5
Medical Testing Methods

Methods to determine the effects of indoor allergens can be divided into two general categories: patient testing and environmental testing. Patient testing evaluates the health status of an individual (clinical) or population (epidemiological). Environmental testing characterizes environments with respect to sources of allergens, dissemination factors, ambient concentrations, and human exposure. Data from both kinds of testing can be used to direct treatment, control, and prevention of allergic disease. This chapter discusses common approaches to patient testing including the medical history, skin tests, in vitro serum tests, and evaluations of pulmonary function. Chapter 6 discusses environmental testing and the assessment of exposure and risk.

MEDICAL HISTORY AND DIAGNOSIS

History

A common dictum in allergy practice is that the patient's medical history is the primary diagnostic test. Laboratory studies, including skin and in vitro tests for specific immunoglobulin E (IgE) antibodies, have relevance only when correlated with the patient's medical history. Furthermore, treatment should always be directed toward current symptomatology and not merely toward the results of specific allergy tests. Several authors of current allergy textbooks reiterate these points:



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Indoor Allergens: Assessing and Controlling Adverse Health Effects 5 Medical Testing Methods Methods to determine the effects of indoor allergens can be divided into two general categories: patient testing and environmental testing. Patient testing evaluates the health status of an individual (clinical) or population (epidemiological). Environmental testing characterizes environments with respect to sources of allergens, dissemination factors, ambient concentrations, and human exposure. Data from both kinds of testing can be used to direct treatment, control, and prevention of allergic disease. This chapter discusses common approaches to patient testing including the medical history, skin tests, in vitro serum tests, and evaluations of pulmonary function. Chapter 6 discusses environmental testing and the assessment of exposure and risk. MEDICAL HISTORY AND DIAGNOSIS History A common dictum in allergy practice is that the patient's medical history is the primary diagnostic test. Laboratory studies, including skin and in vitro tests for specific immunoglobulin E (IgE) antibodies, have relevance only when correlated with the patient's medical history. Furthermore, treatment should always be directed toward current symptomatology and not merely toward the results of specific allergy tests. Several authors of current allergy textbooks reiterate these points:

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Indoor Allergens: Assessing and Controlling Adverse Health Effects ''The selection of appropriate diagnostic tests is fully dependent on the clinical history presented by the patient in question. It therefore follows that diagnostic tests should be ordered only after a careful history and physical examination have been obtained" (Kaplan, 1985). "The degree of success that will be achieved in the treatment of a patient's allergies will be proportional to the exactness of the history obtained" (Weiss and Rubin, 1980). "It is of utmost importance to begin with a thorough, perceptive general medical history…. If the general history suggests an allergic disease, one must ascertain what factors are important in producing the difficulty of the individual patient. The history is the major approach in making this assessment, and the most important clinical skill to be learned in evaluating allergy patients is to acquire facility in asking discerning questions so that logical deductions can be made about the cause of the patient's difficulty" (Korenblat and Wedner, 1984). "The purposes of the medical evaluation are to establish the diagnosis, to estimate the severity of the illness, to determine responses to previous treatment, to identify possible complications, and thus to guide appropriate further management. A thorough medical history is the most helpful tool in achieving these objectives in the field of allergy" (Bierman and Pearlman, 1988). In spite of universal agreement about the primary importance of a patient's allergy history, the same textbooks from which these quotations were taken (and others) devote little or no space to this topic (Tables 5-1 and 5-2). Furthermore, review of the allergy literature reveals no discernible research on the subject. Allergists use a variety of methods to obtain a history, including (1) an open-ended, nondirected question-and-answer session, (2) a series of questions ordered according to a formal protocol to ensure completeness, (3) a structured questionnaire history completed by the physician, or (4) a structured questionnaire history completed by the patient. Many allergists use a combination of these methods. The use of particular history formats or questionnaires depends on the purpose of the examination—for example, whether it is the clinical evaluation of an individual patient or an epidemiological study of a general or selected population (e.g., that of a particular building, factory, or industry). A commonly used format for evaluating a patient's medical history contains the following eight components: Chief complaint—This includes (a) the reason for the patient's visit, such as referral from a primary physician, need for treatment of a current problem, potential need to avoid an allergen (e.g., penicillin, cat), or disability evaluation, and (b) a concise definition of the symptom or complaint

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Indoor Allergens: Assessing and Controlling Adverse Health Effects TABLE 5-1 Textbooks of Clinical Immunology Textbook Publisher Total Pages Allergy Pages Clinical Evaluation Pages History Pages Parker, C.W., Clinical Immunology (2 vols.), 1980 Saunders 1,438 248 0 0 Graziano, F.M., and Lemanske, R.F., Clinical Immunology, 1989 Williams & Wilkins 310 103 0 0 Freedman S.O., and Gold, P., Clinical Immunology (2nd ed.), 1976 Harper & Row 620 133 0 0 Lockey, R.F., and Bukantz, S.C., Principles of Immunology and Allergy , 1987 Saunders 335 214 26 1½ Lockey, R.F., Allergy and Clinical Immunology, 1979 Medical Examination Publishing Co. 1,175 588 9 3 Altman, L.C., Clinical Allergy and Immunology, 1984 G.K. Hall 473 268 0 0 Samter, M., Immunologic Diseases (2 vols., 4th ed.), 1988 Little, Brown 2,044 267 0 0 Stites, D.P., and Terr, A.I., Basic and Clinical Immunology (7th ed.), 1991 Appleton & Lange 794 64 8½ ½ for which the patient is seeking treatment, preferably in the patient's own words. Present illness—A complete description of current symptoms, including severity and duration. Questions such as the following should be answered: Do symptoms vary seasonally, monthly, weekly, or diurnally? Or are they randomly intermittent? What is the relationship of symptoms to location, such as in the home, at work, and while traveling?

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Indoor Allergens: Assessing and Controlling Adverse Health Effects TABLE 5-2 Textbooks of Allergy Textbook Publisher Total Pages Clinical Evaluation Pages History Pages Kaplan, A.P., Allergy, 1985 Churchill Livingstone 692 0 0 Lessof, M.H., Allergy: Immunological and Clinical Aspects, 1984 Wiley 464 0 0 Beall, G.N., Allergy and Clinical Immunology, 1983 Wiley 326 0 0 Korenblat, P.E., and Wedner, H.J., Allergy: Theory and Practice, 1984 Grune & Stratton 512 13 5½ (plus 5-page questionnaire) Lawlor, G., and Fischer, T.J., Manual of Allergy and Immunology: Diagnosis and Therapy, 1981 Little, Brown 409 (plus 13 appendixes) 10 1½ (plus ½-page questionnaire) Klaustermeyer, W.B., Practical Allergy and Immunology, 1983 Wiley 209 25 1½ Weiss, N.S., and Rubin, J.M., Practical Points in Allergy (2nd ed.), 1980 Medical Examination Publishing Co. 211 4½ (appendix) 1½ Middleton, E., et al., Allergy: Principles and Practice (2 vols., 3rd ed.), 1988 C. V. Mosby 1,597 0 0 Bierman, C.W., and Pearlman, D.S., Allergic Diseases from Infancy to Adulthood (2nd ed.), 1988 Saunders 787 6 3 Patterson, R., Allergic Diseases (3rd ed.), 1985 Lippincott 825 20 9 (plus 2-page questionnaire)

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Indoor Allergens: Assessing and Controlling Adverse Health Effects Patients should be asked about known precipitants (e.g., dust, animals, weather). If symptoms occur in discrete attacks, the allergist should ascertain the frequency of attack, and ask the patient to describe in detail a typical or recent episode. The description of the present illness should also include a list of all current medications and the duration of their use, as well as the efficacy of symptomatic medications. The practitioner should address specific efforts made by the patient to avoid certain allergens and the efficacy of such avoidance. Past allergy history—In assessing this component, the practitioner reiterates questions about the patient's present illness but directs them toward other allergic manifestations that are either no longer occurring or not related to the current evaluation. In addition, he or she should specifically ask the patient about known allergies to foods, drugs, vaccines, and insect bites or stings. Results of past allergy testing and immunotherapy are also informative. Because of regional differences in both indoor and outdoor aeroallergens, a chronological listing of the patient's places of residence should be compared with a history of symptoms. Current and past medical history, including review of systems—This is necessary because of the possible effect of other diseases on allergy, and vice versa. In addition, pregnancy may alter certain allergic manifestations. Family history of allergy—The allergy history and general health of immediate family members should be determined. Occupational history—This portion of the evaluation seeks clues to work-related sources of allergens that may explain a patient's illness. In cases evaluated for work disability, this step must include a complete list of all occupations in which the patient has engaged, including employer, location, and job description. Social history—This set of questions may reveal a symptomatic role for psychosocial factors and "substance" use (tobacco, drugs, alcohol). Environmental history—This is a unique feature of the allergy history. It describes specific features of the patient's indoor and outdoor environments and the effects of specific environmental agents on symptoms. It also serves as the basis of recommendations for allergen avoidance. Table 5-3 details appropriate information regarding the patient's environmental history. Conclusion and Recommendation In spite of universal agreement on the primary importance of a patient's allergy history, very little space in medical textbooks is devoted to the topic, and no standard exists for collecting appropriate information. A standardized, validated allergy-history questionnaire would be useful in both clinical and research settings.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects TABLE 5-3 Environmental History for Indoor Aeroallergen Exposure 1. Home: Location_______________________________________________ Age________Years of Residence________Construction_______________ Heating/cooling system_________________________________________ Filter type_______________Frequency of change____________________ Indoor plants________________________________________________ Bedroom: Carpeting type____________________________Age________ Carpet pad__________________Furniture_________________________ Mattress type________________________Age______Dust cover_______ Pillow(s) type________________________Age______Dust cover_______ Quilt or comforter_________________________________Age_________ Living room: Carpeting__________________________Pad_____________ Family room: Carpeting__________________________Pad_____________ Basement: Flooring_____________________________Dampness_________ 2. Animals and Birds Dog(s): No.______ Years______ In or out________ Cat(s): No.______ Years______ In or out________ Others: No.______ Years______ In or out________ Bird(s) No.______ Years______ In or out________ 3. Work: Employer_________________________________Years__________ Occupation___________________________________________________ Effect on symptoms_____________________________________________ 4. Hobbies:______________________________________________________ Effect on symptoms________________________________________________ 5. Exposure Allergens Irritants House dust Auto exhaust Other dust Diesel fumes Mold, mildew Gasoline Feathers Pesticides Cats New carpet Dogs Perfumes Horses Paints Chickens Cleaners Birds Solvents Rats Smoke Mice Newsprint Guinea pigs Others Rabbits  

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Indoor Allergens: Assessing and Controlling Adverse Health Effects Research Agenda Item: Develop, test, and validate a standardized allergy-history questionnaire for use in multi-center studies. Physical Examination The physical examination should be thorough enough to rule out other causes for the patient's symptoms. Because allergic diseases may be episodic, the physical examination should be performed during a period of allergen exposure when objective signs of allergy can be seen. Negative results from a physical examination performed during a period of allergen avoidance does not mean that the patient does not have an allergy. Daily Diaries Daily diaries are sometimes necessary in cases in which the diagnosis is not clear from the history. They allow ongoing symptoms to be recorded and correlated with observed environmental exposures, ingested food, medication use, and other factors. Diaries can also be used in conjunction with such functional measures as the pulmonary peak flow rate (see the discussion later in this chapter). Clinical trials of medications or immunotherapy and studies of occupational asthma have used such diaries extensively and to good advantage. The literature indicates several specific uses that have been made of them. For example, daily diaries have been used to study the acute effects of environmental factors (Cohen et al., 1972; Finklea et al., 1974a,b; Lawther et al., 1970; Lebowitz et al., 1985; McCarroll et al., 1966; Quackenboss et al., 1989a; Schoettlin and Landau, 1961; WHO, 1982; Zagraninski et al., 1979). There have also been some efforts at partial standardization of diaries (Finklea et al., 1974a; WHO, 1982; Zagraninski et al., 1979) and validation for symptom and medication usage (Lebowitz et al., 1985; Zagraninski et al., 1979). Daily diaries for use in surveys of morbidity (e.g., to estimate the prevalence of specific diseases) were developed, tested, and used in the early 1950s. They have higher reporting levels than standard health history questionnaires and may provide better information about minor health events. Diaries are especially useful for accurate reporting of acute episodes and disability (Allen et al., 1954; Laurent et al., 1972; Mooney, 1962; Muller et al., 1952; Peart, 1952; Verbrugge and Depner, 1981). Because symptom recording occurs soon after symptom development, recall is at a maximum, resulting in more comprehensive health information about the individual. Diaries compare favorably with interview surveys in response rate, segment completion rate, and low attrition. Physician visits reported in diaries are generally quite accurate, except for unusual events (e.g., x-rays only) or as part of

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Indoor Allergens: Assessing and Controlling Adverse Health Effects general nonresponse (Marquis, 1978). Thus, diaries may provide important information with great accuracy for certain clinical research studies. The format for diaries must be established on a case-by-case basis to obtain the information needed for the specific purpose of the study. Population studies that require statistical analyses may mandate simplified reporting at specified times of particular symptoms on a yes/no basis or by using a severity scale; clinical evaluation of an individual patient may be better served by open-ended narrative descriptions. Within a household, a daily diary can be completed by each adult and by one adult for all children. The data should include (1) symptoms selected from a list, (2) medication usage, (3) activity, (4) disability, and (5) physician visits. For analysis, symptoms can be aggregated into sets (e.g., irritant, allergic, asthmatic, acute respiratory illness, nonspecific). Other information can also be aggregated—for example, (1) days of restricted activity ("unable to do usual activities"), (2) days of disability ("unable to work, go to school …"), and (3) days requiring physician or emergency room visits (as well as days requiring increased medication usage). In addition, acute respiratory symptoms such as irritative, infectious, or allergic responses can be tracked for periods of 2 or more weeks and then repeated in a different season of the year or at selected regular intervals to measure the reliability of findings and to study the effect of seasonal or other environmental exogenous stimuli. SKIN TESTS Allergen skin testing has been a primary diagnostic tool in allergy since the 1860s. Skin tests, in and of themselves, are not diagnostic of allergic disease but provide evidence of immunologic sensitization. These tests are of particular value in deciding on, and undertaking strategies to avoid exposure to indoor allergens that are causing allergic symptoms (NHLBI, 1992). A positive skin test is the culmination of a number of events that begin with the interaction of the allergen with IgE on the surface of cutaneous mast cells, as described previously in this report. This interaction is followed by the release of chemical mediators such as histamine, which then exert their effects on the skin by causing the blood vessels to dilate and the plasma to leak into the tissue. Neuronal axon reflexes are also involved. The characteristic skin reaction consists of a "wheal" produced by the leakage of fluid into the skin and a surrounding area of redness ("flare") produced by the dilated blood vessels—the "wheal and flare" response. Thus, the skin test is not simply a test for the presence of specific IgE antibodies; it also involves the sensitivity of the mast cell and the biological effect of the chemical mediators on tissue. The size of the reaction is related to several factors including the amount of allergen injected, the

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Indoor Allergens: Assessing and Controlling Adverse Health Effects degree of sensitization of the cutaneous mast cells and their ability to release histamine, and the reactivity of the skin to the mediators released (H. S. Nelson, 1983). The advantages of skin testing are its simplicity, rapidity of results, low cost, and high sensitivity; however, skin tests can be subject to abuse through inappropriate use or overuse. Table 5-4 presents a comparison of some in vivo and in vitro methods for the diagnosis of IgE-mediated allergic disease. Major Methods Two major skin testing methods are commonly used: the skin prick or puncture test and the intradermal test. In the prick method, a drop of allergenic extract is applied to the skin, and the skin is pricked with a needle through the drop. A number of devices are commercially available for testing using this method (Demoly et al., 1991). The most commonly used skin prick method is to introduce the tip of a stylette or a 27 (or smaller) gauge needle into the epidermis at a 15- to 20-degree angle through the drop of test allergen and then to lift up until the tip of the needle pops loose. Alternatively, lancets or solid needles are often used. One concern about the skin prick method is the possible transfer of allergens from one test site to another if the needle is not properly wiped off TABLE 5-4 Comparison of Two In Vivo Skin Tests (Prick and Intradermal) with In Vitro Tests (RAST or Equivalent) for Diagnosing IgE-Mediated Allergic Diseasea   In Vivo Skin Tests   In Vitro (Specific IgE)— RAST or Equivalent Parameter Skin Prick Intradermal Sensitivity Good Excellent Fair-good Specificity Good Poor-fair Excellent Safety Excellent Good Excellent Reproducibility Good Good Excellent Convenienceb Excellent Good Fair Cost Excellent Good Fair NOTE: RAST, radioallergosorbent test. a Ratings are based on the assumption that the procedures are done by well-qualified personnel using properly standardized reagents and adequate quality control. b Convenience is a composite of efficiency and ease of testing, lack of discomfort, and rapid availability of test results. SOURCE: Adapted from Van Arsdel and Larson, 1989.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects between each test. This problem can be avoided by using a fresh needle for each test site. Another potential area of difficulty involves placement of the allergens: if they are too close, overlapping reactions cannot be separated. It is therefore recommended that the extracts be placed at least 2 cm apart. Infection and bleeding can lead to false-positive results. Likewise, insufficient penetration of the skin by the puncture instrument may lead to false-negative results. (This problem is more likely to occur with plastic devices [Bousquet, 1988].) Skin prick tests are applicable to children as young as 1 month of age if clinical indications are present. Use of the test usually requires allergen concentrations of 1:10 to 1:20, weight/volume. Skin prick tests pose an extremely low risk for the development of systemic anaphylactic reactions or fatalities. In intradermal testing, allergenic extracts are diluted in a buffered saline solution containing 0.3 percent human serum albumin as a stabilizer. Volumes of 0.01 to 0.05 ml are injected intradermally. As noted above, individual, unitized syringes should be employed for each skin test to avoid any risk of contamination from syringes with removable needles that have been used repeatedly (Shulan et al., 1985). Solutions containing less than 1 percent glycerine may be used for skin testing; concentrations greater than this amount may induce nonspecific reactions. Because a small but definite risk of anaphylaxis and fatalities exists with intradermal testing (Lockey et al., 1987), skin prick tests should be conducted prior to any such testing. In addition, patients who are suspected of having allergic disease but who have a negative skin prick test may be candidates for intradermal testing because intradermal testing is more sensitive. Properly conducted negative intradermal skin tests virtually exclude the presence of specific IgE antibody. Scratch or abrasion methods should probably be abandoned (Van Arsdel and Larson, 1989). These tests have poor reproducibility because of the variable amount of allergen introduced into the skin. False-positive reactions may occur if bleeding is induced; there is also a risk of systemic allergic reactions (Guerin and Watson, 1988). Variables and Controls Several variables can affect the size of the cutaneous reaction. The magnitudes of both allergen and histamine reactions vary over different parts of the body. The upper and midback are more reactive than the lower back. The back is more reactive than the forearm. The ulnar side of the arm is more reactive than the radial. The wrist area is less reactive than the space in front of the elbow (H. S. Nelson, 1983). There is also some variability in skin test responsiveness at different times of the day. At 7 a.m., the reaction to allergen and histamine is less than that in the late

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Indoor Allergens: Assessing and Controlling Adverse Health Effects afternoon and early evening. The age of the individual undergoing testing also influences the size of the skin test response. Young infants have wheals and flares that are smaller in diameter than those in adults. In addition, skin test reactivity declines after age 60. The reproducibility of epicutaneous skin testing, particularly that using a skin prick test, depends on the degree of pressure applied to the skin. Medications can significantly affect the skin test response. For example, antihistamines and tricyclic antidepressants must be discontinued for at least 4 to 5 days before testing occurs (I. L. Bernstein, 1988). Some long-acting antihistamines such as astemizole (Hismanal®) may interfere with skin test results for up to 6 weeks. Long-term use of high-potency topical steroids also decreases skin test reactivity. Oral corticosteroids at doses of up to 30 mg a day for 1 week do not suppress the allergic skin test response. Because skin tests may be affected by a number of factors, positive and negative controls should be applied. Some general recommendations for skin testing procedures are summarized in Box 5-1. Shortcomings and Precautions One of the major difficulties with reproducibility of skin test responsiveness is the lack of standardized reagents. Certain indoor allergenic extracts (e.g., dust mite and cat) now contain standardized amounts of major allergens, and further efforts at standardization are under way for other allergens. Because extracts often become less potent over time when stored under warm conditions, refrigeration is important. The addition of glycerine to skin prick test reagents enhances their stability, as does the use of BOX 5-1 Allergy Skin Test Procedures Avoid antihistamines and tricyclic antidepressants for 4 to 5 days prior to testing. Long-acting antihistamines e.g., astemizole (Hismanal®) should be avoided for 4 to 6 weeks prior to testing. Topical corticosteroids applied to the test site can reduce the response when used for several weeks. Topical, nasal, inhaled, or systemic corticosteroids have no effect on the skin test response. Appropriate positive (histamine or codeine phosphatase) and negative (diluent) controls should be used. The forearm or upper back skin are appropriate test sites. Appropriately trained personnel and equipment to treat systemic anaphylaxis should be available.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects TABLE 5-7 Coefficients of Variation (percentage) for Spirometric Measurements of Different Subject Groups Subject Slow VC FVC FEV1 FEF25–75% Normal 3 5 7 13 Obstructed   11–14 14 18 NOTE: VC, vital capacity (maximal volume of air exhaled from the point of maximal inhalation); FVC, forced vital capacity (total volume of air exhaled); FEV1, volume of air exhaled in 1 second; and FEF25–75% , forced expiratory flow between 25 and 75 percent of forced vital capacity. SOURCE: ATS (American Thoracic Society), 1987. spirometer mouthpiece, and then to blow out as hard and as fast as they can for at least 6 seconds or until instructed to stop. The spirometer measures changes in volume as a function of time (a volume-based system) or changes in airflow as a function of time (a flow-based system) and plots the tracing on an x–y axis. The results of each tracing are described as volume exhaled in 1 second (FEV1), the total volume exhaled (FVC, forced vital capacity), and the percentage of the total volume exhaled in 1 second ([FEV1/FVC] × 100). Subjects repeat the maneuver until three acceptable tracings are obtained. Criteria for acceptable tracings have been established by the American Thoracic Society. One important criterion is that the technician must judge that the patient has exerted a maximal effort. The best value of three acceptable efforts is taken as the actual measurement. To be a valid measure of lung function, reproducibility criteria must be met. Reproducibility criteria state that the best and the second-best FEV1 and FVC should be within 5 percent or 100 cc, whichever is greater (ATS, 1987). However, the use of these standards may tend to produce underestimates of pulmonary function changes in worker populations, because those with the most disease are the least likely to produce acceptable curves. Diseased workers producing nonreproducible or unacceptable spirometry results would be deleted from the study and thus would not be identified as having disease. This example of "ascertainment bias" has been discussed more extensively by Eisen (1987). Studies summarized in Table 5-7 have quantitated reproducibility in spirometric measurements across days and weeks (ATS, 1991; Lebowitz et al., 1987). Less precise measurement could lead to more variability over time; conversely, stringent quality assurance can result in coefficients of variation below 6 percent for repeated spirometry, even for subjects with obstructive lung disease (Enright et al., 1991). Spirometry results are compared to published reference values, and presented as percent predicted derived from cross-sectional population-based

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Indoor Allergens: Assessing and Controlling Adverse Health Effects studies (Crapo et al., 1981; Knudson et al., 1983; Morris et al., 1971). Predicted values depend on an individual's height, age, and sex. Tall, young men have the greatest predicted lung function. When an individual's actual function is below predicted values, the magnitude of the abnormality may be described according to various schemes such as that presented in Table 5-8 (Engelberg, 1988). Spirometry interpretation characterizes the type of abnormality that is present. Typically, asthma is characterized by airflow obstruction, meaning that a disproportionate decrease in FEV1 relative to FVC exists and peak flow rates are reduced. Hypersensitivity pneumonitis is characterized by a reversible restrictive pattern; that is, FEV1 and FVC are reduced in parallel, and peak flow rates may be unchanged despite significant drops in other measures of lung function. Exceptions to these generalizations, however, are well recognized. In asymptomatic or mild asthma, lung function may fall within the normal range. In more severe asthma, symmetric reductions of FEV1 and FVC occasionally occur and may be misinterpreted as restrictive lung disease. Measurement of lung volumes (see below) will show an increased total lung capacity and air trapping. Clinical evaluation using bronchodilators may also result in improvement. The use of flow rates is helpful in limited circumstances and requires more careful interpretation (ATS, 1991). Spirometry may be repeated after administration of bronchodilators; improvement in pulmonary function indicates the presence of reversible airway obstruction, a characteristic feature of asthma. Spirometry interpretation includes determining whether lung function has changed over time. Comparison with previous tests by the same subject TABLE 5-8 American Medical Association/American Thoracic Society: Description of Respiratory Impairment Parameter None Mild Moderate Severe FVCa ≥80 60–70 51–59 ≤50 FEV1 ≥80 60–79 41–59 <40 FEV1/FVC ≥70 50–69 41–59 <40 DLCOb ≥80 60–79 41–59 <40 or         VO2maxc ml(kg · min) >25 20–25 15–20 <15 a Predicted values of FVC are from Crapo and Morris, 1981; Crapo et al., 1981. b DLCO, diffusing capacity of the lungs for carbon monoxide. c VO2max, maximum volume of oxygen exhaled. SOURCES: Engelberg, 1988; Renzetti et al., 1986.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects adds greatly to the validity of spirometry because it narrows the range of expected values. With this approach, normal is defined with reference to the subject's original value instead of defining ''normal" as any value between 80 percent and 120 percent of standard, predicted values which are derived from population studies. In principle, there is a 95 percent certainty of a decline in lung function if the measured fall is 1.65 times the coefficient of variation for repeated studies (Pennock et al., 1981). However, these guidelines are not uniformly applied or accepted. For example, the cotton dust standard of the U.S. Department of Labor defines a 5 percent, or 200 ml, change across a work shift as significant, yet some studies have shown this magnitude of change to be within expected cross-shift variability for some workers (Glindmeyer et al., 1981; Sheppard, 1988a). Enright and others (1991) achieved a confidence interval of 5.9 percent for duplicate spirometry performed (on average) 25 days apart among subjects with mild to moderate airflow obstruction. Intrasubject variability from year to year, as reported by Nathan and colleagues (1979) for more than 1,000 individuals, indicates that most subjects have greater yearly variability than short-term changes (Lebowitz et al., 1982). Roughly speaking, the expected annual decline in FEV1 is 1 percent. In the clinical setting, a source of potential variability is the use by patients of different laboratories with different equipment and technicians. In theory, of course, these differences should be minimal if proper calibration procedures are used. For the most effective evaluation of individual pulmonary function, epidemiologists must also designate proper criteria by which to define exposure-response relationships. Lebowitz and colleagues (1987) propose that such criteria represent clinically meaningful—as distinct from statistically significant—responses. Spirometry equipment is relatively inexpensive, portable, and accessible. It may be transported to work sites and is available in most hospitals and some physician offices. The equipment is sturdy and usually retains precision. Spirometers are now frequently coupled with computers for automated data calculation. Results appear on a printout or on a computer screen, and sequential tracings are superimposed for ease in assessing reproducibility. "Hard-copy" tracings can also be made and may be required for medicolegal reports. Extensive efforts have resulted in improved precision for spirometry testing. Table 5-9 shows minimum standards for spirometry equipment that have been established by the American Thoracic Society. Nevertheless, S. B. Nelson and coworkers (1990) found that some commercially available spirometers produced FVC errors as large as 1.5 liters (a 25 percent error) primarily as a result of problems with computer software. Technicians and subjects can be trained to perform the test with precision, accuracy, and

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Indoor Allergens: Assessing and Controlling Adverse Health Effects TABLE 5-9 Technical Standards for Peak Flow Meters and Spirometers Device Range of Accuracy Interdevice Variability Precision Reproducibility Peak flow meters Children Adults 100–400 liters/min 100–700 liters/min = 10% ±5% ±10% 5% or 10 liters/min Spirometers 720 liters/min ≥7 liters 15 seconds   ±3% or 0.05 liter 5% or 100 cc NOTE: The test signal for spirometers is the 24 standard waveforms; for peak flow meters, only waveform no. 24 should be used. The waveforms, developed by Hankinson and Gardner, can be used to drive a computer-controlled mechanical syringe for testing actual hardware and software. SOURCES: ATS (American Thoracic Society), 1987; NHLBI, 1991. reproducibility. Technician training courses, certified by the National Institute for Occupational Safety and Health, are available throughout the United States. Efforts to standardize spirometry methods (ATS, 1987) and improve technician training have greatly increased precision, which is now adequate for such applications as clinical diagnosis, disease management, evaluating severity of impairment, and for clinical and epidemiological studies. However, this precision is inadequate to allow a demonstration of subtle longitudinal declines in lung function, because the expected rate of decline for an individual is only about 1 percent per year. Conversely, spirometry is a sensitive measure of disease, since reductions can be detected before severe impairment occurs. Determination of the reversibility of airflow obstruction is made by performing spirometry before and after administration of a bronchodilator. A 15 percent improvement in FEV1 after using a bronchodilator is considered evidence of reversible airflow obstruction. Peak Flow Measurements Peak flow measurements are especially useful to patients in asthma self-management. Patients produce peak flow measurements by inhaling as deeply as possible, sealing their lips around the mouthpiece, and briefly exhaling at maximum velocity. The tube is attached to a measuring device that records the maximum flow rate achieved during exhalation. Patients then read the result and manually record it on a paper record. Patients perform 3 efforts, and the best value is taken as the actual measurement.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects Peak expiratory flow occurs within the first second of a forced expiratory maneuver. Maximum flow occurs within the first few hundred milliliters of volume expired from total lung capacity and is volume and effort dependent. To measure peak flow accurately, the exhalation must begin at maximum inspiration and must be performed with maximum effort. In contrast to spirometry, there is no requirement for a prolonged smooth exhalation, which is an advantage for asthmatics. (Asthmatics often cough immediately following a forced expiratory effort, which can interfere with attempts to obtain acceptable spirometry.) Reduced peak expiratory flow is considered a valid measure of airflow obstruction, and it correlates well with FEV1. Peak flow meters are lightweight, compact, inexpensive ($15–$50) instruments that are small enough to be carried in a purse or coat pocket. Hospitals use peak flow meters for bedside monitoring of asthma severity and response to bronchodilators. Current asthma management guidelines recommend daily home monitoring of peak flow using a peak flow meter (NHLBI, 1991). Peak flow measurements are used extensively in clinical trials of asthma therapy. Efforts are proceeding to improve peak flow meters. The European Respiratory Society and the American Thoracic Society are developing standards for their construction and use. In addition, peak flow meters with a computer chip to allow recording of the time of peak flow effort should be on the market soon. This innovation will increase the cost of peak flow meters but will be a significant advantage for clinical studies. The accuracy of peak flow meters varies among models. Table 5-9 shows technical standards suggested by the National Asthma Education Panel of the National Heart, Lung, and Blood Institute (NHLBI, 1991). Deficiencies in commonly used meters are outweighed by their benefits (Lebowitz, 1991; NHLBI, 1992). Although a flow range of 0–720 liters per minute has been recommended, some units are highly inaccurate within this range. Nevertheless, peak flow meters are invaluable for correlating changes in respiratory obstruction with a variety of activities and events experienced by the patient. Current guidelines suggest that peak flows should be reproducible within 5 percent or 10 liters per minute (NHLBI, 1991). Reproducibility of peak flow measurements using mini-Wright peak flow meters was determined by having 10 subjects perform 30 forced expiratory maneuvers. Coefficients of variation ranged from 2 to 14 percent (Lebowitz et al., 1982). Significant training effects were seen during the first 2 days of a fortnight's study, and Quackenboss and colleagues (1991b) excluded these data from consideration in an epidemiological study. Measurement by standard and mini-Wright peak flow meters has been found to be stable over 6 months (Morrill et al., 1981; Van As, 1982). This stability over time may be more important

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Indoor Allergens: Assessing and Controlling Adverse Health Effects than absolute accuracy, given that the usual application for peak flow involves an assessment of serial changes in peak flow in the same subject over time (Van As, 1982). Interpretation of peak flow variability is best performed by visual inspection of a graph that plots peak flow over time. Computer-based algorithms for interpreting peak flow measures have been shown to be no better than the "eyeball" method for diagnosing work-related asthma (Perrin et al., 1992). Detection of Airway Hyperreactivity Bronchial hyperreactivity, a cardinal feature of asthma, is measured as follows. Patients perform initial spirometry, and the resultant FEV1 is defined as the baseline value. The patient then inhales saline, followed by increasing concentrations of an agonist such as methacholine or histamine, or a stimulus such as cold air or a distilled water aerosol. After each provocation, spirometry is repeated and FEV1 is determined for that dose. The test is stopped when a predetermined reduction in lung function is achieved or the maximum dose is administered. Exercise testing is also used occasionally to measure bronchial reactivity. Typically the test ends when a 20% reduction in FEV1 or a 35 percent reduction in specific airway conductance has occurred, and a provocative dose is calculated. The challenge method and type of data recorded differ among laboratories (Chai et al., 1975; Chatham et al., 1982a). Some record the concentration of agonist at the endpoint, whereas others record the cumulative dose. The percent decrease in FEV1 (targeted as a positive end point) ranges from 10 to 40 percent, with a 20 percent decrease being most common. Popa and Singleton (1988) attempted to determine which of the current provocative doses for histamine optimally separates normal from asthmatic subjects. They concluded that new normative data for diagnostic provocation were needed because of a high misclassification rate using current methods. Inhalation challenge testing with methacholine, histamine, distilled water, exercise, etc., is commonly termed non-specific challenge testing to distinguish these from specific allergen challenge testing. However, each of these chemical and physical agents act on different bronchial receptors and therefore reflect different aspects of non-specific bronchial hyperreactivity. Furthermore, animal studies indicate that inherited hyperreactivity to these agents is transmitted at distinct genetic loci (Levitt et al., 1990). Despite recognized limitations, testing for airways reactivity is widely used because it is a practical test which has great utility in clinical medicine and research. Asthmatics as a group develop reductions in lung function with provocation at much lower doses than do non-asthmatics. The considerable within-subject overlap in hyperreactivity to methacholine, histamine

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Indoor Allergens: Assessing and Controlling Adverse Health Effects and distilled water challenges means that each of these agents is widely used. Increased reactivity has been described in non-asthmatics, particularly in first degree relatives of asthmatics, cigarette smokers, people with allergic rhinitis, and some apparently normal individuals. In general, asthmatics are the most reactive (i.e., require the smallest concentration of agonists to effect a reduction in lung function). The risk of bronchial reactivity increases with increasing skin test reactivity (Burrows and Lebowitz, 1992; Lofdahl and Svedmyr, 1991). In asthmatics, the degree of reactivity correlates with other measures of disease severity. People with allergic rhinitis demonstrate an intermediate level of reactivity. A high proportion of cigarette smokers with airflow obstruction demonstrate increased airways reactivity, but the population distribution of airways reactivity among smokers without airflow obstruction is unknown at present. Data from Pattemore and colleagues (1990) show a 24 percent prevalence of frequent wheezing in children with normal airway responsiveness and a lack of current asthma symptoms in 41 percent of people with hyperresponsiveness. This has led some to criticize the utility of measurement of methacholine or histamine responsiveness in clinical practice. Cockroft and Horgreave (1990) disagree, and point out that when spirometry is normal, methacholine and histamine hyperresponsiveness is a sensitive measure of abnormal airway function that correlates closely with the presence and degree of variable airway obstruction. Cockroft and Horgreave (1990) specifically identify three areas of clinical utility for histamine and methacholine inhalation tests: Exclusion or confirmation of a diagnosis of asthma, especially if the presentation is atypical. Diagnosis and follow-up of occupational asthma. Assessment of the severity of asthma and monitoring of asthma treatment. Bronchoprovocation Testing with Specific Allergens Allergen-specific bronchoprovocation testing is a research tool used to diagnose specific immunologic diseases, identify new etiologic agents, and study the pathogenesis of asthma and hypersensitivity pneumonitis (Chan-Yeung and Lam, 1986; Pepys and Hutchcroft, 1975). Guidelines for allergen challenge have been proposed by the American Academy of Allergy and Immunology (Chai et al., 1975). The limits of allergen inhalation challenge testing outside of a research setting are several. It is time-consuming and staff intensive, and may not be reimbursable. Patients must be monitored for up to 24 hours to detect and treat late reactions. Potentially toxic reactions must be avoided. When an individual has been removed from exposure to an allergen, several days'

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Indoor Allergens: Assessing and Controlling Adverse Health Effects reexposure may be required for a measurable response to occur. Allergen extract in aerosol form is deposited differently in the bronchial system compared with allergen in its natural state. Allergen challenge has been used in connection with bronchoalveolar lavage, in which a bronchoscope is used to sample the fluid in the alveoli. Bronchial biopsies can also be performed. Demonstration of lymphocytosis in bronchoalveolar fluid can suggest the diagnosis of hypersensitivity pneumonitis (Reynolds, 1988). Beasley and others (1989a) performed specific inhalation challenge with allergen followed by bronchial biopsy and lavage, and, later, histamine challenge. Their studies demonstrated an inverse correlation between the number of epithelial cells in lavage fluid and histamine reactivity. Despite its limitations, specific inhalation challenge testing will continue to have a unique place in the study of the health effects of indoor allergens. Lung Volumes Measurement of lung volumes is useful to help evaluate reductions in forced vital capacity. The usual method (gas dilution) involves breathing a known concentration of an inert gas in a closed-circuit system, followed by measurement of the functional residual capacity (volume in the lungs at the end of a normal breath). Total lung capacity is then determined by summing the functional residual capacity and the inspiratory capacity (determined by spirometry). Diffusing Capacity Testing Measurement of diffusing capacity is indicated when the clinician suspects that gas exchange is impaired by the disease process. Diffusion capacity measurements are not necessary in most cases of suspected asthma, but they may be indicated occasionally to exclude interstitial lung disease. In diffusing capacity testing, the patient inhales a known mixture of an inert (nondiffusible) gas and a readily diffusible gas such as carbon monoxide (ATS, 1987). The exhaled gas is collected and analyzed, and the uptake of carbon monoxide is expressed in ml/min/mmHg. Similarly to spirometry, reference values have been determined by cross-sectional studies; interpretation consists of comparing actual values with reference values and with any previously measured values for the patient. Possible confounding factors are also considered. For example, diffusing capacity may be falsely elevated by conditions that raise the metabolic rate, lung blood volume, or red blood cell count; it may be lowered by the presence of carboxyhemoglobin in the blood or by anemia (Gold and Boushey, 1988). Reference standards

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Indoor Allergens: Assessing and Controlling Adverse Health Effects exist for the performance of diffusing capacity testing. As of 1987, however, interlaboratory variability was too great to recommend one set of equations for all laboratories. Rather, laboratories are advised to use internal controls, such as repeated measurements on a normal individual. Exercise Studies Exercise pulmonary function studies can be used as part of a clinical evaluation to quantitate exercise-induced bronchoconstriction in asthmatics (Chatham et al., 1982b), and to exclude the diagnosis of asthma in other cases. Often, however, serial peak flow monitoring during normal activities will be sufficient to document exercise-induced asthma. Exercise testing is also used to evaluate an individual with suspected interstitial lung disease. The occurrence of desaturation or a widening alveolar-arterial oxygen gradient suggests significant interstitial disease (Whipp and Wasserman, 1988). Finally, exercise testing can be used as part of the impairment evaluation when symptoms are disproportionate to static lung function due to deconditioning or unrecognized cardiovascular or pulmonary pathology (Engelberg, 1988). Measures of Upper Airway Function Measures of upper airway function are primarily used in research settings at present. The one exception is the obtaining of a nasal swab with cytologic examination for the presence and characteristics of inflammatory cells. For physiologic measurement of nasal airflow (rhinomanometry), the pressure-flow characteristics during panting maneuvers are used to derive nasal airway resistance (Cole, 1982). Ten to 15 percent of patients are unable to perform the maneuver successfully; normal values are problematic because of normal fluctuations in nasal airway caliber. Nasal resistance measures correlate to a variable degree with congestive symptoms. Peak flow measurements of nasal airflow have been made by adapting a standard peak flow meter with a pediatric anesthetic mask (Ahman, 1992). This method is not without its problems or constraints; for example, technical questions remain about whether to record a nasal inspiratory or expiratory maneuver. Acoustic rhinometry is a new technique that describes the cross-sectional area of the interior of the nose as a function of the distance from the nares. An acoustic pulse is generated, and reflections are recorded by a microphone and analyzed with a computer program using Fourier analysis. Subjects must stop breathing only for approximately half a second; the test is therefore easier to perform than physiological measures of nasal airway

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Indoor Allergens: Assessing and Controlling Adverse Health Effects resistance. The technique has been validated by comparison with cadavers and computerized tomography (Hilberg et al., 1989), but much more extensive clinical trials are needed to evaluate this technique for clinical use. Nasal lavage can be readily performed following nasal inhalation challenge. Analysis of cells, mediators, and proteins can then be conducted to study the pathogenesis of allergic and nonallergic rhinitis (Bascom et al., 1986). However, normal values have not been determined for most measures. Conclusions and Recommendations There are simple, reliable measures of lung function that may be used for studying diseases caused by indoor allergens. Indeed, objective measures of respiratory function should be a part of protocols to determine the efficacy of therapeutic strategies for these diseases. Predicted values for pulmonary function fall along a normal distribution curve with 95 percent confidence intervals for FEV1 and FVC of approximately 80–120 percent. The lower limit of variation in population studies for the midlevel expiratory flow rate (FEF25–75) is approximately 60 percent. Spirometry is limited in its ability to detect impairment of ventilatory function in asymptomatic individuals (Morris et al., 1971) because of the wide range of normal values, even with predicted levels that control for age, sex, and height. Significant inaccuracy can result from errors in spirometry performance, almost all of which lead to underestimation of the true respiratory function. These tests can, however, help to evaluate the effects on an individual of sensitization to specific allergens (J. M. Smith, 1988). They can also help to diagnose respiratory diseases that may be caused or worsened by indoor allergens (Lopez and Salvaggio, 1988; NHLBI, 1991; Woolcock, 1988) and to assess disease severity, which is often critically important in clinical decisionmaking (NHLBI, 1991). Serial pulmonary function testing in the home or workplace can demonstrate causal relationships between the indoor environment and respiratory illness. Serial pulmonary function testing coupled with bronchoprovocation can demonstrate the causal relationship between specific allergens and respiratory responses (Chan-Yeung and Lam, 1986). In epidemiological studies, measures of environmental factors and of pulmonary function can be evaluated for associations that suggest causal relationships (S. Weiss et al., 1983). Pulmonary function tests may also be used to assess the efficacy of therapy, determine response to treatment, or determine the effect of environmental modification (Ehnert et al., 1991; Platts-Mills et al., 1982). Such tests are required when physicians are asked to determine impairment resulting from a respiratory disease for insurance or benefit systems such as workers' compensation and social security disability

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Indoor Allergens: Assessing and Controlling Adverse Health Effects (Engelberg, 1988). Finally, estimates of disease incidence or prevalence often result from epidemiological studies in which pulmonary function tests are used to ascertain disease. Recommendation: Include pulmonary function tests in epidemiological studies to help improve estimates of disease incidence and prevalence. Because they are portable and can be self-administered, tests that utilize peak-flow measurements are most desirable for this purpose. One drawback of many pulmonary function tests is that they must be administered by technicians. Peak flow measurements are less reliable but are highly portable, can be self-administered, and are therefore often more sensitive in the diagnosis of asthma. Recommendation: Include objective measures of respiratory function in experimental protocols designed to determine the efficacy of therapeutic strategies (e.g., pharmacotherapy, environmental modification, avoidance) used to treat respiratory diseases caused by indoor allergens. Bronchial hyperreactivity is a feature of asthma that correlates with clinical severity and does not require repeated measurement (Boushey et al., 1980). It is unclear, however, whether bronchial hyperreactivity can be correlated with exposure to indoor allergens. Research Agenda Item: Determine whether changes in bronchial hyperreactivity can be correlated with exposure to indoor allergens. If such a correlation exists, determine how reducing the level of allergens affects bronchial hyperreactivity.