The detrimental effects of poor air quality and dwelling standards have been recognized for many centuries. Indoor air pollution can be traced to the prehistoric era when humans first moved to colder climates ∼200,000 years ago, requiring the construction of shelters and the use of indoor fires for cooking, warmth and light. Paradoxically fire, which allowed humans to enjoy the benefits of living indoors, resulted in exposure to high levels of pollution as evidenced by the carbon soot found in prehistoric caves.1 In developing countries during the mid-19th century, the recognition of infectious agents and microbes and the empirical evidence that the highest incidence of severe infectious disease in cities occurred where the population was most dense (per hectare or per dwelling) led to a public health concern and the first statutory controls on housing. For example, in Britain the Artisans and Laborers Dwellings Act of 1848 required all habitable rooms to have a window that can open, that the dwellings be connected with a sewer and that an earth or water closet be provided for every 2 dwellings.2 Since then, housing standards have evolved to meet the broader health and social requirements of modern life. It is estimated that now, centuries later, approximately half of the world's population (up to 90% of rural households), predominantly in developing countries, still rely on biomass fuels for energy.3 These raw fuels, burned indoors in open fires or poorly functioning stoves, lead to levels of air pollution that are among the highest ever measured. Such indoor environments have also not been afforded the luxuries of public health acts enforced in developed countries. Therefore, overcrowding, inadequate arrangements for waste disposal, poor ventilation, dampness and numerous other housing problems remain threats to the health of low income groups and are still modern menaces to health. We discuss the relationship of these factors to respiratory and nonrespiratory infections.
AIR QUALITY AND INFECTION
The Historical Menace.
In developed countries, the combustion of biomass fuels indoors has historically led to poor air quality outdoors. Severe outdoor air pollution episodes have occurred since the early 17th century, but with rapid industrialization, such episodes became more severe and more frequent throughout the 19th century.4 Legislation at this time, for example in the United Kingdom, led only to a reduction in smoke from industry, and difficulties in implementation gave little improvement in air quality until the early 20th century. Severe smog episodes through industrial and domestic combustion of solid fuels (coal) occurred during calm, winter weather. Between 1948 and 1962, 8 air pollution episodes occurred in London. The “Great Smog” episode of December 1952 was the most significant, with smoke concentration rising >50 times above the average. At the time, an estimated human death toll of 4000 occurred during this period, signifying a 3-fold increase over the expected mortality rates for that time of year. Most deaths were among infants, the elderly and those with chronic respiratory disease.5 Similar episodes of severe air pollution in the United States after World War II aroused great public concern about the health effects of air pollutants.
Increased public and parliamentary concern led to effective legislation. Subsequent Clean Air Acts of 1956 and 1968 in the United Kingdom and the Clean Air Act of 1970 in the United States considerably reduced air pollution from stationary sources from homes, commerce and industry. Both the emission of smoke and sulfur dioxide fell dramatically.5 The mortality related to these smog episodes has been significantly underestimated. For example, reanalysis of the London winter smog mortality data of 1952 indicated the number of deaths was underestimated at 4000 and was actually closer to 12,000.6 The steep rise in mortality was sustained for several months and did not drop immediately after the resolution of the smog episode (as might be expected if it were simply a triggering phenomenon). Much of the mortality was related to excess episodes of pneumonia and only a fraction were accounted for by a concurrent influenza epidemic.
A Global Menace.
In developing countries, smoking among women is rare and outdoor pollution is restricted to larger cities, yet both women and children suffer a huge burden of respiratory illness, largely through acute respiratory infections (ARIs). ARIs are responsible for nearly a third of all deaths in children younger than 5 years old7 and are the leading cause of the global burden of disease, accounting for more than 6% of worldwide disease and mortality in developing countries.8 Acute lower respiratory infections were estimated to have caused up to 4 million deaths worldwide in 1997.9
Poor sanitation, low birth weight and poverty contribute to the causes of infections, but the combustion of biomass fuels remains a significant problem. Globally the main source of indoor air pollution is the combustion of biomass fuels such as wood, dung and charcoal, because these are the main sources of domestic energy. They produce small amounts of energy but large amounts of indoor pollutants, often emitting 50 times more pollutant concentrations than energy-equivalent natural gas.10 A variety of pollutants, including particulate matter smaller than 10 mm in diameter (PM10), nitrogen dioxide (NO2), carbon monoxide, sulfur dioxide and hydrocarbons, are emitted. The often poor ventilation and dispersion characteristics of dwellings in developing countries allow pollutant concentrations to rise further, and indoor concentrations of particulates between 500 and 100,000 μg/m3 are not uncommon.11,12 Based on the evidence available, peak and daily exposures to indoor particulate levels in developing countries seem to be about 20 times greater than in developed nations. Results from environmental tobacco studies have documented a dose–response relationship between number of cigarettes smoked in the home and respiratory symptoms in children.12 Because there are no internationally recognized standards for indoor air quality, the World Health Organization estimates the number of people exposed to unacceptable levels of indoor pollutants exceeds the number exposed to unacceptable levels of outdoor pollutants in all of the world's cities collectively.13Table 1 summarizes the most important pollutants (with recommended guidelines) and the mechanisms involved from current toxicologic evidence and potential health consequences.
The evidence for a relationship between indoor pollution and respiratory infections in developing countries has been recognized for over 2 decades. The elderly, women who cook and the very young that spend most of their time indoors are likely to be at the highest risk. Infant girls in Gambia whose mothers carried them on their backs while cooking were noted to have more respiratory infections than girls not carried on their mothers’ backs.14 Children in Zimbabwe with recurrent pneumonia were more likely to come from homes where wood was used for fuel,15 and infants and children in Nepal who reported more time spent next to stoves suffered more life-threatening episodes of ARI.16 Recent evidence suggests a strong dose–response relationship between exposure to particulates and the frequency of ARIs in Kenyan children.
The rate of increase of exposure–response is highest for exposures below 1000–2000 μg/m3.11 The implication for public health programs to reduce adverse impacts of indoor air pollution in developing countries is to concentrate on measures that reduce average PM10 exposure to below 2000 μg/m3. The effect of biomass fuel combustion has also been studied in developed countries. Children in Arizona who lived in homes using woodstoves for heating and cooking were 4 times more likely to suffer physician-confirmed ARIs.17 The Harvard Six Cities Study reported the use of wood stoves to be associated with a 30% increase in respiratory symptoms ranging from chronic cough to asthma in children 7–10 years of age.18 There is increasing awareness that new stationary sources in homes are also the basis of the newer photochemical pollutants, such as the oxides of nitrogen from gas cookers and heaters with no flue.
URBAN CROWDING, ASTHMA AND INFECTION: THE SILENT MENACE
The prevalence of asthma varies from country to country, but the countries with the highest prevalence are the United Kingdom, Australia, New Zealand and the Republic of Ireland, followed by North, Central and South America.19 In general, asthma is most common in the industrialized nations with a “Western” lifestyle, but the reasons for such differences are unclear. Possible factors in the etiology of asthma include ethnic origin, childhood respiratory diseases, allergen exposure, diet and socioeconomic differences. It has been suggested that improved hygiene in the Western world has resulted in a reduced exposure to infectious diseases, with one consequence being an increased tendency in atopic responses to environmental allergens.20 The recent epidemic of atopic disease and asthma may have occurred as a consequence of a decline in certain childhood infections or a lack of exposure to a range of infectious agents in the first years of life.
A protective effect of infections on atopy was first described with an inverse association between the number of older siblings, birth order and hay fever.20 This idea was supported by other studies on children in high-risk environments, showing that factors such as attendance at day-care facilities21 and the presence of older siblings22–25 lead to increases in viral infections. One of the most informative studies was of 1035 children as part of the Tucson Children's Respiratory Study.26 Results illustrated that children with older siblings at home or who attended day care had more opportunities to be exposed to respiratory virus infections and were more likely to have frequent wheezing (>3 episodes in the preceding year) at 2 years of age, but less likely to have frequent wheezing from ages 6–13. Furthermore, protective effects against atopy and asthma have been demonstrated after natural exposure to the measles virus,27 hepatitis A23 and Mycobacterium tuberculosis, the exposure to which is suggested by a tuberculin test.28 A study from the Multicenter Allergy Study Group demonstrated that frequent early episodes of a “runny nose” is associated with a reduced risk of subsequent asthma.29
There is also evidence for a lower risk for atopic diseases in rural, less crowded areas as compared with urban areas. Research has verified that asthma and allergic disorders tend to be less common in rural, traditional areas than in urban regions of Africa.30,31 Other recent studies from Europe have also reported that children who lived on a farm during childhood had a substantial reduction in risk for hay fever and asthma when compared with their peers in nonfarming families in the same rural regions.32–35 Increased exposure to livestock was related to a decreased risk for atopic diseases.34,35 Findings from Austria, Switzerland and Germany suggest that exposure to stables and farm milk starting very early in life has a strong protective effect against the development of asthma, hay fever and atopic sensitization.34 Certain components (lipopolysaccharides) of the cell wall of Gram-negative bacteria, which were found to be more prevalent in farming environments, may be involved in the modulation of the immune response, possibly protecting against the development of atopy.36 A further study has shown that another aspect of modern life, treatment with oral antibiotics before the age of 2 years, is associated with subsequent atopic disease.37 The mechanism of this effect is unclear, but it may be that antibiotics are associated with a disruption of the normal bowel flora necessary for maturation of the immune system.
The role of infection in the etiology of asthma and respiratory morbidity is complex. Day care and urban crowding may influence the overall load of infectious agents, including respiratory viruses. If encountered early in life, these infectious agents alter maturation of the immune system from “type 2” bias at birth towards predominantly “type 1” responses, thus avoiding atopic diseases, the enduring premise of the “hygiene hypothesis.”38 Although there is no convincing evidence that specific infections cause atopy or asthma, there is a strong association between severe wheezing episodes in infancy, commonly due to virus infection (particularly respiratory syncytial virus), and subsequent wheezing or asthma later in life, particularly in those children with features of atopy. This evidence is discussed elsewhere in this supplement.
AIR QUALITY AND INFECTION: A MODERN MENACE
It is now accepted that any benefits of air quality legislation have been at least partially offset by the increasing emissions of other modern and photochemical pollutants from mobile sources, such as car exhaust fumes. Many of the epidemiologic studies of outdoor pollution, especially NO2 exposure, have found associations between exposure to the pollutant and health effects, often at levels well below current World Health Organization guidelines. These health effects have included accident and emergency room visits,39,40 hospital admissions,41,42 mortality,43,44 increased symptoms45,46 and reduced lung function.47,48 The Air Pollution on Health: European Approach incorporated data from 15 European cities, with a total population in excess of 25 million people. An increase of 50 μg/m3 NO2 (1 hour maximum) was associated with a 2.6% increase in asthma admissions and a 1.3% increase in daily all-cause mortality.49 There are many methodologic issues that complicate interpretation of outdoor exposure studies. However, the data suggest a role for NO2 and the other pollutants described in Table 1 in precipitating acute exacerbations of respiratory disease, although it is difficult to separate the individual effects of each pollutant from the complex mixture of pollutants found in outdoor air.50
NO2 remains one of the main pollutants in homes in developed countries; its primary source is combustion with unvented gas appliances such as heaters and stoves. Combustion from stoves, fires and smoking produces NO2 as well as volatile organic compounds such as formaldehyde, particulates and carbon monoxide.51 Over recent years, attention has focused on the role of NO2 in ARIs.
A series of studies alluded to the link between infection and air pollution particularly by NO2. Two studies related an increased incidence of pediatrician-reported cases of croup (laryngotracheobronchitis usually caused by influenza or parainfluenza viruses) and air pollution, especially particulates and NO2. Furthermore, there was a significant association between the frequency of croup and the daily means of NO2 for the peak period between September and March (the peak virus season).52,53 In another case-controlled study of outdoor NO2 in Stockholm, the risk of hospital admission with wheezing bronchitis (reasonably assumed to be of infective etiology) was significantly related to outdoor NO2 exposure in girls but not in boys, and presence of a gas stove in the home appeared to be a significant risk factor.54 This body of evidence strongly suggests an association between air pollution and increased severity of illness associated with respiratory infection. There is further evidence linking reduced peak expiratory flow rates, increased respiratory symptoms and higher school absence with higher levels of environmental pollution.55–57
AIR QUALITY, ASTHMA AND INFECTION: AN UNRECOGNIZED MENACE
In areas of poor air quality, individuals with preexisting lung disease may be at greater risk for the effects of respiratory infection.58 The majority of the studies of air pollution and infection have been conducted in children, although until recently studies had not clarified the exact nature of the respiratory illness and infection. There is now sufficient evidence of this link in children with preexisting asthma. A recent study has related upper respiratory virus infections, confirmed microbiologically, personal NO2 exposure and the severity of asthma exacerbations in children.59 A cohort of 114 asthmatic children 8–11 years of age prospectively recorded daily upper respiratory tract infection and lower respiratory tract infection symptoms and peak expiratory flow and measured personal NO2 exposures every week for up to 13 months. Outdoor concentrations of NO2 were also available from a central monitoring station. Nasal aspirates were taken during reported episodes of upper respiratory tract illness and tested for infection caused by common respiratory viruses and atypical bacteria with reverse transcription polymerase chain reaction assays. Viruses were detected in 78% of episodes. The severity of associated asthma exacerbations was analyzed in relation to high versus low NO2 exposures in the week before the viral infection. In the high category there were significant increases in the severity of asthma symptoms, with 60% increased severity for all viruses and >200% for respiratory syncytial virus infections compared with low NO2 exposure in the week before the start of the virus-induced exacerbation. The highest category of NO2 exposure was also associated with falls in peak expiratory flow of up to 75% with viral infection compared with the lowest category of NO2 exposure. These effects were observed at levels within current air quality standards. Potential mechanisms of how air quality, asthma and infection may interact have recently been described. These mechanisms include impaired bronchial immunity, reduced alveolar macrophage function and impaired responses to viral infections.60
TOBACCO SMOKE, ASTHMA AND INFECTION: THE PERSISTENT MENACE
The inhalation of environmental tobacco smoke (ETS), or “passive smoking,” has been a matter of great public debate over recent years. More than 4000 compounds have been identified as components of ETS and at least 42 of these are classified as carcinogenic. ETS is known to have adverse fetal, perinatal and postnatal effects. The well-documented risks of ETS have recently led many governments in both developing and developed countries to ban smoking in public and in workplaces in an attempt to protect nonsmokers from the deleterious effects of ETS. This does not account for the fact that there are currently no restrictions on smoking at home, where many children spend up to 90% of their time.61 Consequently children exposed to ETS are more likely to suffer from bronchitis, pneumonia, cough, wheezing and asthma and are more likely to require illness-related hospitalization compared with unexposed children.62–64 Research has provided evidence of a dose-response relationship between exposure to parental smoking and lower respiratory illness in infants. Data for these pooled risk estimates are typically in the range of 1.5 to 2.5.62,65 Respiratory illness in the first year of life has been reported to significantly increase, even if the mother smokes only after birth, despite the cessation of smoking during pregnancy.66,67 Bottle-fed infants exposed to maternal smoke are also at increased risk for respiratory illness compared with breast-fed infants.68 Previous metaanalyses and systematic reviews have confirmed the effect of ETS exposure on several other respiratory symptoms and outcomes in school age children and adolescents as shown in Table 2. 70–73
Our recent study investigated the risk of wheezing illnesses in relation to contemporaneous pollutant exposures (smoking, gas cooking and heating) in childhood and adolescence in a cohort of 2289 subjects.74 The risks of wheezing in childhood were increased by exposure to gas cooking (odds ratio, 1.47) and increased further in those exposed throughout childhood and adolescence. All wheezing groups were associated with contemporaneous exposure to combined smoking by both parents (odds ratio, 1.93). Data analysis suggested that exposure to gas cooking and smoking in childhood and adolescence increases the overall risk of wheezing.74
The associations between exposure to ETS in children and both lower respiratory illness and respiratory symptoms are likely to be causal given the consistency of findings and evidence of dose response.69 The increased risk in households where individuals other than the mother smoke, suggests that postnatal, rather than prenatal, exposure to ETS is responsible for the effect. Furthermore, there is evidence that exposure to ETS leads to increased infant mortality from respiratory illnesses as well as increased morbidity.62 Several studies suggest that exposure to ETS can cause small reductions in lung function and increases in bronchial hyperresponsiveness in schoolchildren.75 It is likely that ETS is a cofactor provoking wheezing attacks rather than a cause of the underlying asthmatic tendency. Because respiratory illness and asthma in children are more closely associated with maternal smoking than the smoking of other household members, the greater amount of time spent with their mother in the home, especially by infants and younger children, may be reflected.
There is a growing body of evidence that suggests that much of the morbidity and mortality related to air pollution, urban crowding, day care and tobacco smoke occur by causing or interacting with respiratory infection in addition to other acute or chronic health effects. It is increasingly recognized that improvements in air quality can lead to improved health.60 The further recognition of the role of infection early in life in modulating the immune system away from a state where atopic disease and asthma are likely to develop offers hope of strategies to identify and treat high-risk individuals. In truly making a difference in global public health, future advances will have to tackle all known environmental hazards including air pollution, tobacco smoke and other dangers of modern life, as well as find a way to mimic the protective effects of early infection without the accompanying morbidity.
Question: In developed countries there is tremendous indoor pollution due to toxic cleaning products and wash products. It is estimated that there are about 300 chemicals in people's houses. Some of them are neurotoxins and others may be from other origins with effects on the respiratory system that have not been determined. Is there any existing data on these pollutants?
Anoop Chauhan, MD: The indoor environment is a mixed soup of different pollutants. For example, cigarette smoke contains 4000 chemicals, more than 42 of which are carcinogenic; thus ETS is a multipollutant. There are many sources of pollution from household products, including furniture polish and perfumes, which also emit a variety of pollutants such as volatile organic compounds. We know a little about some of them, but there are many more that affect health and are poorly understood; a matter for future research, perhaps.
Question: Is there any data to differentiate a true “outside smoker” compared with the parent who blows smoke indoors, right in the child's face?
Anoop Chauhan, MD: It is my understanding that salivary, urinary or serum cotinine levels can determine the amount of secondhand smoke inhaled by a child. We've previously described a study on 78 adolescents, followed-up as part of an air pollution study and measured urinary cotinine every 3 months. There was a direct relationship between increased cotinine levels in children and the amount of secondhand smoke exposure from parental smokers, and that there was significant variation in cotinine between smoking households. Other studies have also confirmed higher cotinine levels in children from homes with smokers. We also occasionally found unexpectedly high levels of cotinine in children from smoking and nonsmoking homes as well; this may indicate different smoking habits within households, or even active smoking by the children. It is conceivable that children from homes of outdoor smokers may have lower levels than indoor smokers.
Question: Can you speculate on the increased incidence of respiratory infections in the face of environmental pollution? Can we conclude that there is actually an effect on the rate of transmission of infection or simply on the severity, so patients with subclinical infections don't get scored as having acute respiratory infection?
Anoop Chauhan, MD: The relationship between pollution and infection is intriguing. Data I have presented confirm that children from higher pollution homes have more frequent and more severe respiratory infections. In those with underlying respiratory disease such as asthma, air pollution and infection may act synergistically by direct lung damage or by impairing local bronchial immunity. There is good animal data to show that for NO2 there are effects on alveolar macrophages and NK cells, which reduces viral or bacterial clearance. One study in a murine model that looked at Mycoplasma pulmonis suggested that high levels of NO2 given before the infection causes the M. pulmonis to persist for a lot longer. There is otherwise no data on the effect of air pollution on the transmissibility of infection but this is an interesting hypothesis.
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