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Respiratory Diseases in Children

3. Which circumstances can affect children’s sensitivity to respiratory diseases?

  • 3.1 What is the role of genetic factors?
  • 3.2 Could gender affect the development and frequency of asthma?
  • 3.3 Are the earliest stages of life critical for later respiratory health?
  • 3.4 Does poverty increase the risk of respiratory diseases?
  • 3.5 How are infections, asthma and allergies linked to living conditions?

The source document for this Digest states:

Host factors including genes gender age developmental stage ethnicity and social conditions will modify the effects of environmental exposure.

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 4.1 Preamble

3.1 What is the role of genetic factors?

The source document for this Digest states:

One of the most prominent and obvious examples in this regard is asthma and related atopy. In these conditions there is a genetic component in that children of affected parents have two to threefold increased risk of disease expression which is modified and influenced by environmental factors as evidenced by the large increases in prevalence over the past three to four decades.

Host suseptibility

Genetics

Pulmonary disease may accompany a number of genetic disorders in children and some pulmonary diseases have a genetic basis, although this is seldom based on simple Mendelian inheritance but may have polygenic or multifactorial aetiology. A clear exception to this is cystic fibrosis, which results from a variety of mutations in a single gene located on chromosome 7q that encodes the CFTR protein.

Asthma is a complex, polygenic disease that results from the exposure of genetically susceptible individuals to environmental triggers, possibly at critical stages of development, for the disease to be expressed. Linkage studies and genome-wide searches have identified a number of potential candidate genes for asthma and atopy [Anderson & Morrison, 1998] but no single gene accounts for a major part of the expression of the disease. Also, the rate of increase in asthma prevalence in the United Kingdom and other western countries is inconsistent with major shifts in population genetics. Therefore, attention has focussed on identification of environmental exposures that may be causally implicated in the aetiology of asthma and atopy and in triggering episodes.

Other pulmonary diseases that have a genetic basis but rarely present during childhood include interstitial lung disease in association with collagen disorders, such as lupus erythematosus, and sarcoidosis. There is increasing interest in the origins of chronic obstructive pulmonary disease (COPD), which has been demonstrated in several studies to cluster within families, independent of smoking status. It is possible that mechanisms such as oxidative lung injury due to deficiencies of components of the anti-oxidant defences, such as superoxide dysmutase and glatathione-S-transferases, are responsible for respiratory morbidity in childhood and that could be the antecedent of COPD in adults. Increasing knowledge of the genetic and cellular regulation of pulmonary inflammation and defence is likely to lead to new insights into the origins of pulmonary diseases. The challenge will be to recognise individuals at risk and develop effective interventions to prevent the onset or alter the natural history of some of these conditions. While genetic factors predispose children to develop asthma, convincing evidence demonstrates that a number of environmental factors – environmental tobacco smoke, poor indoor/outdoor climate and some allergens– contribute to the onset of allergic disease. Once the disease is established, these factors may also trigger symptoms. This points towards an interaction of genetic and environmental factors.

The results of genome screens for asthma-related traits in several populations have identified already at least 18 regions of the genome that probably house asthma/atopy genes [Cookson, 2002; Xu et al, 2001; Yokouchi et al, 2000; Hakonarson et al, 2002]. The most consistently replicated regions are on chromosomes 2q, 5q, 6p, 7q, 11q, 12q, 13q, 14q and 17q. Positional cloning projects are ongoing in laboratories around the world to identify the asthma susceptibility loci in these regions. In addition, many candidate genes have been associated with asthma phenotypes, such as the genes in the IL-4/IL-13 pathway. A research team in the UK and USA found multiple polymorphisms in the ADAM33 gene, which were associated significantly with an increased risk of asthma but no for atopy [Eerdewegh et al, 2002].

Substantial research efforts are made in US, Europe and Japan to elucidate the genetic background for the development of allergies and asthma. Asthma researchers perform gene-environment investigations by correlating genes important for asthma and allergy to the environmental exposures considered significant to immune system ontogeny and asthma symptoms phenotypes [Young Kreeger, 2003]. The scientific efforts in this area are facilitated by rapid technological developments in molecular biology (gene arrays, high-throughput screening systems).

Steven Kleeberger, of the U.S. National Institute of Environmental Health Sciences (NIEHS), found regions on chromosome 17 and 11 that are important contributors to ozone allergen susceptibility, as manifested by inflammation in the murine model's lung. The candidate gene is TNF-* on chromosome 17, a potent pro-inflammatory cytokine [Kleeberger et al, 1997]. Kleeberger and colleagues have also showed a link between the phenotype of ozone-induced increased permeability of lung tissue in a murine model and the Toll receptor Tlr-4 gene, which determines susceptibility to decreased lung epithelial cell function [Kleeberger et al, 2000]. If there is a mutation in Tlr-4, the mouse is protected against ozone-induced lung hyperperme- ability. Interestingly, Tlr-4 is also turned on during an endotoxin response. This evidence points to a critical role of the innate immune system in asthma.

Tarja Laitinen, of the University of Helsinki, and colleagues conducted a genome scan of a homogenous population from the Kainuu province of Finland. They found linkage in a region of chromosome 7 for three phenotypes: asthma, a high level of immunoglobulin E (IgE), and a combination of the two, with the strongest being the IgE level [Laitinen et al, 2001]. IgE is the most well-known molecular marker for allergies. Currently her group is trying to narrow the region on chromosome 7 to find a candidate gene. Along with colleagues at the Karolinska Institute in Stockholm, the Helsinki group is conducting an epidemiological study of young children in Finland and Sweden; they are looking for environmental triggers in conjunction with the chromosome 7 genotype.

Gene/environmental interactions

A recent study in Norway showed the significance of the joint effect of parental atopy and exposure to environmental tobacco smoke for asthma disease aggravation in children. This phenomenon – effect modification of environmental exposure by genetic constitution, or gene by environment interaction – suggests that certain genetic markers could indicate susceptibility to environmental factors [Jaakkola et al, 2001]. Starting in 2003, the Global Allergy and Asthma European Network (GALEN), co-funded by the European Commission (in the context of FP6) will bring together epidemiological, basic and clinical researchers to investigate allergy and asthma across the life course, including intra-uterine life and foeto-maternal interface; interaction between genetic and environmental factors in early life, translation of allergic sensitisation into disease and persistence of disease.

Genetic characterisation is also combined with epidemiology. An example of this is a US NIEHS funded project, which is approaching the causes of asthma by studying how and why different populations have such vastly different prevalences of the disease. Small cohorts in Southern California are compared with populations in Wuhan, China (where asthma prevalence is low) and Mexico City (where prevalence is slightly higher than in China but still lower than in the United States) to analyse how life patterns as well as exposures to known asthma-promoters such as ozone are implicated in the complex causation of the disease.

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 4 Modifiers

3.2 Could gender affect the development and frequency of asthma?

The source document for this Digest states:

Asthma is initiated in childhood with the majority of cases starting starting less than 5 years. In early childhood there is a male excess of asthma cases with a male:female ratio of 2:1. During adolescence this ratio reverses to a female predominance. Further evidence for these sex patterns is apparent in hospital admissions with asthma. This characteristic pattern may be informative in understanding the origins of this complex disease and in formulating novel therapies.

The timing of the sex reversal suggests a role for sex hormones in the expression of asthma. Despite the epidemiological evidence of sex predispositions, to date there are few data relating sex steroids to the pathogenesis of asthma. The powerful role played by sex hormones in the field of autoimmunity is already well established. This knowledge has led me to speculate the stimulatory properties of female hormones and the suppressant effects of male hormones on the immune system may explain the sex reversal in asthma. The effects of sex steroids on T helper cells, which initiate and perpetuate inflammatory responses, may influence the expression of asthma.

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 4.3 Gender

3.3 Are the earliest stages of life critical for later respiratory health?

The source document for this Digest states:

Fetal programming of lung disease in children and adults

There is growing evidence that fetal life and early childhood are critical periods of development during which many diseases that present during child and adult life may have their origins. In humans and other long-gestation species, the development of lung architecture occurs during fetal and early postnatal life. A number of epidemiological studies have demonstrated associations between prenatal factors that restrict intrauterine growth and respiratory symptoms in infancy. This observation led to speculation that factors, which impair fetal growth, may also constrain fetal lung development resulting in permanent changes to lung architecture. Barker et al (1991) described an association between low birth weight and lung function decrements in over 5000 adult males. Furthermore, respiratory infection during early childhood was associated with further decrements in adult lung function in this population, suggesting that either impaired lung function at birth was associated with predisposition to pulmonary infections during infancy or that respiratory infections, such as pneumonia and whooping cough, cause airway and lung remodelling which further impairs lung function. A follow up study of lung function in infancy has demonstrated reduced forced expiratory flows at the age of 2 months in infants who subsequently developed pneumonia [Castro Rodriguez et al, 1999] supporting a role for predisposition to infections in infants who already have pre- existing lung function impairment. Other epidemiological studies have confirmed an association between respiratory infections during infancy and early childhood and later functional abnormalities consistent with airway obstruction in adults [Shaheen et al, 1995]. In this context the typical U shaped distribution of symptomatic respiratory disease seen in whole populations (figure 3a) may in part reflect a link between the expression of early respiratory symptoms and the development of respiratory disease in late adult life.

Although lung diseases that have a clearly defined and identifiable genetic basis are rare in childhood there is increasing interest in the origins of chronic obstructive pulmonary disease (COPD), which has been demonstrated in several early studies to cluster within families, independent of smoking status [Kueppers et al 1977, Larson et al 1970]. It is possible that mechanisms such as oxidative lung injury due to deficiencies of components of the anti-oxidant defences, such as superoxide dysmutase and glutathione-S-transferases, are responsible contribute to respiratory morbidity in childhood [Fryer et al 2000, Gilliland et al 2002] and may continue as risk factors for COPD in adults [Ishii et al 1999]. Increasing knowledge of the genetic and cellular regulation of pulmonary inflammation and defence is likely to lead to new insights into the origins of pulmonary diseases. The challenge will be to recognise individuals at risk and develop effective interventions to prevent the onset or alter the natural history of some of these conditions.

Lung development and implications for disease

The links between development and disease are well illustrated in the respiratory system. Although anatomically there is no sudden change at the time of birth, enormous alterations in function occur during subsequent growth and development. The observation that respiratory illness has high prevalences in infancy and early childhood and again in late adult life points to possible links between early adverse environmental exposures and lifelong respiratory health [Barker 1991, Burrows 1980]. The most clearly identified adverse exposure at a whole population level is fetal tobacco smoke exposure associated with maternal smoking in pregnancy. Whereas postnatal or environmental tobacco smoke (ETS) exposure has a significant influence on respiratory morbidity in the young [Taylor & Wadsworth 1987] the effects of prenatal exposure are likely to be more long lasting. Studies which have assessed lung function soon after birth, when the effects of ETS would be expected to be small have shown evidence of reduced airway function [Hanrahan et al 1992, Young et al 1991]. Whereas it is clearly not possible to identify the exact mechanisms of these effects in humans, animal studies have shown that fetal ETS significantly reduces cell division in the lung as evidenced by reduced DNA, alveolar number and connective tissue within the lung [Collins et al1985, Vidic et al 1989].

Unique vulnerabilities

Apart from the evidence for intrauterine affects on the developing respiratory system the respiratory pattern, airway anatomy and physiology of the newborn infant are also likely to be contributory to a unique vulnerability to environmental exposure. The increasing metabolic demands of the rapidly growing infant requires a high ventilatory turnover. Infants have the same tidal volume as the adult on a per kilogram body weight basis but have an approximately three-fold increase in respiratory rates [Polgar & Weng 1979]. The consequence is an approximate three-fold increase in alveolar ventilation relative to body mass. Combined with a greater likelihood of sedimentation of respirable particulates in the conducting airways [Hislop et al 1972]. It should therefore not be surprising that exposures in fetal and life have lifelong implications for respiratory health.

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 4.4 Age/developmental stage

3.4 Does poverty increase the risk of respiratory diseases?

The source document for this Digest states:

Using the World Bank definition of $1/person/day, it is estimated that 2.1 billion of the world’s population live in conditions of absolute poverty below this threshold. Diseases associated with poverty are primarily infectious diseases, which are linked to inadequate income, lack of access to clean water and sanitation, malnutrition and poor access to medical services. In developing countries, the commonest causes of death in children under 5 years of age are lower respiratory infections, diarrhoeal illnesses and measles. Acute lower respiratory tract infections account for 2.1 million deaths annually in young children in the developing world with approximately 40% estimated to be related to malnutrition [WHO Report on Childhood Illnesses, 1997; State of the World’s Children

2000, UNICEF]. Some developing countries have achieved lower rates of poverty related ill health by government interventions in health, education and social security and also by active programmes to increase the levels of female literacy in their populations.

In the United Kingdom, adults and children of lower socio-economic status have also been demonstrated to be at higher risk of communicable diseases, particularly respiratory infections [Cohen, 1999]. A longitudinal study of a U.K. cohort born in 1946 demonstrated that a poor home environment, parental bronchitis and atmospheric pollution were the best predictors of lower respiratory infections in the first two years after birth and these factors together with later smoking and childhood respiratory infections were the best predictors of lower respiratory tract diseases in adults [Mann et al, 1992]. It is possible that increased infections in socially disadvantaged populations are related to crowding and increased exposure to infectious agents or to alterations in host immunity, possibly related to nutritional status. One of the characteristic diseases of social deprivation, tuberculosis, has recently shown a reversal of the decline in notified cases in England. (Public Health Laboratory Service (http://www.phls.co.uk)) with the largest number of cases reported from urban regions. Studies of variations in tuberculosis rates between electoral wards in inner cities have suggested that the country of birth was the single most explanatory variable, with measures of poverty being of only secondary importance [Beckhurst et al, 2001; Bennett et al, 2001].

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 4.5 Ethnic groups/Social deprivation

3.5 How are infections, asthma and allergies linked to living conditions?

The source document for this Digest states:

Host factors may modify both the expression of genes and also the responses to environmental stimuli. Thus, in theory they provide a powerful place to intervene in order to prevent disease. There is already much evidence that environmental factors can modify host factors with respect to the expression of a number of important childhood respiratory diseases.

All conditions result from interactions between genes and the environment. Even primarily genetic conditions such as cystic fibrosis may be influenced importantly by environmental factors while environmental conditions such as pneumonia may have genetic pre-determinants. In this section we consider the more important respiratory conditions, asthma, infections, cot death and cystic fibrosis.

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 6 Host Factors

3.5.1 Infections

The source document for this Digest states:

Infectious diseases in Europe exemplify the effectiveness of classical public health action in dealing with known risk factors. Even before antibiotics and immunisation, tuberculosis declined as a consequence of case finding, segregation of infectious people into sanatoria and improvement of housing, nutrition and living standards, with reduction of overcrowding. Immunisation with BCG is an effective method of reducing the expression of childhood tuberculosis and of preventing the important complications such as meningitis in countries where the infection is still prevalent. The incidence of measles has responded to mass immunisation programmes, although resurgence may be expected in response to public fears of vaccination, echoing the early days of the prevention of smallpox.

In terms of deaths caused, pneumonia is the most important childhood respiratory disease. The immediate cause is infection but poverty, poor housing, overcrowding, malnutrition and poor medical services are contributory causes. Similar factors contribute to viral bronchiolitis of childhood. It should be noted that the benefits of antibiotics since the 1950s in treating infectious diseases of childhood have to some extent been countered by a growing problem of antibiotic resistance and the development of organisms, particularly Staphylococcus aureus and Mycobacterium tuberculosis, resistant to multiple drugs. Much of this may be attributed to inappropriate use of antibiotics. Despite the obvious benefits of antibiotics there is some evidence that their early administration may be a factor in the rise in allergic disease [Helms 2001].

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 6.1 Infections

3.5.2 Asthma and Atopy

The source document for this Digest states:

Unlike most of the conditions mentioned above, asthma and allergies have become increasingly frequent in the prosperous countries of Western Europe, although they remains much less common in the Eastern part of the continent. A number of genetic polymorphisms have been described (see section 4.2.1) as associated with the risk of asthma, but the change in prevalence over a short period of two or three decades and the variation from country to country within Europe and the wider world speaks for important environmental determinants. In the broadest sense, this appears to be something associated with increasing national prosperity (not "westernisation", since it has been observed, for example, in Saudi Arabia). Two plausible hypothetical explanations have been advanced for increasing population susceptibility to allergic disease - changes in patterns of exposure to micro-organisms (the hygiene hypothesis) and alterations in diet and energy output.

The Hygiene hypothesis

The hygiene hypothesis was originally based on an inverse relationship between infections and hayfever. leading the concept that protection of younger infants may be derived from infections passing round the family, altering their immune development from one primarily allergic (mediated by T helper 2 lymphocytes) to an anti-infective T helper 1 lymphocyte response. This concept has to answer two important objections. First, there has in fact also been an increase in T helper 1 associated diseases such as diabetes, and the two types of disease are not mutually exclusive. Secondly, the immunological features of the family size effect appear to be present in cord blood before the child is born, suggesting that the effect is unrelated to infections acquired in post-natal life, but is more likely due to the mother's increasing immune tolerance of her children in utero. Nevertheless, there is evidence that some infections early in childhood, including measles and hepatititis A and possibly tuberculosis, may protect against later allergies and perhaps asthma. Recent research along these lines has investigated the possibility of temporal changes in the species of micro-organisms colonising the gut as patterns of early diet change, altering immune programming in the infant - in fact, a variant of the dietary hypothesis.

Strachan (1989) first proposed the 'hygiene hypothesis' that infections in early childhood prevented the development of allergic diseases. An inverse relationship was observed between family size, particularly the presence of older siblings, and features of allergic disease, including hay fever and positive skin prick test responses, but not with asthma. Recent observations that the prevalence of allergy is reduced in farming communities [von Ehrenstein et al, 2000] might also be explained by increased exposure to infections in early life in this setting, although other differences in lifestyle between rural farming and urban communities are possible confounders of this relationship. T cell responses may be central to the mechanisms of these observed associations. Activated T lymphocytes are important in maintaining lung inflammation in adults with asthma and the demonstration of increased concentrations of soluble interleukin 2 receptors in children with asthma suggests that activated T cells are important in this context also. Atopy in children has been proposed to represent persistence of fetal Th2 responses [Prescott et al, 1999] with the production of type 2 cytokines (interleukins 4, 5, 6, 10, 13) in response to allergens. Infections may be important in early childhood by stimulating Th1 predominant responses (IL 2, interferon, TNF). Survivors of a measles epidemic in Guinea-Bissau were found to have decreased prevalence of atopy compared with immunised children [Shaheen et al, 1996], although the possibility that children with impaired Th1 responses were more susceptible to dying during the epidemic has been raised. Also, exposure to tuberculosis has been shown to result in lower prevalence of atopy, but not asthma, in a large Finnish study [Von Hertzen et al, 1999]. The potential for immune modulation of T helper response by bowel flora and the effect of antibiotics on bowel colonisation has also been studied. These clinical observations together with laboratory studies of T cell sensitisation have led to the development of strategies to modulate the switch from Th2 to Th1 predominant responses, either by allergen avoidance from early gestation [Jones et al, 1998] or by the development of vaccines, Th1 selective adjuvants or immunotherapy.

In addition to potential protective effects on later development of asthma, viral respiratory infections have also been proposed as contributors to the development of obstructive airways disease. A number of studies have reported persistent or recurrent wheezing after RSV bronchiolitis in infants . However, there is still debate about whether RSV causes asthma or whether severe RSV infection is a manifestation of pre- existing risk factors for both bronchiolitis and asthma [Sigurs, 2001]. It is hoped that randomised control trials of RSV prophylaxis will be able to address some of these questions but these are currently restricted to high-risk infants.”

Diet

The prenatal effects of maternal famine were studied in a Dutch population exposed to the famine of 1944-45. The prevalence of obstructive airways diseases in the offspring of famine-exposed mothers was higher, particularly when the exposure occurred in early gestation. This effect did not appear to be mediated through increased prevalence of atopic disease in this population, suggesting that impairment of fetal lung development was an important factor.

A number of dietary constituents have been examined in relation to their potential role in the aetiology of lung diseases, including fatty acids, anti-oxidants and sodium intake. The observation that Eskimos had a low prevalence of lung disease and a diet high in oily fish prompted speculation that n-3 fatty acids, which competitively inhibit the metabolism of arachidonic acid, may be protective against asthma [Schwartz, 2000]. However, there is only weak evidence for this and no intervention studies have yet been done.

Oxidative damage to the lungs, mediated through oxygen free radicals, is believed to be important in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Fruit is a major source of antioxidant vitamins and epidemiological associations between fruit intake and lung function in adults have been established. A positive association between fresh fruit consumption and lung function has also been demonstrated in children [Cook et al, 1997]. Selenium is essential to the activity of glutathione peroxidase enzymes that are involved in the lung's antioxidant defences. Low serum concentrations of selenium have been demonstrated in subjects with asthma but it is unclear whether selenium deficiency contributes to the development of asthma or if selenium consumption occurs as a consequence of oxidant injury. A recent ecological study of asthma and allergy (ISAAC) did not demonstrate an increased prevalence in countries in which selenium deficiency is endemic [Moreno-Reyes et al, 1998] compared with areas with abundant dietary selenium sources. Low dose vitamin A supplementation has been examined for its possible protective role in the development of lower respiratory infections in children. Two intervention studies in developing countries have suggested that this effect is strongly related to nutritional status with decreased acute lower respiratory infections observed in underweight children only [Sempertegui al, 1999; Fawzi et al, 2000] and adverse effects noted in children of normal nutritional status.

Regional differences in asthma mortality have been correlated with table salt purchase, leading to the possibility that dietary sodium may be an important factor in asthma pathogenesis. However, dietary salt intake in children has been associated with increased bronchial responsiveness to methacholine but not with a diagnosis of asthma or with exercise induced bronchospasm [Demissie et al, 1996].”

In utero and infant environment

There is evidence that intra-uterine factors influence risks of asthma and allergies, but not always in the same direction. The strongest associations are with allergic rhinitis, the risks of which are increased in the children of young mothers and decreased in premature and low birthweight children. In contrast, asthma is more likely in children of older mothers and less likely in high birthweight children. Maternal smoking in pregnancy is associated with lower birthweight, reduced lung function and increased respiratory symptoms in the infant, but the effects on longer-term risks of asthma and allergies are equivocal. Breast-feeding, if prolonged for about 6 months or more, appears to protect against early respiratory symptoms, possibly by transfer of immunity, but again effects on longer-term risks of asthma and allergy are equivocal.

Source & ©: EU   "Baseline Report on Respiratory Health" in the framework of the European Environment and Health Strategy (COM(2003)338 final), Section 6.2 Asthma and Atopy


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