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See section 1, "Overall Methods Used To Develop This Report," for literature search strategy and tally of results for the EPR—3: Full Report 2007 on this component, "Control of Environmental Factors and Comorbid Conditions That Affect Asthma." Two Evidence Tables were prepared: 9, Allergen Avoidance; and 10, Immunotherapy. For successful long-term management of asthma, it is essential to identify and reduce exposures to relevant allergens and irritants and to control other factors that have been shown to increase asthma symptoms and/or precipitate asthma exacerbations. These factors are in five categories: inhalant allergens, occupational exposures, irritants, comorbid conditions, and other factors. Ways to reduce the effects of these factors on asthma are discussed in this component of asthma management.

The Expert Panel recommends that patients who have asthma at any level of severity should be queried about exposures to inhalant allergens, particularly indoor inhalant allergens, and their potential effect on the patient's asthma (Evidence A). Exposure of a person who has asthma to inhalant allergens to which the person is sensitive increases airway inflammation and symptoms. Substantially reducing such exposure may significantly reduce inflammation, symptoms, and need for medication (See a summary of the evidence in .).

Demonstrating a patient's relevant sensitivity to inhalant allergens will enable the clinician to recommend specific environmental controls to reduce exposures. It will also help the patient understand the pathogenesis of asthma and the value of allergen avoidance. The Expert Panel recommends that, given the importance of allergens and their control to asthma morbidity and asthma management, patients who have persistent asthma should be evaluated for the role of allergens as possible contributing factors as follows (): ▪ Determine the patient's exposure to allergens, especially indoor inhalant allergens. (See relevant questions in .) ▪ Assess sensitivity to the allergens to which the patient is exposed. — Use the patient's medical history, which is usually sufficient, to determine sensitivity to seasonal allergens. — Use skin testing or in vitro testing to determine the presence of specific IgE antibodies to the indoor allergens to which the patient is exposed year round. (See for a comparison of skin and in vitro tests.) Allergy testing is the only reliable way to determine sensitivity to perennial indoor allergens (See for further explanation.). — For selected patients who have asthma at any level of severity, detection of specific IgE sensitivity to seasonal or perennial allergens may be indicated as a basis for education about the role of allergens for avoidance and for immunotherapy.

The Expert Panel recommends that patients should reduce exposure, as much as possible, to allergens to which the patient is sensitized and exposed: ▪ The first and most important step in controlling allergen-induced asthma is to advise patients to reduce exposure to relevant indoor and outdoor allergens to which the patient is sensitive (Evidence A) (See Evidence Table 9, Allergen Avoidance.). ▪ Effective allergen avoidance requires a multifaceted, comprehensive approach; individual steps alone are generally ineffective (Evidence A). ▪ Consider multifaceted allergen-control education interventions provided in the home setting that have been proven effective for reducing exposures to cockroach, dust-mite, and rodent allergens for patients sensitive to those allergens (Evidence A). Further research to evaluate the feasibility of widespread implementation of such programs will be helpful (see "Component 2: Education for a Partnership in Asthma Care.").

Effective ways patients can reduce their exposures to indoor and outdoor allergens are discussed below and summarized in , which also addresses irritants. Although these recommendations focus on the home environment, reductions in exposures to allergens and irritants are also appropriate in other environments where the patient spends extended periods of time, such as school, work, or daycare. For information about companies that distribute products to help reduce allergen exposure, contact the Asthma and Allergy Foundation of America toll-free hotline at 800–727–8462 or the Allergy and Asthma Network/Mothers of Asthmatics at 800–878–4403. See "Component 2: Education for a Partnership in Asthma Care" for a description of allergen-control education programs that are delivered in patients' homes. Multifaceted programs that focus on educating patients and providing tools for reducing exposure to cockroach, dust-mite, and rodent allergens have demonstrated success in reducing exposure and reducing asthma morbidity. Further evaluation is needed of the cost-effectiveness and feasibility for widespread implementation of these interventions; however, the efficacy of the interventions warrants their consideration, if available, for patients sensitive to these allergens. Animal allergens. The Expert Panel recommends the following actions to control animal antigens (Evidence D):

▪ If the patient is sensitive to an animal, the treatment of choice is removal of the exposure from the home. ▪ If removal of the animal is not acceptable: — Keep the pet out of the patient's bedroom. — Keep the patient's bedroom door closed. — Remove upholstered furniture and carpets from the home, or isolate the pet from these items to the extent possible. — Mouse allergen exposure can be reduced by a combination of blocking access, low-toxicity pesticides, traps, and vacuuming and cleaning. All warm-blooded animals, including pets and rodents, produce dander, urine, feces, and saliva that can cause allergic reactions (; ). Given recent evidence that exposure to cat allergens can be significant in homes, schools, and offices without animals, the issue of allergen avoidance in sites without animals has become more relevant. Successful controlled trials of animal dander avoidance have now been reported for schools and for homes without an animal (). Studies suggest that mouse and rat allergen exposure and sensitization are common in urban children who have asthma ().

High-efficiency particulate air (HEPA) cleaners reduce airborne Can f 1 in homes with dogs. Furthermore, preventing the dog from having access to the bedroom, and possibly the living room, may reduce the total allergen load inhaled (). Weekly washing of the pet will remove large quantities of dander and dried saliva that will otherwise accumulate in the house; however, the role of washing in allergen avoidance is not established (, , ). House-dust mite allergen. The Expert Panel recommends the following mite-control measures; effective allergen avoidance requires a multifaceted approach (Evidence A). ▪ Recommended actions to control mites include: — Encase the mattress in an allergen-impermeable cover. — Encase the pillow in an allergen-impermeable cover or wash it weekly. — Wash the sheets and blankets on the patient's bed weekly in hot water. — A temperature of >130 °F is necessary for killing house-dust mites. Prolonged exposure to dry heat or freezing can also kill mites but does not remove allergen. If high temperature water is not available, a considerable reduction in live mites and mite allergens can still be achieved with cooler water and using detergent and bleach. ▪ Actions to consider to control mites include: — Reduce indoor humidity to or below 60 percent, ideally between 30 and 50 percent. — Avoid sleeping or lying on upholstered furniture.

— Remove from the home carpets that are laid on concrete. — In children's beds, minimize the number of stuffed toys, and wash them weekly. House-dust mites are universal in areas of high humidity (most areas of the United States) but are usually not present at high altitudes or in arid areas unless moisture is added to the indoor air (). Mites depend on atmospheric moisture and human dander for survival. High levels of mites can be found in dust from mattresses, pillows, carpets, upholstered furniture, bed covers, clothes, and soft toys. The patient's bed is the most important source of dust mites to control. Washing bedding is advised, preferably in hot water, but cold water, detergent, and bleach can also be effective (; ). Several recent studies support the efficacy of allergen avoidance in the treatment of asthma (; ; ; ; ; ; ). Other studies provide important insight into the details of allergen avoidance. For example, three studies reported that mattress covers without other measures were not effective (; ; ). Likewise, two well-conducted studies failed to show an effect of HEPA filters alone (; ). Thus, the conclusion remains that effective allergen avoidance requires a comprehensive approach, and that individual steps alone are generally ineffective ().

Chemical agents are available for killing mites and denaturing the antigen; however, the effects are not dramatic and do not appear to be maintained for long periods. Therefore, use of these agents in the homes of persons who have asthma and are sensitive to house-dust mites should not be recommended routinely (). Vacuuming removes mite allergen from carpets but is inefficient at removing live mites. Room air-filtering devices are not recommended for control of mite allergens, because the allergens are associated with large particles which remain airborne for only a few minutes after disturbance. They are, therefore, not susceptible to removal by air filtration. Cockroach allergen. The Expert Panel recommends that cockroach control measures should be instituted if the patient is sensitive to cockroaches and infestation is present in the home (Evidence B).

Cockroach sensitivity and exposure are common among patients who have asthma and live in inner cities (; ; ; ). In a study of asthma in an inner-city area, asthma severity increased with increasing levels of cockroach antigen in the bedrooms of children who were sensitized (). Another major study demonstrated efficacy of cockroach avoidance as part of an overall plan for allergen avoidance (). Patients should not leave food or garbage exposed. Poison baits, boric acid, and traps are preferred to other chemical agents, because the latter can be irritating when inhaled by persons who have asthma. If volatile chemical agents are used, the home should be well ventilated, and the person who has asthma should not return to the home until the odor has dissipated. Care should be taken so that young children do not have access to cockroach baits and poisons.

Indoor fungi (molds). The Expert Panel recommends consideration of measures to control indoor mold (Evidence C). Indoor fungi are particularly prominent in humid environments and homes that have problems with dampness. Children who live in homes with dampness problems have increased respiratory symptoms (; ), but the relative contribution of fungi, house-dust mites, or irritants is not clear. Because an association between indoor fungi and respiratory and allergic disease is suggested by some studies (; ; ), measures to control dampness or fungal growth in the home may be beneficial. Outdoor allergens (tree, grass, and weed pollen; seasonal mold spores). The Expert Panel recommends that patients who are sensitive to seasonal outdoor allergens consider staying indoors, if possible, during peak pollen times—particularly midday and afternoon ( . The strongest associations between mold-spore exposure and asthma have been with the outdoor fungi, such as Alternaria (; ; ). Patients can reduce exposure during peak pollen season by staying indoors with windows closed in an air-conditioned environment (), particularly during the midday and afternoon when pollen and some spore counts are highest (; ; ). Conducting outdoor activities shortly after sunrise will result in less exposure to pollen. These actions may not be realistic for some patients, especially children.

The Expert Panel recommends that allergen immunotherapy be considered for patients who have persistent asthma if evidence is clear of a relationship between symptoms and exposure to an allergen to which the patient is sensitive (Evidence B) (see Evidence Table 10, Immunotherapy).

Immunotherapy is usually reserved for patients whose symptoms occur all year or during a major portion of the year and in whom controlling symptoms with pharmacologic management is difficult because the medication is ineffective, multiple medications are required, or the patient is not accepting the use of medication. Reports, however, that immunotherapy can prevent the development of new sensitivities in monosensitized children and adults (; ; ) and that immunotherapy with birch and timothy pollen extracts can prevent the development of asthma in children who have allergic rhinitis (), along with evidence of persisting effect for at least 3 years after discontinuation (), suggest that immunotherapy should be considered when there is a significant allergic contribution to the patient's symptoms. Specific immunotherapy has been shown to induce a wide range of immunologic responses that include the modulation of T- and B-cell responses by the generation of allergen-specific Treg cells; increases in allergen-specific IgG4, IgG1, and IgA; decrease in IgE and decreased tissue infiltration of mast cells and eosinophils. The relevance of these immunologic changes to the clinical efficacy of specific immunotherapy has yet to be established ().

Controlled studies of immunotherapy, usually conducted with single allergens, have demonstrated reduction in asthma symptoms caused by exposure to grass, cat, house-dust mite, ragweed, Cladosporium, and Alternaria (; ; ; ; ; ). A meta-analysis of 75 randomized, placebo-controlled studies has confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication and with improvement in bronchial hyperreactivity (). This meta-analysis included 36 trials for allergy to house dust mites, 20 for pollen allergy, and 10 for animal dander. On the other hand, only three trials for mold allergy and only six trials with multiple allergen therapy were included. In the United States, standardized extracts are available for house-dust mites, grasses, short ragweed, and cat, and there are unstandardized extracts of other pollens and for dog that appear to have similar potency (). Available extracts for cockroach and mold, on the other hand, are of very variable allergen content and allergenic potency, and their effectiveness in specific immunotherapy has not been demonstrated (). Few studies have been reported on multiple-allergen mixes that are commonly used in clinical practice. One, which included high doses of all allergens to which the children were sensitive (), demonstrated reduction in asthma symptoms compared to lower doses of the same allergens or placebo. Another study, in which the children were given optimal medical therapy and in which the only perennial allergen administered was house-dust mite, demonstrated no improvement in asthma symptoms between active and placebo therapy ().

The course of allergen immunotherapy is typically of 3–5 years' duration. Severe and sometimes fatal reactions to immunotherapy, especially severe bronchoconstriction, are more frequent among patients who have asthma, particularly those who have poorly controlled asthma, compared with those who have allergic rhinitis (; ). If use of allergen immunotherapy is elected, it should be administered only in a physician's office where facilities and trained personnel are available to treat any life-threatening reaction that can, but rarely does, occur (). For this reason, enthusiasm for the use of immunotherapy in asthma differs considerably among experts (;; ). In Europe, interest has increased in high-dose sublingual immunotherapy (). It has been reported to be effective in asthma, with benefit persisting 4–5 years after its discontinuation (), and to be free of systemic reactions, thus allowing home administration. Comparative studies suggest it is less effective, however, than immunotherapy administered by subcutaneous injection (; ).

The Expert Panel recommends the following actions to modify indoor air: ▪ Vacuuming carpets once or twice a week to reduce accumulation of house dust. Patients sensitive to components of house dust should avoid using conventional vacuum cleaners, and these patients should stay out of rooms where a vacuum cleaner is being or has just been used ( ;). If patients vacuum, they can use a dust mask, a central cleaner with the collecting bag outside the home, or a cleaner fitted with a HEPA filter or with a double bag (; ). ▪ Air conditioning during warm weather, if possible, for patients who have asthma and are allergic to outdoor allergens (Evidence C) , because air conditioning allows windows and doors to stay closed, thus preventing entry of outdoor allergens (). Regular use of central air conditioning also will usually control humidity sufficiently to reduce house-dust mite growth during periods of high humidity (). Reducing relative humidity is a practical way to control house-dust mites and their allergens in homes in temperate climates (). ▪ Use of a dehumidifier to reduce house-dust mite levels in areas where the humidity of the outside air remains high for most of the year ( . House-dust mite levels can be reduced by use of dehumidifiers to maintain levels to or below 60 percent, ideally 30–50 percent, relative humidity ().

▪ There is insufficient evidence to recommend indoor air cleaning devices. They may reduce some, but not all airborne allergens, but evidence is limited regarding their impact on asthma control. Indoor air-cleaning devices cannot substitute for the more effective dust-mite and cockroach control measures described previously, because these heavy particles do not remain airborne (). However, air-cleaning devices (i.e., HEPA and electrostatic precipitating filters) have been shown to reduce airborne dog allergen (), cat dander (; ; ), mold spores (), and particulate tobacco smoke (). Use of an air cleaning device containing a HEPA filter may reduce exposure, especially if added to other avoidance measures (). However, most studies of air cleaners have failed to demonstrate an effect on asthma symptoms or pulmonary function (; ; ; ; ). Air cleaners that are designed to work by the generation of ozone and that emit ozone into the air should be avoided by persons who have asthma. ▪ There is insufficient evidence to recommend cleaning air ducts of heating/ventilation/air conditioning systems (Evidence D). Cleaning has been reported to decrease levels of airborne fungi in residences (). The effect on levels of house-dust mite or animal dander has not been studied. Limited evidence continues to preclude the Expert Panel's making a recommendation in this area.

The Expert Panel does not generally recommend use of humidifiers and evaporative (swamp) coolers for use in the homes of house-dust mite-sensitive patients who have asthma (Evidence C) . If use of a humidifier is desired to avoid excessive dryness, the relative humidity in the home should be maintained below 60 percent, ideally between 30 and 50 percent. These machines are potentially harmful because increased humidity may encourage the growth of both mold () and house-dust mites (; ). In addition, humidifiers may pose a problem because, if not properly cleaned, they can harbor and aerosolize mold spores ().

The Expert Panel recommends that clinicians query patients who are employed and have asthma about possible occupational exposures, particularly those who have new-onset disease ( . Early recognition and control of exposures are particularly important in occupationally induced asthma, because the likelihood of complete resolution of symptoms decreases with time (). Occupational asthma is suggested by a correlation between asthma symptoms and work, as well as with improvement when away from work for several days. Other indications of workplace exposure are listed in . The patient may fail to recognize the relationship with work, because symptoms often begin several hours after exposure. Recently, common jobs—such as domestic cleaner, laboratory technician, and house painter—have been associated with the disease (). Serial peak flow records at work and away from work can confirm the association between work and asthma (). Workplace exposure to sensitizing chemicals, allergens, or dusts can induce asthma which often persists after the exposures are terminated (). This effect should be distinguished from allergen- or irritant-induced aggravation of preexisting asthma.

Patient confidentiality issues are particularly important in work-related asthma. Because even general inquiries about the potential adverse health effects of work exposures may occasionally result in reprisals against the patient (e.g., job loss), patients who have asthma need to be informed of this possibility and be full partners in the decision to approach management regarding the effects or control of workplace exposures. This situation may require referral to an occupational asthma specialist.

The Expert Panel recommends that clinicians query patients who have asthma at any level of severity about exposures to irritants that may cause their asthma to worsen, and advise them accordingly about reducing relevant exposures ( . Sample assessment questions are in .

The Expert Panel recommends that clinicians advise persons who have asthma not to smoke or be exposed to ETS (Evidence C). Query patients about their smoking status and specifically consider referring to smoking cessation programs adults who smoke and have young children who have asthma in the household (Evidence B). Exposure to ETS is common in the United States (). ETS is associated with increased symptoms, decreased lung function, and greater use of health services among those who have asthma () in all age groups, although exact negative effects may vary by age (). Exposure to maternal smoking has been shown to be a risk factor for the development of asthma in infancy and childhood (; ; ). Effects of ETS on a child's asthma are greater when the mother smokes than when others in the household smoke (; ; ). Heavy smokers may be more unaware than those who smoke less of the effects of ETS exposure on children (). The primary modes of exposure to ETS for adults who have asthma may be when they are at work () or traveling (). ETS exposure operates as a cofactor in wheezing, along with other insults such as infections (). Smoking out of doors to avoid exposing others may not adequately reduce exposure for children (). See "Component 2: Education for a Partnership in Asthma Care" for discussion of programs to encourage parents of children who have asthma not to smoke.

The Expert Panel recommends that clinicians advise patients to avoid, to the extent possible, exertion or exercise outside when levels of air pollution are high (Evidence C). Increased pollution levels—especially of particulate matter 10 micrometers (PM10) (; ; ; ; ; ; ; ; ) and ozone (; ; ; ; ; ; ; ), but also of SO 2 () and nitric oxide (NO 2 ) (; )—have been reported to precipitate symptoms of asthma (; ; ; ), increase SABA use (), and increase ED visits and hospitalizations for asthma (; ; ; ; ; ; ; ). High exposure to NO 2 in the week before the start of a respiratory viral infection, at levels within current air quality standards, may increase the severity of virus-induced asthma exacerbations (). Exposure to pollutants may increase airway inflammation () and enhance the risk of allergic sensitization through simultaneous exposure to aeroallergens (; ; ). The propensity for particulate pollution to enhance allergic sensitization may be genetically regulated (; ).

Formaldehyde and VOCs—which can arise from sources such as new linoleum flooring, synthetic carpeting, particleboard, wall coverings, furniture, and recent painting—have been implicated as potential risk factors for the onset of asthma and wheezing (; ; ). Clinicians should advise patients to be aware of the potential irritating effects of newly installed furnishings and finishes.

The Expert Panel recommends that clinicians advise patients to avoid, if possible, exposure to gas stoves and appliances that are not vented to the outside, fumes from wood-burning appliances or fireplaces, sprays, or strong odors (Evidence C).

Use of unvented gas stoves and appliances results in increased indoor levels of NO 2 . Use of gas stoves for cooking has been associated with increased respiratory symptoms, including wheezing in school children (; ) and increased prevalence of bronchial hyperresponsiveness in atopic adults (). However, data from the National Health and Nutrition Examination Survey III (NHANES III) did not suggest any impact of gas-stove use on pulmonary function or respiratory symptoms in adults who have asthma (). Infants at high risk for asthma who were exposed to higher levels of NO 2 —but levels which currently are not considered to be harmful—had increased days of wheezing and shortness of breath (). In school-aged children, increased levels of NO 2 were associated with increased bronchitis, wheeze, and asthma in girls but not boys (). When unflued gas heaters in schools were replaced, NO 2 levels decreased by two-thirds, accompanied by significant reduction in both daytime and nighttime asthma symptoms (). Exposure to gas heaters and appliances in infancy has been found to be a risk for wheezing, asthma, and bronchial hyperresponsiveness as well as sensitization to house-dust mites in school-aged children (; , ). Current use of gas appliances also was found to be a risk for decreased FEV 1 in children sensitized to house-dust mites (). Fumes from wood-burning appliances or fireplaces can precipitate symptoms in persons who have asthma (). Sprays and strong odors, particularly perfumes, can also irritate the lungs and precipitate asthma symptoms.

The Expert Panel recommends that clinicians evaluate a patient for presence of a chronic comorbid condition when the patient's asthma cannot be well controlled. Treating the following conditions may improve asthma management: ABPA (Evidence A), gastroesophageal reflux (Evidence B), obesity (Evidence B, limited studies), OSA (Evidence D), rhinitis/sinusitis (Evidence B), chronic stress/depression (Evidence D). Several chronic comorbid conditions have been demonstrated to impede asthma management. Evidence suggests that if the conditions are treated appropriately, asthma control can improve, although clearly some conditions are more readily addressed than others. Clinical judgment is needed to weigh the level of asthma control and patient circumstances to determine the appropriate approach.

The Expert Panel recommends that ABPA should be suspected in patients who have asthma and have the presence or a history of pulmonary infiltrates. It should also be specifically considered in patients who have evidence of IgE sensitization to Aspergillus (positive prick skin test or in vitro tests) and in corticosteroid-dependent patients who have asthma (Evidence A) . ABPA complicates both asthma and cystic fibrosis (). The fungus grows saphrophytically in bronchial mucus in the bronchi. Although there is no tissue invasion, a surrounding, predominantly eosinophilic inflammation occurs and often leads to damage to the bronchial wall and development of the typical proximal bronchiectasis, which may be varicose (beaded), cylindrical, or saccular (cystic). The classic clinical presentation includes transient migratory lung shadows on chest x ray or computer tomography (CT), peripheral blood eosinophilia, pyrexia, and sputum containing brown plugs or flecks. Occasionally, the same presentation is produced by another organism, usually another fungus. Clear diagnostic criteria for ABPA are lacking; minimum criteria for the diagnosis of ABPA complicating asthma include (): ▪ Positive immediate skin test to Aspergillus ▪ Elevated serum IgE and/or immunoglobulin G (IgG) to Aspergillus ▪ Central bronchiectasis (inner two-thirds of the chest CT fields)

An earlier form of the disease, before it has progressed to produce central bronchiectasis, can be diagnosed based on the first three criteria above in patients who have asthma. Additional supporting findings for a diagnosis of ABPA include a history of pulmonary infiltrates, serum precipitating antibodies to Aspergillus, peripheral blood eosinophilia, and production of mucus plugs containing Aspergillus. The standard treatment for ABPA is prednisone, initially 0.5 mg per kilogram, with gradual tapering monitored by repeat chest x rays and measurement of total serum IgE concentrations (). Azole antifungal agents have also been tried as adjunctive treatment in patients who are stable and who have ABPA (). Itraconazole administered orally for 16 weeks reduced sputum eosinophilia, serum IgE and IgG levels, and the number of exacerbations requiring oral corticosteroids ().

The Expert Panel recommends that medical management of GERD be instituted for patients who have asthma and complain of frequent heartburn or pyrosis, particularly those who have frequent episodes of nocturnal asthma (Evidence B). For patients who have poorly controlled asthma, particularly with a nocturnal component, investigation for GERD may be warranted even in the absence of suggestive symptoms (; ). ▪ Avoiding heavy meals, fried food, caffeine, and alcohol. ▪ Avoiding food and drink within 3 hours of retiring (). ▪ Elevating the head of the bed on 6- to 8-inch blocks (). ▪ Using appropriate pharmacologic therapy (). For patients who have persistent reflux symptoms following optimal therapy, further evaluation is indicated. The symptoms of GERD are common in both children and adults who have asthma (). Reflux during sleep can contribute to nocturnal asthma (; ; ; ). Although a systematic review concluded that there was no overall improvement in asthma following medical treatment for GERD (), treatment with a proton pump inhibitor was reported to reduce nocturnal symptoms (), reduce asthma exacerbations, and improve quality of life related to asthma (). Surgical treatment has been reported to reduce the symptoms of asthma and the requirement for medication (; ; ).