. Current models of immune ontogeny depict a "layered" expansion of increasingly complex defenses, which may be permanently altered by maternal malnutrition. One programming mechanism involves activation of the maternal hypothalamic-pituitary-adrenal axis in response to nutritional stress. Fetal or neonatal exposure to elevated stress hormones is linked in animal studies to permanent changes in neuroendocrine-immune interactions, with diverse manifestations such as an attenuated inflammatory response or reduced resistance to tumor colonization. Maternal malnutrition may also have a direct influence, as evidenced by nutrient-driven epigenetic changes to developing T regulatory cells and subsequent risk of allergy or asthma. A 3rd programming pathway involves placental or breast milk transfer of maternal immune factors with immunomodulatory functions (e.g. cytokines). Maternal malnutrition can directly affect transfer mechanisms or influence the quality or quantity of transferred factors. The public health implications of nutrition-mediated immune programming are of particular importance in the developing world, where prevalent maternal undernutrition is coupled with persistent infectious challenges. However, early alterations to the immune system, resulting from either nutritional deficiencies or excesses, have broad relevance for immune-mediated diseases, such as asthma, and chronic inflammatory conditions like cardiovascular disease.     

In utero DNA immunisation. Immunity over tolerance in fetal life

The function and plasticity of the developing immune system during embryonic life has been central to immunological thinking for half a century. A classical view is that antigen encountered during fetal life induces a state of acquired immunological tolerance. However, the ability to develop T cell immune responses during the perinatal period would be of great importance against intracellular pathogens. Recent experiments have challenged this notion and shown that neonatal tolerance can be circumvented by extrinsic immunological manipulations. Here, we used DNA immunization targeted at B lymphocytes to induce a CD4 T cell response that could be measured 2 weeks after birth. We conclude that T cell immunity can be programmed in utero by manipulating the parameters of the immune response in the fetal environment. Furthermore, our data suggest that under appropriate conditions the fetal immune system can be programmed to immunity.     

Pesticides and childhood cancer: an update

OBJECTIVES: Epidemiological studies have reported associations between childhood cancer and either parental or child exposure to pesticides. Reviews have been published in 1997, 1998 and 2006 where the evidence was found suggestive but not conclusive. The present review is an extended update of the latter one. METHODS: The PubMed database was searched to identify published studies on this topic issued between 1998 and 2006. RESULTS: Thirty-six new studies have been identified for this review. Some cohort studies and the majority of the case-control studies suggest an increased risk for the cancer types studied, associated with exposure to pesticides in at least one of a large variety of exposure categories. However, the evidence is conflicting with regard to cancer types as well as to causative factors across studies. The major shortcomings concern exposure assessment, where, e. g., "farming" is treated equal to "exposure to pesticides", disregarding other possible exposures, e.g., to biological or infectious agents, and hitherto unidentified lifestyle factors. Also, many exposure categories used, mainly in case-control studies, lack chemical or toxicological plausibility. In most studies exposures were categorized as "ever vs. never", with little regard of exposure intensity or duration. CONCLUSIONS: The available literature does not allow firm conclusions with regard to pesticides and any type of childhood cancer. But even if the reported associations were true, exposure to pesticides could not explain the vast majority of childhood cancer cases. Investing in the acquisition and critical review of exposure information appears to be the crucial step for causal assessment in future research. However, focusing on the presence of pesticides, and not asking the question why they were used, might mask relevant associations to other causative agents.     

Sun exposure, vitamin D, and risk of Hodgkin and non-Hodgkin lymphoma

Similarities in the epidemiology of melanoma, other skin cancers, and non-Hodgkin lymphoma (NHL) have led to the hypothesis that UV exposure, the major risk factor for cutaneous cancers, could play a role on NHL risk too. Epidemiologic studies, however, including a pooled analysis of 10 case-control studies performed by the Interlymph consortium, have failed to confirm this hypothesis. If anything, an inverse association between sun exposure and NHL risk was reported, which appeared confined to recreational sun exposure. Given that sun exposure is the major determinant of vitamin D status in several populations and that vitamin D has been suggested to protect against cancer at several sites, it has been postulated that vitamin D may protect against NHL. Studies that have investigated the association of nutritional sources of vitamin D or serum levels of 25 hydroxy-vitamin D-an indicator of vitamin D status-with NHL are scanty and not totally consistent. Thus, the epidemiologic evidence to date suggests that sun exposure is not likely to increase NHL risk, whereas the vitamin D-NHL relation remains largely undefined. The paucity of information on the relation of sun exposure or vitamin D with adult Hodgkin lymphoma (HL) or childhood lymphomas prevents any definite conclusion.     

Sun Exposure,Vitamin D,and Risk of Hodgkin and Non-Hodgkin Lymphoma

Similarities in the epidemiology of melanoma, other skin cancers, and non-Hodgkin lymphoma (NHL) have led to the hypothesis that UV exposure, the major risk factor for cutaneous cancers, could play a role on NHL risk too. Epidemiologic studies, however, including a pooled analysis of 10 case-control studies performed by the Interlymph consortium, have failed to confirm this hypothesis. If anything, an inverse association between sun exposure and NHL risk was reported, which appeared confined to recreational sun exposure. Given that sun exposure is the major determinant of vitamin D status in several populations and that vitamin D has been suggested to protect against cancer at several sites, it has been postulated that vitamin D may protect against NHL. Studies that have investigated the association of nutritional sources of vitamin D or serum levels of 25 hydroxy-vitamin D—an indicator of vitamin D status—with NHL are scanty and not totally consistent. Thus, the epidemiologic evidence to date suggests that sun exposure is not likely to increase NHL risk, whereas the vitamin D-NHL relation remains largely undefined. The paucity of information on the relation of sun exposure or vitamin D with adult Hodgkin lymphoma (HL) or childhood lymphomas prevents any definite conclusion.     

Protecting you/protecting me: effects of an alcohol prevention and vehicle safety program on elementary students

This paper describes an evaluation of Protecting You/Protecting Me (PY/PM), a classroom-based, alcohol-use prevention and vehicle safety program for elementary students in first through fifth grades developed by Mothers Against Drunk Driving. PY/PM lessons and activities focus on teaching children about (I) their brains (why their brain is important, how their brain continues to develop throughout childhood and adolescence, what alcohol does to the developing brain, and why it is important to protect their brain); (2) vehicle safety (what to do to protect themselves should they ever ride with an impaired driver); and (3) life skills (decision making, stress management, and media literacy). Fourth- and fifth-grade students from schools in the fourth year of PY/PM implementation were surveyed. Results indicated that, relative to comparison students from matched schools, PY/PM students increased their knowledge of alcohol's effect on development; gained decision-making, stress-management, and vehicle safety skills; and demonstrated changes in attitudes toward underage alcohol use and its harm. Further, students retained lessons learned in previous years and their scores improved with increased exposure to PY/PM. In addition, the findings demonstrate that it is possible to design and implement a program that can improve young children's knowledge regarding alcohol and their developing brains, teach them skills to protect themselves in dangerous situations, increase already high antialcohol attitudes, and change perceptions of alcohol's harmfulness.     

Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure

Fetal and early postnatal life represent critical periods in vertebrate immune system development. Disruption of such development by perinatal immunotoxic chemical exposure has been widely described in experimental animal models. The resultant inhibited postnatal immune responses in such animals are often more dramatic and persistent than those after exposure during adult life. Further, recent reports suggest that prenatal exposure to immunotoxicants may exacerbate postnatal aberrant immune responses (e.g., hypersensitivity disorders and autoimmune disease) in genetically predisposed rodents. Limited information is available regarding the possibility of inhibited postnatal immune capacity in humans as a result of developmental immunotoxicant exposure. The multifactorial nature of hypersensitivity and autoimmune responses will further complicate the elucidation of possible relationships between chemical exposure during ontogeny of the human immune system and immune-mediated disease later in life. Taken together, however, the available animal data suggest the potential for altered postnatal immune function in humans exposed to immunotoxicants (e.g., environmental chemicals and therapeutic agents) during fetal and/or early postnatal life.     

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。     

Health and environment information systems for exposure and disease mapping, and risk assessment

A large number of chemicals are used on a regular basis in modern society. Thousands of new chemicals are added each year, many of which may have toxic properties constituting potential health hazards. Rapid assessment of the risk associated with the use of these chemicals is therefore essential to protect people from exposure to potentially harmful substances. Exposures to chemicals (and physical agents) are typically unevenly distributed geographically as well as temporally. Disease occurrence also shows geographically varying patterns. Geographic information systems (GIS) may be used to produce maps of exposure and/or disease to reveal spatial patterns. Exposure mapping using advanced GIS modeling may enhance exposure assessment in environmental epidemiology studies. Disease maps can be valuable tools in risk assessment to explore changes in disease patterns potentially associated with changes in environmental exposures. Spatial variations in risk and trends related to distance from pollution sources may be studied using software tools such as the Rapid Inquiry Facility, developed by the U.K. Small Area Health Statistics Unit and enhanced in the European Health and Environment Information System project, for an initial quick evaluation of any potential health hazards associated with an environmental pollutant.     

Identifying critical windows of exposure for children's health

Several authors have considered the importance of exposure timing and how this affects the outcomes observed, but no one has systematically compiled preconceptional, prenatal, and postnatal developmental exposures and subsequent outcomes. Efforts were undertaken to examine the information available and to evaluate implications for risk assessment for several areas: a) respiratory and immune systems, b) reproductive system, c) nervous system, d) cardiovascular system, endocrine system, and general growth, and e) cancer. Major conclusions from a workshop on "Critical Windows of Exposure for Children's Health" included a) broad windows of sensitivity can be identified for many systems but detailed information is limited; b) cross-species comparisons of dose to target tissue and better data on the exposure-dose-outcome continuum are needed; c) increased interaction among scientific disciplines can further understanding by using laboratory animal results in designing epidemiological studies and human data to suggest specific laboratory studies on mechanisms and agent-target interactions; and d) thus far, only limited attention has been given to peripubertal/adolescent exposures, adult consequences of developmental exposures, and genome-environment interactions. More specific information on developmental windows will improve risk assessment by identifying the most sensitive window(s) for evaluation of dose-response relationships and exposure, evaluation of biological plausibility of research findings in humans, and comparison of data across species. In public health and risk management, information on critical windows may help identify especially susceptible subgroups for specific interventions.     

Immunosuppression and vaccinations

Immunocompromised subjects have a higher risk of infection. Some infectious risks could be controlled by vaccination, carried out according to normal schedules, in the absence of effective curative treatment. According to the type of immunodeficiency and its severity, certain vaccines may be recommended, others should be avoided and still others may be used with no particular risk. Thus, in immuno-compromised subjects, vaccines consisting of inactivated, inert or dead microorganisms are indicated. In contrast, those consisting of live microbes are not recommended for several reasons: 1) there is a risk that the immunocompromised host will be unable to control infection with the vaccine; 2) there is a risk of an increase in viral replication, particularly in HIV-infected subjects and 3) there is a risk that the response of the immune system will be poor. HIV-infected individuals now account for most of the cases of secondary immuno-deficiency, following the emergence of AIDS in 1980. They are increasing in number, especially in developing countries, where antiretroviral treatment is not widely available. In this context, vaccinations against transmissible childhood viral and bacterial diseases (e.g. measles and polio) with a high prevalence is advisable, with modifications according to the risk of contagion and the degree of immunodeficiency. However, these vaccines do not target opportunist infections, the prognosis of which is poor and against which we have no vaccines. Other vaccines are recommended only for immunocompromised subjects visiting countries with specific epidemiological situations (endemic or epidemic diseases) or if vaccination is required by the country visited.     

Childhood cultural experience and the incidence of coronary heart disease in Hawaii Japanese men.

Possible effects of cultural variables on the risk of coronary heart disease (CHD) were examined in 7705 men of Japanese ancestry living in Hawaii. The six-year incidence of CHD was related to birthplace (Japan or elsewhere), number of years spent in Japan, ability to read and write Japanese, ability to speak Japanese, and to an index of preference for a traditional Japanese diet. Statistically significant inverse relationships were found between CHD incidence and all of these variables which reflect the degree of exposure to Japanese culture during childhood. In multivariate analyses where the major CHD risk factors were taken into account, years spent in Japan and ability to read and write Japanese remained significant. Hence, exposure to Japanese culture during childhood appears to protect against CHD in adulthood. This may explain, in part, the gradient of CHD frequency among Japanese in Japan, Japanese-Americans, and Caucasians that could not be entirely attributed to the established risk factors.     

Immunization

Immunization is an essential component of primary health care and child survival activities throughout the world. Since the establishment of the World Health Organization's Expanded Programme on Immunization (EPI) in 1974, the estimated incidence of childhood vaccine-preventable diseases has declined significantly. Today, immunization against the 6 diseases targeted by EPI--diphtheria, measles, pertussis, polio, tetanus and tuberculosis--prevents approximately 2 million childhood deaths per year. Nevertheless, many women and children in the developing world remain unimmunized, resulting in the death or disability from vaccine-preventable diseases of over 3 million children annually. Currently, efforts are focused on expanding immunization services for women and children with the goal of protecting all children against the 6 EPI-targeted diseases. Recent initiatives call for the eradication of polio by 2000, the elimination of neonatal tetanus by 1995, and a 95% reduction in measles incidence by 1995. Expanding immunization coverage against hepatitis B and yellow fever also are objectives in areas where these diseases are endemic. To achieve these goals, current immunization program priorities include: 1) the continued use of current vaccines as well as the introduction of new more effective, and more stable ones; 2) the development and improvement of cold chain technologies to safely transport, store, and distribute vaccines; 3) the development and improvement of injection technologies to ensure proper administration of vaccines and safe handling of injection equipment; and 4) efficient program management that strives to achieve and sustain expanded coverage and service delivery through improved training, supervision, evaluation and community mobilization. The most recent developments in these areas are reviewed, updating a 1983 "Directions" issue on the same topic.     

Infectious etiologies of childhood leukemia: plausibility and challenges to proof

Infections as well as environmental exposures are proposed determinants of childhood acute lymphoblastic leukemia (ALL), particularly common precursor B-cell ALL (cALL). Lines of investigation test hypotheses that cALL is a rarer result of common infection, that it results from uncommon infection, or that it ensues from abnormal immune development; perhaps it requires a preceding prenatal or early childhood insult. Ideally, studies should document that particular infections precede leukemiA and induce malignant transformation. However, limited detection studies have not directly linked specific human or nonhuman infectious agents with ALL or cALL. Primarily based on surrogate markers of infectious exposure, indirect evidence from ecologic and epidemiologic studies varies widely, but some suggest that infancy or early childhood infectious exposures might protect against childhood ALL or cALL. Several others suggest that maternal infection during pregnancy might increase risk or that certain breast-feeding practices decrease risk. To date, evidence cannot confirm or refute whether at least one infection induces or is a major co-factor for developing ALL or cALL, or perhaps actually protects against disease. Differences in methodology and populations studied may explain some inconsistencies. Other challenges to proof include the likely time lag between infection and diagnosis, the ubiquity of many infections, the influence of age at infection, and the limitations in laboratory assays; small numbers of cases, inaccurate background leukemia rates, and difficulty tracking mobile populations further affect duster investigations. Nevertheless, existing evidence partially supports plausibility and warrants further investigation into potential infectious determinants of ALL and cALL, particularly in the context of multifactorial or complex systems.     

Strategies for prevention and management of hypertension throughout life

Hypertension has been acknowledged as one of the greatest and established risk factors for cardiovascular diseases. In this special article, strategies for the prevention and management of hypertension throughout human's life were discussed. Studies showing the relationship of birth weight and height increase in childhood to future blood pressure suggest that both environments during pregnancy and during childhood and adolescence are important to prevent hypertension. The promotion of a DASH (Dietary Approach to Stop Hypertension) dietary pattern, rich in fruits and vegetables, is important not only for treatment of high blood pressure but also for long-term prevention of blood pressure rise as well. Blood pressure measured in young adulthood can effectively predict long-term risks of cardiovascular and all-cause mortality, so population-wide primary prevention of high blood pressure for young adults is important. Recent large scale cohort studies confirmed that detection and evaluation of hypertension based mainly on systolic blood pressure remains the most practical and easy approach in the general population for young adult, middle-aged, and older men and women. Researchers in Asia are desired to establish high-quality epidemiologic evidences for Asian for the prevention and management of hypertension.