Advances in the Use of Inhalation Provocation Tests in Clinical Evaluation

3 O'Brien R1 Drizd TA. Roentgenographic determination of total lung capacity: Normal values from a national population survey. Am Rev Respir Dis 1983; 128:949-52 4 Clausen ]L, Zarins L~ Estimation of lung volumes from chest radiographs. In: Clausen JL, Zarins ~ eds: Pulmonary function testing guidelines and controversies: Equipment, methods, and normal values. New York: Academic Press, 1982:155-63 5 Hecksher 1: Bass H, Oriol A, Rose B, Anthonisen NR, Bates O. Regional lung function in patients with bronchial asthma. J Clin Invest 1968;47:1063-70 6 Bleecker Eft, Cotton OJ, Fischer S~ GrafPO, Gold WM, Nadel JA. The mechanism of rapid, shallow breathing after inhaling histamine aerosol in exercising dogs. Am Rev Respir Dis 1976;

114:909-16

7 Cotton OJ, Bleecker ER, Fischer S~ GrafPO, Gold WM, Nadel JA. Rapid, shallow breathing after AICtJ,;, mum antigen inhalation: Role of vagus nerves. J Appl Physioll977; 42:101-6

Advances In the Use of Inhalation Provocation Tests In Clinical Evaluatlon* Fredericle E. Hargreave, M.D.; E. Helen Ram8dale, B.M.;t Peter J Sterle, M.B.; and Elizabeth F.Juniper, M.C.S.~

T

hree types of inhalation provocation tests are used in clinical practice to characterize bronchial asthma. Methacholine or histamine tests measure the response of the airways to pharmacologic bronchoconstrictive stimuli. 1 Allergen inhalation tests and occupational exposure tests measure the response to allergens and speci6c chemical sensitizers such as toluene diisocyanate. I Recent advances in the use of inhalation tests in clinical practice have been made especially with methacholine and histamine tests. These simulate the effect of endogenous mediators on bronchial smooth muscle, which is an important determinant of the response to natural clinical stimuli, such as exercise" and allergens....' Methacholine and histamine tests can now be better standardized, do not stimulate prolonged responses, are safe, can be performed by the unsupervised laboratory technician, and have the greatest clinical value ...We will therefore discuss the advances in their standardization, interpretation, and use in clinical practice. In contrast, allergen inhalation and occupational exposure tests cannot be as well standardized, often produce prolonged responses, are potentially dangerous, must be performed under direct supervision of the physician, and are chiefty used in research." We will not discuss them further: METHODS AND STANDARDIZATION

Methacholine and histamine tests have been confusing to many people because of the numerous methods used and the poor understanding of their regulation. Basical1y, the tests consist of the inhalation of an aerosol of saline control followed by increasing concentrations of methacholine chloride or histamine acid phos·From McMaster University and St. Josephs Hospital, Hamilton, Ontario, Canada. tFellow of the Ontario Ministry of Health. Supported by a grant from the Medical Research Council of Canada.

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phate.1.1.1 The concentrations are best increased twofold to obtain a

quantitative result. The bronchooonstrictive response is usually

measured by FEV1, and the inhalations are generally discontinued when this value has fallen by 20 percent or more below the lowest postsaline value or when the top concentration has been given. The result is usually expressed as the provocation concentration or dose to cause a 6ill in FEV1 of 20 percent (PC. or PD.). The response to methacholine is similar in magnitude to the response to histamine. The lower the pc. or PO., the greater the degree of responsiveness. There is now a better understanding of how the tests must be regulated to interpret and compare results. The pc. and PO. are determined by the dose of aerosol deposited in the lung and biologic factors existing in the subject. The dose of methacholine or histamine deposited in the lung results from the dose delivered to the mouth, and from the method of aerosol generation and inhalation which inJIuences the entry of particles into the lung and their deposition. 81Wo methods of aerosol generation and inhalation have been reflned. The simplest, introduced by de Vries et al' and modi&ed by Cockcroft et ai,» consists of the continuous generation of aerosol by ajet nebulizer and inhalation by tidal breathing for a fixed time. Only nebulizer output and the time of inhalation need be regulated' when the aerosol particle size is between about 1 and 4 ,., aerodynamic mass median diameter; eg, in the method of Cockcroft et al, these are 0.13 mlImin and 2 min, respectively, and the pc. (mglml) measurements quoted below are derived from this method. The other method, introduced by Cbai and collaboratorsU and m0di6ed by Yan et al,II consists of generation of a puff of aerosol with a dosimeter or band-operated nebulizer, respectively, at the beginning of each of a certain number ofinspired breaths. Again the output per puffand the number of puffs must be measured. In addition, the lung volume at the start of inhalation (residual volume or functional residual capacity1 the time of inhalation, and the time that the breath is held after each inhalation must be regulated, at least until their significance has been investigated. These methods have been documented in detail and compared.1LJ3 The results are currently expressed in different units: as the noncumulative concentration (PC.) in mglml,)o'13 which does not include the volume delivered; as cumulative breath units. U which are arbitnry units and alsodo not include the volume delivered; and as the cumulative dose (PO.) in ,.,moles,1I which considers both concentration and volume. The last seems most appropriate; it necessitates measurement of the dose delivered to the mouth (during tidal breathing or a number of inspired breaths) and makes. easier the comparison of results from the same method between laboratories. The biologic factors whichcan influence results are medications, baseline airway caliber, and events which can heighten responsiveness. Bronchodilators and antihistamines (in the case of hlstamine) reduce the response, and their use must be withheld ilr their duration of action befOre the test. Spirometric values must be within normal limits to interpret accurately the results, since a reduced PC. or PD. in the presence of airftow obstruction does not necessarily mean that bronchia1 responsiveness is increased."-m Bronchia1 infection- or exposure to allergens!' or to chemical

sensitizers- can heighten responsiveness for days, weeks, or months, and need to be considered when interpreting results. USE IN THE DIAGNOSIS OF AsTHMA

The use of methacholine or histamine tests to validate the diagnosis of asthma has been recognizedfor some time, but the interpretation of results has improved. For example, there is now a better understanding of the disbibution of responsiveness in populations, of what is regarded as increased or normal, and of the relationship to other features of asthma.

Bronchial responsiveness seems to have a unimodal distribution in the general population, with asthmatic patients representing the hyperresponsive tail." Asthmatic patients with current symptoms tend to have a PC 20 less than 8 mg/ml (by the method of Cockcroft et allO) , and those who deny past symptoms of asthma tend to have a PC m greater than 8 mg/ml, 1.19.20 Thus, a PC 20 of less than 8 mg/ml has been regarded as decreased and of greater than 8 mg/ml as normal, although there is a borderline gray area between 4 and 16 mg/ml, partly as a result of the reproducibility of the measurement, which is usually within a ± twofold concentration difference.1.13•21 This arbitrary division lies within a considerable range of measurable responsiveness. The PC 20 can be reduced (bronchial responsiveness can be increased) by at least eight doubling concentrations (ie, 0.03 to 8 mg/ml) and increased into the normal range up to three (ie, 8 to 64 mg/ml), In the latter, maximal bronchoconstriction becomes limited22. 23 and the dose-response curves plateau at a lower level as the PC 20 becomes higher," if the PC 20 has not been determined by 64 mg/ml, it usually cannot be obtained. However, the use of more sensitive measures of How, such as volume-standardized partial How-volume curves, demonstrate a normal range of responsiveness of greater than six doubling concentrations." The arbitrary division between increased and normal within such a wide range of responsiveness stresses the importance of regulating the dose of aerosol deposited in the lung; results obtained from methods which do not do this cannot be accurately interpreted. The interpretation of the reduced PC so depends on whether spirometric values are normal or airflow obstruction is present. When spirometric test results are normal, increased responsiveness indicates that spontaneous or stimulated bronchoconstriction will occur more easily, ie, that variable airflow obstruction (asthma) is more likely.1.24.25 Thus, increased responsiveness in an apparently asymptomatic patient or in a patient with rhinitis is not a false positive observation." When spirometry is reduced, however, as in smokers with chronic obstructive bronchitis.e" the PC 20 will be low in association with the decrease in airway caliber and does not necessarily mean that there is hyperresponsiveness of bronchial smooth muscle and asthma. A more specific measurement of asthma in these patients may be the demonstration of bronchoconstriction after hyperventilation or exercise. 15 A PC so of greater than 8 mglml is unlikely to be associated with symptoms due to variable airflow obstruction, but these can occur if the stimulus for bronchoconstriction is strong. 27.28 In addition, normal responsiveness does not exclude past or future asthma, because responsiveness can vary over time between normal and increased. 28 Thus, methachoiine or histamine tests are a very sensitive indicator of the presence or absence of current asthma, defined as variable airflow obstruction, as long as spirometry study is normal at the time of the test. They are more sensitive and specific than the history,26 diurnal variation of peak flow rates (when this is measured twice daily, on waking in the morning and at the end of the afternoon), 24 and exercise tests. 1 Asthma in most people is mild, and the tests are commonly useful to investigate the significance of symptoms in patients with normal spirometric evaluation.

SEVERITY OF BRONCHIAL RESPONSIVENESS

It is now evident that, like spirometry for the measurement of airflow obstruction, measurement of bronchial responsiveness is clinically useful, not only to determine the presence or absence of an abnormality, but also to determine the severity of the abnormality and the changes caused by inducers of asthma or treatment. The severity ofhyperresponsiveness relates closely to the degree of variable airflow obstruction as indicated by the degree"of morning dipping of peak flow rates" and the ease of bronchoconstriction stimulated by clinical nonallergic'r" and allergic" stimuli. These relationships indicate that, if there is a history of symptoms at night or on waking, or if symptoms are readily triggered by cold air exposure or exercise, responsiveness is likely to be moderately or severely increased. The relationship to the ease of stimulation of bronchoconstriction by allergen has made it possible to predict the dose of allergen extract required to trigger an early asthmatic response" and has removed its need to be verified by allergen inhalation tests. The degree of hyperresponsiveness also relates to the amount of bronchodilator required to control symptoms of variable airflow obstruction:' the greater the hyperresponsiveness, the greater the amount of bronchodilator required. Asthmatic patients requiring treatment with corticosteroids tend to be more hyperresponsive,' but there are exceptions, particularly when the corticosteroid is needed to control troublesome cough or sputum (unpublished observations, 1984). Therefore, methacholine or histamine tests are often of value to quantify the level of responsiveness when the severity is in any doubt. This might happen, for example, in a person who is very symptomatic in the presence of only trivial airflow obstruction, who has normal spirometric values at the time of the clinic visit, and who might be overtreated with bronchodilators without the knowledge that bronchial responsiveness is only mildly increased. Conversely, the person who tolerates or does not recognize symptoms may be undertreated without the knowledge of the presence of a severe increase in responsiveness to suggest a trial of regular treatment. CHANGES IN RESPONSIVENESS

Changes in responsiveness have been observed after infection," exposure to allergens" and chemical sensitizers,18.28 and treatment. 19 They help the investigation of the cause and cure of asthma. Serial measurements can be useful in clinical practice to prove objectively the presence of occupational asthma, defined as asthma caused by exposure to materials at work (usually as a result of sensitization).18.30 Occupational asthma defined in this way needs to be distinguished from bronchoconstriction stimulated by nonsensitizing stimuli, such as exercise and irritant dust or fumes, in a person whose asthma has developed from nonoccupational causes. The differentiation is best made by daily measurements of peak 80w rate and weekly measurements of methacholine responsiveness performed several hours after the last exposure at the end of the work week (eg, on Friday morning). Occupational asthma is associated with a decrease in PC ICh which recovers when the work is discontinued. Coincidental asthma is usually associCHEST I 87 I 1 I JANUARY, 1985 I Supplement

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ated with a moderate-to-severe increase in responsiveness, which remains the same whether the person is at work or away from work." Serial measurements of responsiveness might also be useful to establish the optimal treatment of asthma. For example, asthma is usually treated to control symptoms and return postbronchodilator spirometric values to normal. However, in view of the close relationship between the occurrence and severity of variable airflow obstruction and the degree of responsiveness, optimal control of asthma might also include an attempt to reduce hyperresponsiveness as much as possible." The value of measurements used for this reason requires further investigation. SUMMARY

Recent advances in the use of inhalation provocation tests in the clinical evaluation of asthma have been made with methacholine and histamine tests. The tests can be better standardized and the results more accurately interpreted. The ease of stimulation of bronchoconstriction by methacholine and histamine (bronchial responsiveness) relates closely to the presence and the degree of variable airflow obstruction that occurs spontaneously or is triggered by natural stimuli. Responsiveness can be heightened by bronchial infection and by exposure to allergens or sensitizing chemicals, such as toluene dilsocyanate, and can be reduced by treatment. These observations indicate three uses of the tests in clinical practice. First, they can be used to validate the presence ofhyperresponsiveness which, when spirometric study is normal, is synonymous with the presence of asthma. Second, they can be used to quantify the severity of hyperresponslveness which relates closely to the amount of bronchodilator required to treat asthma. Finally, they can be used to measure a change in responsiveness, which is useful to document occupational asthma (defined as hyperresponsiveness caused by materials at work), and to optimize the treatment required to reverse or reduce hyperresponsiveness as much as possible. REFERENCES 1 Hargreave FE, Ryan G, Thomson NC, O'Byrne PM, Latimer K, Juniper EF, et ale Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol 1981; 68:347-55 2 Pepys J, Hutchcroft BJ. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975; 112:829-59 3 Lee TH, Nagy L, Nagakura 1: Walport MJ, Kay AB. Identification and partial characterization of an exercise-induced neutrophil chemotactic factor in bronchial asthma. J Clin Invest 1982; 69:889-99 4 Nagy L, Lee TH, Kay AB. Neutrophil chemotactic activity in antigen-induced late asthmatic reactions. N Eng} J Moo 1982; 306:497-501 5 Atkins PC, Bedard P-M, Zweiman B, Dyer J, Kaliner MA. Increased antigen-induced local and systemic mediator release with pulmonary symptoms in the pollen season. J Allergy Clin Immunol 1984; 73:341-47 6 Hargreave FE, Dolovich J, Boulet L-~ Inhalation provocation tests. Semin Respir Med 1983; 43:224-35 7 Eiser NM, Kerrebijn KF, Quanjer PH. Guidelines for standardization of bronchial challenges with (nonspecific) bronchoconstricting agents. Bull Eur Physiopathol Respir 1983; 34S

19:495-514 8 Ryan G, Dolovich MB, Obminsky G, Cockcroft D~ Juniper EF: Hargreave FE, et al. Standardization of inhalation provocation tests: influence of nebulizer output, particle size and method of inhalation. J Allergy Clin ImmunoI1981; 67:156-61 9 de Vries K, Goeifl: Booy-Noord H, Orie NGM. Changes during 24 hours in the lung function and histamine hyperreactivity of the bronchial tree in asthmatic and bronchitic patients. Int Arch Allergy 1962; 20:93-101 10 Cockcroft D~ Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235-43 11 Chai H, Farr RS, Froelich LA, Mathison DA, McLean JA, Rosenthal RR, et ale Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975; 56:323-28 12 Yan K, Salome C, WoolcockAJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983; 38:760-65 13 Ryan G, Dolovich MB, Roberts RS, Frith PA, Juniper EF, Hargreave FE, et al. Standardization of inhalation provocation tests: two techniques of aerosol generation and inhalation compared. Am Rev Respir Dis 1981; 123:195-9 14 Bahous J, Cartier A, Ouimet G, Pineau L, Malo J-L. Nonallergic bronchial hyperexcitability in chronic bronchitis. Am Rev Respir Dis 1984; 129:216-20 15 Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and cold air responsiveness. Thorax 1984; (in press) 16 De Jongste jc, Degenhart HJ, Neijens HH, Duiverman EJ, Raatgreep HC, Kerrebijn Kit: Bronchial responsiveness and leucocyte reactivity after influenza vaccine in asthmatic patients. Eur J Respir Dis 1984; 65:196-200 17 Cartier A, Thomson NC, Frith PA, Roberts R, Hargreave FE. Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber. J Allergy Clio Immunol 1982; 70:170-7 18 Chan-Yeung M, Lam S, Koener S. Clinical features and natural history of occupational asthma due to western red cedar (Thuja plieata). Am J Med 1982; 72:411-15 19 Cockcroft DW, Berscheid BA, Murdock KY. Unimodal distribution of bronchial responsiveness to inhaled histamine in a random human population. Chest 1983; 83:751-4 20 Malo J-L, Pineau L, Cartier A, Martin RR. Reference values of the provocation concentrations of methacholine that cause 6% and 20% changes in forced expiratory volume in one second in a normal population. Am Rev Respir Dis 1983; 128:8-11 21 Debaut ~ Rachiele A, Martin RR, Malo JL. Histamine doseresponse curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax 1983; 38:516-22 22 WoolcockAJ,Salome CM, Yan K. The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis 1984; 130:71-5 23 Sterk PJ, Daniel EE, lamel N, Hargreave FE. Limited bronchoeonstriction to methacholine using partial flow-volume curves in nonasthmatic subjects. Am Rev Respir Dis (submitted) 24 Ryan G, Latimer KM, Dolovich J, Hargreave FE. Bronchial responsiveness to histamine: reiationship to diurnal variation of peak flow rate, improvement ~er bronchodilator and airway calibre. Thorax 1982; 37:423-9 25 Weiss JW, Rossing TH, McFadden ER Jr, Ingram RH Jr. Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma. J Allergy Clin Immunol 1983; 72:140-4 26 Ramsdale EH, Morris M, Hargreave FE. The diagnostic significance of increased bronchial responsiveness to methacholine in subjects with rhinitis. J Allergy Clin Immunol 1983; 71(suppl): 143A

27 Cockcroft DW, Ruffin RE, Frith PA, Cartier A, Juniper EF, Dolovich J, et ale Determinants of allergen-induced asthma: dose of allergen, circulating IgE antibody concentration, and bronchial responsiveness to inhaled histamine. Am Rev Respir Dis 1979; 120:1053-8 28 Hargreave FE, Ramsdale EH, Pugsley so. Occupational asthma without bronchial hyperresponsiveness. Am Rev Respir Dis 1984; 130:516-5 29 Juniper EF, Frith PA, Hargreave FE. Long-term stability of bronchial responsiveness to histamine. Thorax 1982; 37:288-91 30 Cartier A, Pineau L, Malo J-L. Monitoring of maximum expiratory peak flow rates and histamine inhalation tests in the investigation of occupational asthma. Clio Allergy 1984; 14:193-6 31 Woolcock AJ. Aims of management-should it differ in adults and children? In: Asthma: similarities and contrasts in children and adults. Oxford: Medical Education Services Ltd, 1984:42

Distinguishing Among Asthma, Chronic Bronchitis, and Emphysema Gordon L. Snider, M.D., EC.C.P.*

Asthma, chronic bronchitis, and emphysema all diffusely the bronchial tree and may give rise to the syndrome of wheezing, cough, and shortness of breath. It is clinically difficult to distinguish among these disorders, and for this reason estimates of their prevalence are not very accurate. However; they are common. It is estimated that some degree of emphysema is found in the lungs of about two-thirds of adults at autopsy, although the proportion of persons with severe emphysema is probably under 10 percent. 1 Chronic bronchitis is predominantly a disease of smokers, and at present it is estimated that there are about 55 million adult cigarette smokers in the United States, of whom about 30 million are long-standing, heavy smokers. About half of the long-standing smokers, perhaps as many as 15 million persons, have mucous hypersecretion, the hallmark of chronic bronchitis, and 15 percent of the longstanding smokers, or about 4.5 million persons, have chronic airHowobstruction. Asthma is believed to afBict at least 3 percent of the U. S. population; thus, conservatively estimated, there are about 7 million persons suffering from asthma in the United States." On the basis of these admittedly rough estimates of prevalence alone, one would expect a considerable number of patients to suffer from two or even all three of these disorders (Fig 1). Clear descriptions of the entities which we now call asthma, chronic bronchitis, and emphysema first were recorded in the latter part of the 18th century and the first quarter of the 19th century. From the beginning, there was confusion as to the nature, manifestations, and even the existence of the three entities," not difficult to understand in the light of current understanding. Diffuse airflow limitation

1"1 affect

*Director of the Pulmonary Center, Boston University School of Medicine and Chief, Pulmonary Section, Boston Veterans Administration Medical Center, Member of the Evans Memorial Department of Clinical Research, University Hospital, Boston. Supported by the National Heart, Lung, and Blood Institute Program Project grant HL 19717 and the Veterans Administration Research Service. Reprint requests: Dr. Snider, Pulmonary Section, VA Medical

Center, 150South Huntington, Boston02130

and its manifestations are common to all three entities. Wheezing, dyspnea, and difficult breathing due to increased resistance to the movement of air through the conducting airways are common to all three disorders. Cough, which is varyingly productive of secretion, is also frequently observed with all three disorders. Although asthma is generally a paroxysmal disease, nonremitting airflow obstruction may develop. It matters not, from the point of view of the clinical syndrome produced, that the pathogenesis of the airHow limitation differs among these three entities. Loss of elastic recoil with collapse of the small, poorly supported, distal airways at high lung volumes is the major mechanism of airHowlimitation in emphysema;" this change is irreversible. Bronchial hyperreactivity, manifested as contraction of smooth muscle, an excess amount and viscosity of bronchial secretion, and inflammatory changes in the airways, is responsible for the airflow obstruction of asthma. H yperplasia and hypertrophy of the submucosal bronchial glands are primarily responsible for the mucous hypersecretion of chronic bronchitis, but these changes probably do not produce airways obstruction." Inflammatory changes, alterations in the epithelium, and secretion in the small airways are the major mechanisms of airways obstruction in chronic bronchitis." The confusion is compounded, because bronchial hyperreactivity may be a complication of obstructive chronic bronchitis, increasing the symptomatic similarity of

L

~J

AIRWAY OBSTRUCTION 1. Nonproportional Venn diagram showing interrelations of asthma, chronic bronchitis, emphysema, and airways obstruction. Chronic bronchitis and emphysema (subsets 1to 3) may exist without airways obstruction; asthma (subset 10), by de6nition, never does. Pure chronic bronchitis and pure emphysema (subsets 4 and 5, respectively) are infrequent; the combination of the two entities (subset 6) is very common. Occasional patients (subset 7) have features of asthma as well. Chronic bronchitis and asthma (subset 8) frequently occur together; asthma and emphysema (subset 9) may coexist but are not causally related. Subset 11includes patients who have airways obstruction on some other basis, such as cystic 6brosis of the pancreas. (Republished with permission from Little, Brown & Co from Snider GL, ed. Clinical Pulmonary Medicine, 1981:249.) FIGURE

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