Environmental Asthma: 9 Questions Physicians Often Ask

ABSTRACT: The increased exposure to indoor and outdoor pollutants in developed countries may be partly responsible for the increased prevalence of asthma. Sensitization to allergens derived from mites, cockroaches, mammalian pets, and rodents has also been associated with severe asthma. Mite allergen control measures include frequent vacuum cleaning and the use of protective covers for bedding. Pets should be kept outdoors and washed frequently. Reducing moisture—along with vigorous cleaning—can help decrease cockroach infestation. Fungal allergens can be controlled if leaks are repaired and areas prone to moisture are cleaned properly. Key words: asthma, allergy, allergic rhinitis, environmental triggers _____________________________________________________________________________________________________________ The prevalence of asthma in the United States is estimated to be 5% to 8%.1 Asthma is responsible for approximately 5000 deaths annually in this country. It is a leading cause of emergency department (ED) visits, hospitalizations, and school and work absenteeism. The total estimated direct cost of the disease in the United States was $12.7 billion in 1998.2  Asthma is a multifactorial disease with complex genetic and environmental components. It can be exacerbated by exercise, laughter, exposure to allergens and environmental tobacco smoke, cold air, viral infections, nitrogen dioxide, sulfur dioxide, ozone, endotoxins, sulfites, and -blockers. In this article, we discuss the most important natural and manmade pollutants (other than those associated with occupational asthma) that cause or exacerbate asthma and the most appropriate preventive measures. These contaminants can be classified as either causal pollutants (inhaled allergens) or contributing pollutants (such as tobacco smoke, air pollution, and endotoxins, which irritate the airways). According to the World Health Organization (WHO) estimations, asthma is allergic in more than 50% of adults and in 80% of affected children.3 1. What is responsible for the increase in the prevalence of asthma? The estimated prevalence of atopic diseases in some developed countries exceeds 30%.1,4 A variety of factors may account for this.5-7 Longer and more concentrated exposure to indoor allergens. Table 1 provides a summary of the most important indoor and outdoor contaminants. Many studies suggest that exposure to indoor allergens is an important factor in the increased incidence and prevalence of allergic diseases. The average person in developed countries spends more than 90% of his or her time indoors; exposure to indoor allergens is therefore more prolonged than it is to outdoor seasonal allergens, and the concentration of most indoor allergens is greater. This exposure of genetically predisposed persons to various allergens, especially indoor allergens during infancy, sensitizes them.8-10 Viral respiratory tract infections, as well as passive exposure to cigarette smoke and other contaminants, can enhance the airway response to inhaled allergens in atopic persons.11,12 More outdoor air pollutants. Epidemiologic studies demonstrate that outdoor levels of air pollutants— including nitrogen dioxide, sulfur dioxide, ozone, and respirable diesel exhaust particles—associated with the use of fossil fuels have progressively increased during the past decade.13,14 In the United States, the National Ambient Air Quality Standards (NAAQs) offer specific standards for air quality, including ozone, particulate matter (both particulate matter 10 [PM10] and particulate matter 2.5 [PM2.5]), sulfur dioxide, nitrogen dioxide, lead, and carbon monoxide. The NAAQs have been recently revised for both ozone and particulate matter based on data that suggested health risks at levels below those established in previous standards.15 Several outcome variables have been used in different studies to investigate a potential association between air pollution and asthma. A comparative study performed in 4 European cities reported an association between levels of nitrogen and sulfur dioxide and ED admissions for asthma in both children and adults.16 An association between nitrogen dioxide and ozone levels and asthma deaths has also been suggested.17 Nitrogen dioxide and PM10 levels have also been associated with lower forced vital capacity and forced expiratory volume in 1 second in children.18 Although an association between air pollution and asthma morbidity seems to be consistent, the possible effects of air pollution on the increased prevalence of asthma in developed countries remain controversial. Studies that compared the former East and West Germany suggested that the prevalence of asthma was greater in West Germany than in East Germany, where air pollution is more severe.19  Another study performed in Australia and New Zealand also indicated that the prevalence of asthma among children in these countries was greater than in countries with much higher levels of air pollution.20 Because traffic exhaust is one of the most important sources of air pollution in developed countries, a number of studies are being conducted to investigate the effects of this type of pollution on asthma. A study of children in the Netherlands reported a significant correlation between physician- diagnosed asthma during the first year of life and several traffic-related pollutants, such as PM2.5, soot, and nitrogen dioxide.21 Altered immune response (the hygiene hypothesis).  The hygiene hypothesis suggests that the reduced microbial exposure of children—as a result of westernized lifestyles—is primarily responsible for the increased prevalence of allergic diseases during the past decades in developed countries. Two main theories have been suggested to explain the hygiene hypothesis. The initial theory suggests that a lack of shifting from helper T cell 2 (TH 2) dominance to T-helper T cell 1 (TH 1) dominance—which is induced by exposure to immune stimulants, such as viruses, bacteria, and endotoxins, especially during the prenatal period and first years of life—is responsible for the increased prevalence of allergic diseases.22,23  TH 1 cells produce interleukin (IL)-2, interferon (IFN- ), and tumor necrosis factor (TNF- ); TH 2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. IL-4, IL-13, and IL-5 promote the production of IgE in response to allergens, and IFN- suppresses this IgE production. Bacterial and viral infections enhance IL-12 synthesis. IL-12, produced mainly by monocytes and macrophages, induces IFN-  synthesis by TH 1 cells, resulting in a suppressed TH 2 response.2  A more recent theory emphasizes the role of reduced activity of T regulatory cells (immune suppression) in the increased prevalence of allergic diseases.24 The results of several types of epidemiologic studies support the hygiene hypothesis. The factors that have been studied include parasitic and other infections, exposure to microbial products and cats and dogs, and breast-feeding. Parasitic infections. The high prevalence of parasitic infections in developing countries protects against allergic diseases.25  Like allergic tissue responses, immune defenses against parasites involve IgE, mast cells, eosinophils, and TH 2 lymphocytes. IgE responses are, therefore, immunoprotective against parasites and are not restricted to allergic diseases. This is illustrated by epidemiologic studies in Africa, South America, and Asia that indicate an increased prevalence of asthma associated with population shifts from rural to urban environments. Other studies investigating the effectiveness of anthelmintic treatment on allergic reactivity have demonstrated a decrease of total IgE levels accompanied by an increase in skin reactivity after treatment. Childhood infections. Infections associated with siblings, day-care attendance, and household crowding protect against allergies and asthma.26-28  The frequency of several allergic diseases has been found to be inversely associated with the number of childhood infections and with the number of siblings and age of daycare attendance, as a measure of exposure to infections. Siblings and day-care attendance promote crossinfections and, thus, the stimulation of TH 1 lymphocytes. Microbial products. Exposure to microbial products associated with farming protects against allergies and asthma.29  It has been suggested that growing up on a farm protects against allergic sensitization in early life. High concentrations of endotoxins (lipopolysaccharide fragments that coat the outer membrane of Gram-negative bacteria) have been reported in farming environments. Endotoxins regulate various processes in the immune system, such as production of IL-12 and IFN- . Exposure to cats and dogs.  Exposure to these animals in early life may protect against allergies.30  The presence of pets in the home may be associated with increased exposure to endotoxins and other microbial products and, thus, the immune system is indirectly affected. Breast-feeding.  The role of breast-feeding in the development of allergic sensitization is controversial.31  Some epidemiologic studies suggest a protective role of breastfeeding,32,33  and it has been hypothesized that the immunologic components of milk, such as secretory IgA, may account for this protective effect. However, other studies indicate an increased risk of allergy and asthma associated with breast-feeding.34,35 The mechanisms by which breast-feeding may increase allergies and asthma in children have been studied. Exclusively breast-fed infants may have lower levels of Gram-negative enterobacteria in their GI tract than non–breast-fed infants. In addition, breast-feeding protects against infections. The majority of studies that support the hygiene hypothesis are cross-sectional and cohort studies, not randomized controlled-intervention studies. Therefore, nonreported confounding factors may partially account for the observation of positive results. Moreover, many observations contradict the hygiene hypothesis and negative findings are less likely to be published than positive findings. The effects of a number of confounding factors on the hygiene hypothesis have been discussed elsewhere.36,37 Dietary influences. Other investigations indicate that dietary changes—such as a decrease in the consumption of fatty fish—may partially account for the increase in asthma.38,39  Epidemiologic studies suggest that omega-3 fatty acids, which are abundant in fish and have antiinflammatory effects, may decrease symptoms of asthma.40  However, the effectiveness of dietary supplementation with omega-3 fatty acids in the primary prevention of asthma has not been thoroughly investigated. 2. What are the important allergens associated with sensitization and asthma? Many different allergens are present indoors. Evidence for a dose-response relationship between exposure and sensitization has been described for both dust mites and other allergens. Sensitization to allergens derived from mites (Dermatophagoides species), German cockroaches (Blattella germanica ), American cockroaches (Periplaneta americana ), rats (Rattus norvegicus ), and mice (Mus musculus ) is a common cause of asthma in North American cities.41-44  Cats and dogs are the most important sources of indoor allergens in northern Scandinavia and in the US mountain states.45,46  However, cat and dog allergens are also present in the majority of US homes at levels that, in some cases, exceed proposed threshold levels to cause sensitization.47 In Arizona and central Australia, Alternaria,  an outdoor mold, is the principal allergen associated with asthma.48,49  Sensitization to mite, cat, cockroach, or Alternaria  allergens has been associated with severe asthma in adults and children seen in US clinics or EDs.50,51  An association between ED admissions for asthma and sensitization to dry-air spores, such as Alternaria  and Cladosporium,  has been reported.52 An association between severity of asthma or allergic rhinitis and exposure to total fungal spores,53  ascospores,54  or basidiospores55-57  has been described. Inhalation of fungal allergens has also been associated with asthma outbreaks in different parts of the world.58-60 Sensitization to grass and ragweed pollen allergens has been shown to trigger asthma exacerbations that necessitate emergency treatment.61  However, in population studies using multiple regression analysis, sensitization to grass, ragweed, or tree pollen has not been shown to be an independent risk factor for asthma.62,63  Platts-Mills and colleagues64  have described in detail the characteristics of the main indoor allergens, using the WHO and International Union of Immunology Societies nomenclature. Recent observations suggest that children raised in homes with cats are less likely to become allergic to cats.65,66  Many of these exposed children have a specific IgG and IgG4 response to Fel d1 without specific IgE (“modified TH 2 response”). 3. What are the threshold levels of indoor allergens that sensitize and cause asthma? With dust mites, a level of 2 μg of group 1 (Der  p1 + Der f1 ) allergens per gram of dust and/or 100 mites per gram of dust is a risk factor for sensitization in genetically predisposed persons. Some investigators hypothesize that the threshold level for sensitization may be lower than 2 μg of group 1 allergens per gram of dust and that there is no “safe” minimum level of exposure for some susceptible persons.64  Ten micrograms of group 1 (Der  p1 + Der  f1) allergens per gram of dust and/or 500 mites per gram of dust causes asthma symptoms in persons sensitive to dust mites, but lower levels may also cause symptoms. Eight micrograms per gram or more of the major cat allergen Fel d1 and 2 units per gram or more of the major cockroach allergen Bla g1 have been proposed as the threshold levels to sensitize and cause symptoms.64,67  The threshold levels of other allergens that sensitize and cause symptoms (eg, dog and fungal allergens) have not been established. 4. How can exposure to domestic mite allergens be reduced? The term "domestic mites” refers to all mites found in house dust, including dust mites and storage mites. Mite allergens are carried on particles 10 μm or larger and become airborne primarily with household disturbance. They settle out of the air in 30 minutes or less. Domestic mites feed mainly on mammalian skin scales. They live primarily in bedrooms—where people normally spend at least one third of their day—in the dust that accumulates in bedding, carpeting, and upholstered furniture. The bedroom is therefore the focal point for mite allergen avoidance measures. Other areas of the home in which family members spend much of their time— such as the living room or recreation room—are also potential sources of dust mite allergens. A variety of measures can help control exposure to mite allergens. Eliminating mites. Mite allergen avoidance measures recommended by the American Thoracic Society are given in Table 2.  Other measures include the following: •Freezing.  Under experimental conditions, mites can be killed by freezing with sprayed liquid nitrogen. A domestic freezer has been recommended for killing mites in stuffed toys. In areas with below-freezing cold spells, mites in rugs, mattresses, and other items can be killed by placing the items outdoors for 2 to 3 days. •Acaricides.  These agents, which kill mites, traditionally are applied every 2 to 3 months. This process is expensive and time-consuming. However, disodium octaborate tetrahydrate (DOT), a compound of insignificant toxicity to humans, has proved efficient at killing dust mites in carpets and sofas. A single application of DOT, combined with vacuuming, effectively reduced mite numbers and mite allergen levels in one 6-month study.68  Information about DOT can be found at www.ecologyworks.com. •Impermeable covers.  Although the use of impermeable covers alone has not proved effective in reducing the symptoms of asthma or allergic rhinitis among dust mite–sensitized subjects,69,70  they are an important tool in a comprehensive allergen avoidance program. Vinyl covers have traditionally been used to encase pillows, mattresses, and box springs. However, because they are impermeable to air, they can be hot and uncomfortable. Fabrics that are more comfortable than vinyl are being used to manufacture pillows and bedding casings. They may be more expensive than vinyl covers and are available at department stores and from manufacturers of products for patients with allergies. Fabrics with a pore size of 6 μm permit air exchange and block both group 1 mite and Fel  d1 cat allergens.71  Information about pore size from the manufacturer, is available for some, but not all, of these products. Information about some manufacturers of antiallergic products can be found on the Internet. Preventing mite population growth. An alternative approach to mite allergen exposure is to create environmental conditions that prevent the growth of mite populations, but this is a difficult task. Wholehouse dehumidifiers decrease dust mite infestation in some locations.72 They are expensive, however, and cannot be recommended for routine use. They are also not very effective in areas such as the Deep South, where high humidity levels exist year-round.73  Bedroom dehumidifiers are not effective in controlling humidity and are therefore not recommended. More research is needed on this subject. Air purifiers, which can either be incorporated into the central heating, ventilation, and air-conditioning systems or moved from room to room as portable units, are available in a wide range of models.74  Tabletop units are small and inexpensive but have limited airflow and inefficient filters. Room units, larger than tabletop units but still portable, are more effective in cleaning the air. Central airconditioning with air filtration can decrease the aeroallergen levels in a home but must be in constant operation to do so. Several studies64,75  indicate that air purifiers alone are not an appropriate solution for indoor allergen control. Dust mite allergens do not remain airborne for extended periods. Air purifiers do not affect the reservoirs of mite allergens, which are local sources of exposure. They can decrease—but not eliminate—cat and dog allergens, which remain airborne for hours or days. Clinical benefits of such devices have not been documented, and they are expensive. They are therefore not routinely recommended for the patient with allergies, especially if more effective control measures have not been instituted.  5. How can my patients effectively reduce their exposure to pet allergens? Mammalian pets are important sources of allergens. The best therapy for animal allergy is to remove the pet from the living environment. However, many pets are considered members of the family and the idea of banning them from the home is not readily accepted. Cat and dog aeroallergens have an average size of less than 5 μm. The major cat allergen, Fel d1, readily becomes airborne and remains in the undisturbed air for hours or even days. Fel d1 is primarily found in cat saliva and dander, and 90% of persons allergic to cats have IgE specific to this allergen. The production of Fel d1 is partially under hormonal control: females release less allergen than do males. However, the accumulation of Fel d1 over time does not appear to differ in homes according to whether the cats are female or male. When a cat is removed from a home, the allergen concentration gradually decreases 100- to 1000-fold over a period of 6 months. The major dog allergen, Can f1, is similar in many ways to Fel d1. Roughly 60% to 70% of persons allergic to dogs have IgE that is specific to this allergen. Can f1 is a potent allergen, but allergy to dogs occurs less frequently than it does to cats, perhaps because more dogs than cats are kept outdoors. Recommended avoidance measures for mammalian allergens are detailed in Table 3. Minimizing exposure to cat and dog allergens may require treating reservoirs of these allergens in schools, public buildings, and houses without pets, since pet allergens are readily transferred to these sites on clothing and other objects. 6. What avoidance measures are recommended for cockroach allergens? There are more than 4000 species of cockroaches worldwide, only 8 of which live indoors. The German cockroach (B germanica) and American cockroach (P americana) are the most prevalent species in the United States. Bla g1, Bla g2, and Per a1, to which 50% to 60% of patients allergic to cockroaches have specific IgE, are the major cockroach allergens. The highest allergen levels are found in the kitchen and are present even if there are no visible signs of infestation. Cockroach allergenshave aerodynamic characteristics similar to those of mite allergens. Cockroaches are not easy to eradicate in domestic environments and are an important health problem. Not only are they sources of potent allergens, but they also may be contaminated with potentially pathogenic bacteria, including Salmonella species and Klebsiella species, fungi such as Aspergillus species, and protozoa such as Toxoplasma species. There is indirect evidence that cockroaches can transmit infectious diseases.76,77 Research in the area of cockroach allergen avoidance is limited. Successful avoidance also requires behavioral changes that prevent reinfestation. Brenner and colleagues78  have shown that vigorous “spring cleaning” (ie, thorough cleaning and washing of all surface areas of the furniture, walls, and floors of each room) eliminates cockroach debris. Recommended avoidance measures for cockroach allergens are detailed in Table 4. 7. What avoidance measures are recommended for fungal allergens? Fungal spores are abundant in the outdoor environment and commonly infiltrate buildings. Humans and pets may transport outdoor spores indoors on clothes and on fur. Indoor fungal growth results from domestic activities and the presence of indoor plants or pets in the home. In fact, some fungal genera, such as Penicillium and Aspergillus, are commonly found indoors. Fungi can grow indoors in large amounts when a home has a moisture problem, such as a plumbing leak or elevated ambient humidity levels. Fungal spores—whether they originate outdoors or indoors—accumulate in dust reservoirs within homes and may become airborne upon disturbance. Thus, indoor fungal aerosols are complex mixtures of spores and fungal fragments of both outdoor and indoor origin. Table 5 lists recommended avoidance measures for fungal allergens. Does environmental tobacco smoke play a role in asthma? A survey indicates that 53% to 76% of American children live in homes in which at least one person smokes.79 Environmental tobacco smoke is composed of more than 3800 different chemical compounds. Passive exposure to tobacco smoke has been linked to increased viral respiratory tract infections and can exacerbate asthma (especially in children) and chronic cough.38,80  Smoking may also retard the efficacy of asthma medications.81 The most effective precaution is to eliminate smoking from the home and prohibit it in public buildings, other than in designated smoking rooms. Ideally, these rooms should be ventilated separately from the rest of the building. 9. Which other pollutants might be associated with asthma? Nitrogen dioxide, sulfur dioxide, and ozone are primarily outdoor pollutants, but sometimes they are also found indoors at various concentrations. They act as irritants to the conjunctiva and mucosa of the upper and lower respiratory tracts. The relatively low water solubility of nitrogen dioxide results in minimal mucous membrane irritation. However, this chemical may increase bronchial reactivity in some persons with asthma, decrease lung function in persons with chronic obstructive pulmonary disease, and increase the risk of respiratory tract infections. Very high levels can cause such symptoms as irritation of the conjunctiva, sneezing, and cough in persons without respiratory disease. High-dose exposure to nitrogen dioxide may cause pulmonary edema and diffuse lung injury, and continued exposure can cause acute and chronic bronchitis.82,83 Sulfur dioxide is highly watersoluble; therefore, minimal amounts are irritating to the conjunctiva and upper respiratory tract. Concentrations above 6 parts per million produce mucous membrane irritation even in healthy persons. Epidemiologic studies indicate that long-term exposure is associated with increased respiratory symptoms and impaired pulmonary function. Clinical studies have also shown that some patients with asthma experience bronchoconstriction even with brief exposure to sulfur dioxide levels as low as 0.4 parts per million.84,85 Studies have found that ozone significantly affects persons with and without asthma.86  Ozone causes epithelial damage and inflammation of the upper and lower airways. Studies of the effects of ozone inhalation demonstrate concentration and timerelated changes in respiratory symptoms and lung function, including an increase in airway resistance, a reduction in lung volumes, and an increase in airway hyperreactivity.86 Studies suggest that exposure to sulfur dioxide, ozone, and the combination of nitrogen dioxide and sulfur dioxide may increase the airway responsiveness of persons with asthma to inhaled allergens.87,88  The interaction between air pollutants and allergens may thus play an important role in exacerbating airway disease in susceptible persons. Avoidance of respiratory irritants is difficult; however, certain measures may be helpful and should be stressed to susceptible persons: • Stay indoors in an air-conditioned environment during pollution alerts. • Make sure that no source of such pollutants exists in the home. • Be sure that outdoor air-conditioning units are placed in an area in which pollutants from car and truck exhausts are minimal. Endotoxins are ubiquitous; they are abundant in organic dust, including house dust. The role of endotoxin exposure as a risk factor for asthma is controversial. Studies performed in different parts of the world indicate that endotoxin exposure from house dust may be a risk factor for asthma or for exacerbations of preexisting asthma.86-88  Inhaled endotoxin has been shown to cause dose-related bronchoconstriction that is exacerbated in persons with asthma.89  However, as previously explained, long-term exposure to endotoxins during infancy may reduce the risk of allergic sensitization and even asthma.90,91 Dr Codina is principal environmental scientist at SDII Global Corporation in Tampa, Fla, and affiliated assistant professor of medicine in the division of allergy and immunology, Joy McCann Culverhouse Airway Disease Research Center, department of medicine, at University of South Florida College of Medicine and James A. Haley VA Hospital in Tampa. Dr Lockey is professor of medicine, pediatrics and public health; Joy McCann Culverhouse Chair in Allergy and Immunology; and director of allergy and immunology at the University of South Florida College of Medicine and James A. HaleyVA Hospital. REFERENCES: 1. O’Connell EJ. The burden of atopy and asthma in children. Allergy. 2004;59:7-11. 2. Weiss KB, Sullivan SD. The health economics of asthma and rhinitis, I: assessing the economic impact. J Allergy Clin Immunol. 2001;107:3-8. 3. Prevention of Allergy and Allergic Asthma. Geneva: World Health Organization; 2003. 4. Gupta R, Sheikh A, Strachan DP, Anderson HR. Burden of allergic disease in the UK: secondary analyses of national databases. Clin Exp Allergy. 2004;34:520-526. 5. Wright AL. The epidemiology of the atopic child: who is at risk for what? J Allergy Clin Immunol. 2004;113:S2-S7. 6. Frew AJ. Advances in environmental and occupational diseases, 2003. 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