Abstract
Bronchial provocation tests that use stimuli that act indirectly to cause airway narrowing have a high specificity for identifying people with active asthma who have the potential to respond to treatment with antiinflammatory drugs. The first test to be developed was exercise and it was used to assess the efficacy of drugs such as sodium cromoglycate. Eucapnic voluntary hyperpnea was developed later, as a surrogate test for exercise. Hypertonic aerosols were introduced to mimic the dehydrating effects of evaporative water loss that occurs during hyperpnea. A wet aerosol of 4.5% saline or a dry powder formulation of mannitol is used. At present the indirect challenge tests are becoming increasingly recognised as appropriate for monitoring treatment with inhaled steroids. Indirect tests identify those with potential for exercise-induced bronchoconstriction, an important problem for some occupations, such as the defence forces, fire fighters and the police force and for some athletic activities. The advantage in using an indirect challenges, over a direct challenge with a single pharmacological agonist, is that a positive response indicates that inflammatory cells and their mediators (prostaglandins, leukotrienes and histamine) are present in the airways in sufficient numbers and concentration to indicate that asthma is active at the time of testing. The corollary to this is that a negative test in a known asthmatic indicates good control or mild disease. Another advantage is that healthy subjects do not have significant airway narrowing to indirect challenge tests. The protocols used for challenge with indirectly acting stimuli are presented in detail.
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Van Schoor, J., Joos, G. F., and Pauwels, R. A. (2000), Indirect bronchial hyperresponsiveness in asthma: mechanisms, pharmacology and implications for clinical research. Eur. Respir. J. 16, 514–533.
Joos, G. F., Kips, J. C., and Pauwels, R. A. (1993), Direct and indirect bronchial responsiveness. Respir. Med. 87, 31–36.
Carlsen, K.-H., Engh, G., Mork, M., and Schroder, E. (1998), Cold air inhalation and exercise-induced bronchoconstriction in relationship to methacholine bronchial responsiveness: different patterns in asthmatic children and children with other chronic lung diseases. Respir. Med. 92, 308–315.
Lim, T. K., Taylor, R. G., Watson, A., Joyce, H., and Pride, N. B. (1988), Changes in bronchial responsiveness to inhaled histamine over four years in middle aged male smokers and ex-smokers. Thorax 43, 599–604.
Silverman, M. and Anderson, S. D. (1972), Standardization of exercise tests in asthmatic children. Arch. Dis. Child. 47, 882–889.
Anderson, S. D., Silverman, M., Konig, P., and Godfrey, S. (1975), Exercise-induced asthma. A review. Br. J. Dis. Chest. 69, 1–39.
Eggleston, P. A., Rosenthal, R. R., Anderson, S. D., Anderton, R., Bierman, C. W., Bleecker, E. R., et al. (1979), Guidelines for the methodology of exercise challenge testing of asthmatics. J. Allergy Clin. Immunol. 64, 642–645.
Phillips, Y. Y., Jaeger, J. J., Laube, B. L., and Rosenthal, R. R. (1985), Eucapnic voluntary hyperventilation of compressed gas mixture. A simple system for bronchial challenge by respiratory heat loss. Am. Rev. Respir. Dis. 131, 31–35.
Anderson, S. D., Schoeffel, R. E., and Finney, M. (1983), Evaluation of ultrasonically nebulised solutions as a provocation in patients with asthma. Thorax 38, 284–291.
Anderson, S. D. (1984), Is there a unifying hypothesis for exercise-induced asthma? J. Allergy Clin. Immunol. 73, 660–665.
Anderson, S. D., Brannan, J., Spring, J., Spalding, N., Rodwell, L. T., Chan, K., et al. (1997), A new method for bronchial provocation testing in asthmatic subjects using a dry powder of mannitol. Am. J. Respir. Crit. Care Med. 156, 758–765.
Brannan, J. D., Anderson, S. D., Koskela, H., and Chew, N. (1998), Responsiveness to mannitol in asthmatic subjects with exercise and hyperventilation-induced asthma. Am. J. Respir. Crit. Care Med. 158, 1120–1126.
Holzer, K., Anderson, S.D., Chan, H.-K., Douglass, J. (2002), Mannitol as a challenge to identify exercise-induced bronchoconstriction in elite athletes. Am. J. Respir. Crit. Care Med. 27th November.
Brannan, J. D., Anderson, S. D., Gomes, K., King, G. G., Chan, H.-K., and Seale, J. P. (2001), Fexofenadine decreases sensitivity to and montelukast improves recovery from inhaled mannitol. Am. J. Respir. Crit. Care Med. 163, 1420–1425.
Brannan, J. D., Koskela, H., Anderson, S. D., and Chan, H.-K. (2002), Budesonide reduces sensitivity and reactivity to inhaled mannitol in asthmatic subjects. Respirology 7, 37–44.
Cushley, M. J., Tattersfield, A. E., and Holgate, S. T. (1983), Inhaled a denosine and guanosine on airway resistance in normal and asthmatic subjects. Br. J. Clin. Pharmacol. 15, 161–165.
Polosa, R. and Holgate, S. T. (1997), Adenosine bronchoprovocation: a promising marker of allergic inflammation in asthma? Thorax 52, 919–923.
Sterk, P. J., Fabbri, L. M., Quanjer, P. H., Cockcroft, D. W., O'Byrne, P. M., Anderson, S. D., et al. (1993), Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur. Respir. J. 6, 53–83.
Joos, G. F., O'Conner, B., Anderson, S. D. Chung, F., Cockcroft, D. W., Dahlén, B., et al. (2002), ERS Task Force—Indirect Airway Challenges. Eur. Respir. J. In press.
Vathenen, A. S., Knox, A. J., Wisniewski, A., and Tattersfield, A. E. (1991), Effect of inhaled budes-onide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation in patients with asthma. Thorax 46, 811–816.
Anderson, S. D., du Toit, J. I., Rodwell, L. T., and Jenkins, C. R. (1994), Acute effect of sodium cromoglycate on airway narrowing induced by 4.5 percent saline aerosol. Outcome before and during treatment with aerosol corticosteroids in patients with asthma. Chest 105, 673–680.
du Toit, J. I., Anderson, S. D., Jenkins, C. R., Woolcock, A. J., and Rodwell, L. T. (1997), Airway responsiveness in asthma: bronchial challenge with histamine and 4.5% sodium chloride before and after budesonide. Allergy Asthma Proc. 18, 7–14.
Pedersen, S. and Hansen, O. R. (1995), Budesonide treatment of moderate and severe asthma in children: a dose-response study. J. Allergy Clin. Immunol. 95, 29–33.
Doull, L., Sandall, D., Smith, S., Schrieber, J., Freezer, N. J., and Holgate, S. T. (1997), Differential inhibitory effect of regular inhaled corticosteroid on airway responsiveness to adenosine 5′ monophosphate, methacholine, and bradykinin in symptomatic children with recurrent wheeze. Pediatr. Pulmonol. 23, 404–411.
O'Connor, B. J., Ridge, S. M., Barnes, P. J., and Fuller, R. W. (2001), Greater effect of inhaled budesonide on adenosine 5′-monophosphate-induced than on sodium-metabisulfite-induced bronchoconstriction in asthma. Am. Rev. Respir. Dis. 146, 560–564.
Van den Berge, M., Kerstjens, H. A., Meijer, R. J., de Reus, D. M., Koëter, G. H., Kauffman, H. F., et al. (2001), Corticosteroid-induced improvement in the PC20 of adenosine monophosphate is more closely associated with reduction in airway inflammation than improvement in the PC20 of methacholine. Am. J. Respir. Crit. Care Med. 164, 1127–1132.
Brannan, J. D., Gulliksson, M., Kumlin, M., Anderson, S. D., and Dahlén, S.-E. (2001), Inhalation of mannitol, used as a model for exercise-induced bronchoconstriction (EIB), causes release of leukotrienes and a mast cell marker in asthmatic subjects. Eur. Respir. J. 18, 102S.
O'Sullivan, S., Roquet, A., Dahlén, B., Larsen, F., Eklund, A., Kumlin, M., et al. (1998), Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur. Respir. J. 12, 345–350.
Polosa, R., Ng, W. H., Crimi, N., Vancheri, C., Holgate, S. T., Church, M. K., et al. (1995), Release of mast-cell-derived mediators after endobronchial adenosine challenge in asthma. Am. J. Respir. Crit. Care Med. 151, 624–629.
Rodwell, L. T., Anderson, S. D., du Toit, J., and Seale, J. P. (1992), Nedocromil sodium inhibits the airway response to hyperosmolar challenge in patients with asthma. Am. Rev. Respir. Dis. 146, 1149–1155.
Anderson, S. D., Rodwell, L. T., Daviskas, E., Spring, J. F., and du Toit, J. (1996), The protective effect of nedocromil sodium and other drugs on airway narrowing provoked by hyperosmolar stimuli: a role for the airway epithelium. J. Allergy Clin. Immunol. 98, S124–134S.
Brannan, J. D., Anderson, S. D., Freed, R., Leuppi, J. D., Koskela, H., and Chan, H.-K. (2000), Nedocromil sodium inhibits responsiveness to inhaled mannitol in asthmatic subjects. Am. J. Respir. Crit. Care Med. 161, 2096–2099.
Phillips, G. D., Ng, W. H., Church, M. K., and Holgate, S. T. (1990), The response of plasma histamine to bronchoprovocation with methacholine, adenosine 5′-monophosphate and allergen in atopic non asthmatic subjects. Am. Rev. Respir. Dis. 141, 9–13.
Baki, A. and Orhan, F. (2002), The effect of loratadine in exercise-induced asthma. Arch. Dis. Child. 86, 38–39.
Rodwell, L. T., Anderson, S. D., and Seale, J. P. (1991), Inhaled clemastine inhibits airway narrowing caused by aerosols of non-isotonic saline. Eur. Respir. J. 4, 1126–1134.
Finnerty, J. P. and Holgate, S. T. (1990), Evidence for the roles of histamine and prostaglandins as mediators in exercise-induced asthma: the inhibitory effect of terfenadine and flurbiprofen alone and in combination. Eur. Respir. J. 3, 540–547.
Rafferty, P., Beasley, C. R. W., and Holgate, S. T. (1987), The contribution of histamine to immediate bronchoconstriction provoked by inhaled allergen and adenosine 5′-monophosphate in atopic asthma. Am. Rev. Respir. Dis. 136, 369–373.
Israel, E., Dermarkarian, R., Rosenberg, M., Sperling, R., Taylor, G., Rubin, P., et al. (1990), The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N. Engl. J. Med. 323, 1740–1744.
Kemp, J. P., Dockhorn, R. J., Shapiro, G. G., Nguyen, H. H., Reiss, T. F., Seidenberg, B. C., et al. (1998), Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J. Pediatr. 133, 424–428.
Rorke, S., Jennison, S., Jeffs, J. A., Sampson, A. P., Arshad, H., and Holgate, S. T. (2002), Role of cysteinyl leukotrienes in adenosine 5′-monophosphate induced bronchoconstriction in asthma. Thorax 57, 323–327.
Edmunds, A., Tooley, M., and Godfrey, S. (1978), The refractory period after exercise-induced asthma: its duration and relation to the severity of exercise. Am. Rev. Respir. Dis. 117, 247–254.
Bar-Yishay, E., Ben-Dov, I., and Godfrey, S. (1983), Refractory period after hyperventilation-induced asthma. Am. Rev. Respir. Dis. 127, 572–574.
Anderson, S. D. (1985), Exercise-induced asthma. The state of the art. Chest 87S, 191S-195S
Soto, M. E., Schnall, R., and Landau, L. (1985), Refractoriness to bronchoconstriction following hyperventilation with cold dry air. Pediatr. Pulmonol. 1, 80–84.
Belcher, N. G., Rees, P. J., Clark, T. J. M., and Lee, T. H. (1987), A comparison of the refactory periods induced by hypertonic airway challenge and exercise in bronchial asthma. Am. Rev. Respir. Dis. 135, 822–825.
Daxun, Z., Rafferty, P., Richards, R., Summerell, S., and Holgate, S. T. (1989), Airway refractoriness to adenosine 5′-monophosphate after repeated inhalation. J. Allergy Clin. Immunol. 83, 152–158.
Reiss, T. F., Hill, J. B., Harman, E., Zhang, J., Tanaka, W. K., Bronsky, E., et al. (1997), Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchosphasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 52, 1030–1035.
Anderson, S. D., Smith, C. M., Rodwell, L. T., du Toit, J. I., Riedler, J., and Robertson, C. F. The use of non-isotonic aerosols for evaluating bronchial hyperresponsiveness, in Provocation Challenge Procedures, Spector, S., ed. Marcel Dekker, New York, 1995, pp. 249–278.
Riedler, J., Reade, T., Dalton, M., Holst, D. I., and Robertson, C. F. (1994), Hypertonic saline challenge in an epidemiological survey of asthma in children. Am. J. Respir Crit. Care Med. 150, 1632–1639.
Riedler, J., Gamper, A., Eder, W., and Oberfeld, G. (1998), Prevalence of bronchial hyperresponsiveness to 4.5% saline and its relation to asthma and allergy symptoms in Austrian children. Eur. Respir. J. 11, 355–360.
Rabone, S., Phoon, W. O., Anderson, S. D., Wan, K. C., Seneviratne, M., Gutierrez, L., et al. (1996), Hypertonic saline challenge in an adult epidemiological field survey. Occup. Med. 46, 177–185.
Brannan, J. D., Anderson, S. D., Koskela, H., and Subbarao, P. (2002), Inhaled mannitol does not cause bronchoconstriction in non-asthmatic healthy persons. Respirology 7, A16.
Hurwitz, K. A., Argyros, G. J., Roach, J. M., Eliasson, A. H., and Phillips, Y. Y. (1995), Interpretation of eucapnic voluntary hyperventilation in the diagnosis of asthma. Chest 108, 1240–1245.
Godfrey, S., Springer, C., Bar-Yishay, E., and Avital, A. (1999), Cut-off points defining normal and asthmatic bronchial reactivity to exercise and inhalation challenges in children and young adults. Eur. Respir. J. 14, 659–668.
O'Cain, C. F., Dowling, N. B., Slutsky, A. S., Hensley, M. J., Strohl, K. P., McFadden, E. R., et al. (1980), Airway effects of respiratory heat loss in normal subjects. J. Appl. Physiol.: Respirat. Environ. Exerc. Physiol. 49, 875–880.
Henriksen, J. M. and Dahl, R. (1983), Effects of inhaled budesonide alone and in combination with low-dose terbutaline in children with exercise-induced asthma. Am. Rev. Respir. Dis. 128, 993–997.
Waalkans, H. J., van Essen-Zandvliet, E. E. M., Gerritsen, J., Duiverman, E. J., Kerrebijn, K. F., Knol, K., and the Dutch CNSLD Study Group (1993), The effect of an inhaled corticosteroid (budesonide) on exercise-induced asthma in children. Eur. Respir. J. 6, 652–656
Jonasson, G., Carlsen, K. H., and Hultquist, C. (2000), Low-dose budesonide improves exercise-induced bronchospasm in schoolchildren. Pediatr. Allergy Immunol. 11, 120–125.
Rodwell, L. T., Anderson, S. D., and Seale, J. P. (1992), Inhaled steroids modify bronchial responses to hyperosmolar saline. Eur. Respir. J. 5, 953–962.
Juniper, E. F., Kline, P. A., Vanzieleghem, M. A., Ramsdale, E. H., O'Byrne, P. M., and Hargreave, F. (1990), Effect of long-term treatment with inhaled corticosteroids on airway hyperresponsiveness and clinical asthma in non-steroid dependent asthmatics. Am. Rev. Respir. Dis. 142, 832–836.
Reddel, H. K., Jenkins, C. R., Marks, G. B., Ware, S. I., Xuan, W., Salome, C. M., et al. (2000), Optimal asthma control, starting with high doses of inhaled budesonide. Eur. Respir. J. 16, 226–235.
Sont, J. K., Willems, L. N., Bel, E. H., van Krieken, J. H., Vandenbroucke, J. P., and Sterk, P. J. (1999), Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am. J. Respir. Crit. Care Med. 159, 1043–1051.
Dessanges, J.-F., Prefaut, C., Taytard, A., Matran, R., Naya, I., Compagnon, A., et al. (1999), The effect of zafirlukast on repetitive exercise-induced bronconstriction: the possible role of leukotrienes in exercise-induced refractoriness. J. Allergy Clin. Immunol. 1155–1166.
American Thoracic Society (1995), Standardization of spirometry: 1994 update. Am. J. Respir. Crit. Care Med. 152, 1107–1136.
Anderson, S. D., Lambert, S., Brannan, J. D., Wood, R. J., Koskela, H., Morton, A. R., et al. (2001), Laboratory protocol for exercise asthma to evaluate salbutamol given by two devices. Med. Sci. Sports Exer. 33, 893–900.
Anderson, S. D., Schoeffel, R. E., Follet, R., Perry, C. P., Daviskas, E., and Kendall, M. (1982), Sensitivity to heat and water loss at rest and during exercise in asthmatic patients. Eur. J. Respir. Dis. 63, 459–471.
Anderson, S. D. and Daviskas, E. (2000), The mechanism of exercise-induced asthma is ....... J. Allergy Clin. Immunol. 106, 453–459.
McFadden, E. R., Lenner, K. A., and Strohl, K. P. (1986), Postexertional airway rewarming and thermally induced asthma. J. Clin. Investig. 78, 18–25.
McFadden, E. R., Nelson, J. A., Skowronski, M. E., and Lenner, K. A. (1999), Thermally induced asthma and airway drying. Am. J. Respir. Crit. Care Med. 160, 221–226.
Anderson, S. D., Schoeffel, R. E., Black, J. L., Daviskas, E. (1985), Airway cooling as the stimulus to exercise-induced asthma—a re-evaluation. Eur. J. Respir. Dis. 67, 20–30.
Anderson, S. D. and Daviskas, E. (1992), The airway microvasculature and exercise-induced asthma. Thorax 47, 748–752.
Smith, C. M., Anderson, S. D., Walsh, S., and McElrea, M. (1989), An investigation of the effects of heat and water exchange in the recovery period after exercise in children with asthma. Am. Rev. Respir. Dis. 140, 598–605.
Haby, M. M., Anderson, S. D., Peat, J. K., Mellis, C. M., Toelle, B. G., and Woolcock, A. J. (1994), An exercise challenge protocol for epidemiological studies of asthma in children: comparison with histamine challenge. Eur. Respir. J. 7, 43–49.
Bardagi, S., Agudo, A., Gonzalez, C. A., and Romero, P. V. (1993), Prevalence of exercise-induced airway narrowing in schoolchildren from a Mediterranean town. Am. Rev. Respir. Dis. 147, 1112–1115.
Rundell, K. W., Wilber, R. L., Szmedra, L., Jenkinson, D. M., Mayers, L. B., and Im, J. (2000), Exercise-induced asthma screening of elite athletes: field vs laboratory exercise challenge. Med. Sci. Sprots Exerc. 32, 309–316.
Mannix, M. T., Farber, M. O., Palange, P., Galassetti, P., and Manfredi, F. (1996), Exercise-induced asthma in figure skaters. Chest 109, 312–315.
Provost-Craig, M. A., Arbour, K. S., Sestili, D. C., Chabalko, J. J., and Ekinci, E. (1996), The incidence of exercise-induced bronchospasm in competitive figure skaters. J. Asthma 33, 67–71.
Nish, W. A. and Schwietz, L. A. (1992), Underdiagnosis of asthma in young adults presenting for USAF basic training. Ann. Allergy 69, 239–242.
Sinclair, D. G., Sims, M. M., Hoad, N. A., and Winfield, C. R. (1995), Exercise-induced airway narrowing in army recruits with a history of childhood asthma. Eur. Respir. J. 8, 1314–1317.
Crapo, R. O., Casaburi, R., Coates, A. L., Enright, P. L., Hankinson, J. L., Irvin, C. G., et al. (2000), Guidelines for methacholine and exercise challenge testing—1999. Am. J. Respir. Crit. Care Med. 161, 309–329.
Woolley, M., Anderson, S. D., and Quigley, B. (1990), Duration of protective effect of terbutaline sulphate and cromolyn sodium alone and in combination on exercise-induced asthma. Chest 97, 39–45.
Anderson, S. D., Rodwell, L. T., Du Toit, J., and Young, I. H. (1991), Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest 100 1254–1260.
Dahlén, B., Roquet, A., Inman, M. D., Karlsson, Ö., Naya, I., Anstrén, G., et al. (2002), Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction. J. Allergy Clin. Immunol. 109, 789–793.
Haby, M. M., Peat, J. K., Mellis, C. M., Anderson, S. D., and Woolcock, A. J. (1995), An exercise challenge for epidemiological studies of childhood asthma: validity and repeatability. Eur. Respir. J. 8, 729–736.
Backer, V., Dirksen, A., Bach-Mortensen, N., Hansen, K., Laursen, E. M., and Wendelboe, D. (1991), The distribution of bronchial responsiveness to histamine and exercise in 527 children and adolescents. J. Allergy Clin. Immunol. 88, 68–76.
Holzer, K., Anderson, S. D., Douglass, J. (2002), Exercise in elite summer athletes: Challenges for diagnoris. J. Allergy Clin. Immunol. 110(3);374–380.
Barnes, N. C., Piper, P. J., and Costello, J. F. (1984), Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects. Thorax 39, 500–504.
Roca, J., Whipp, B. J., Agustí, A. G. N., Anderson, S. D., Casaburi, R., Cotes, J. E., et al. (1997), Clinical exercise testing with reference to lung diseases: indications, standardization and interpretation strategies. Position document of the European Respiratory Society. Eur. Respir. J. 10, 2662–2689.
Mannix, E. T., Manfredi, F., and Farber, M. O. (1999), A comparison of two challenge tests for identifying exercise-induced bronchospasm in figure skaters. Chest 115, 649–653.
Rundell, K. W., Im, J., Mayers, L. B., Wilber, R. L., Szmedra, L., and Schmitz, H. R. (2001), Self-reported symptoms and exercise-induced asthma in the elite athlete. Med. Sci. Sports Exerc. 33, 208–213.
Carlsen, K. H., Engh, G., and Mørk, M. (2000), Exercise induced bronchoconstriction depends on exercise load. Respir. Med. 94, 750–755.
Gandevia, B. and Hugh Jones, P. (1957), Terminology for measurements of ventilatory capacity. Thorax 12, 290–293.
Folgering, H., Palange, P., and Anderson, S. (1997), Clinical exercise testing with reference to lung diseases: indications and protocols. Eur. Respir. Mon. 6, 51–71.
CRC Handbook of Chemistry and Physics, 78th edition, 1997–1998, CRC Press, Inc., New York, D.R. Lide (editor-in-chief) Section 15 page 24.
Malo, J. L., Cartier, A., L'Archeveque, J., Ghezzo, H., and Martin, R. R. (1986), Bronchoconstriction due to isocapnic cold air inhalation minimally influences bronchial hyperresponsiveness to methacholine in asthmatic subjects. Bull. Eur. Physiolopathol. Respir. 22, 473–477.
Zach, M., Polgar, G., Kump, H., and Kroisel, P. (1984), Cold air challenge of airway hyperreactivity in children: practical application and theoretical aspects. Pediatr. Res. 18, 469–478.
O'Byrne, P. M., Ryan, G., Morris, M., McCormack, D., Jones, N. L., Morse, J. L., et al. (1982), Asthma induced by cold air and its relation to nonspecific bronchial hyperresponsiveness to methacholine. Am. Rev. Respir. Dis. 125, 281–285.
Deal, E. C., McFadden, E. R., Ingram, R. H., and Jaeger, J. J. (1979), Hyperpnea and heat flux: initial reaction sequence in exercise-induced asthma. J. Appl. Physiol.: Respirat. Environ. Exerc. Physiol. 46, 476–483.
Jones, N. L. Clinical Exercise Testing, 4th ed., W.B. Saunders, Philadelphia, 1997.
Anderson, S. D. (1984), A simple guide to clinical exercise testing. Aust. NZ J. Med. 14, 803–806.
Godfrey, S.. Exercise Testing in Children. W.B. Saunders, London, 1974.
Brudno, D. S., Wagner, J. M., and Rupp, N. T. (1994), Length of postexercise assessment in the determination of exercise-induced bronchospasm. Ann. Allergy 73, 227–231.
Crapo, R. O., Morris, A. H., and Gardner, R. M. (1981), Reference spirometric values using techniques and equipment that meet ATS recommendations. Am. Rev. Respir. Dis. 123, 659–664.
Quanjer, P. H., Tammeling, G. J., Cotes, J. E., Pedersen, O. F., Peslin, R., and Yernault, J. C. (1993), Lung volumes and forced ventilatory flows. Eur. Respir. J. 6, 5–40.
Anderson, S. D., Seale, J. P., Ferris, L., Schoeffel, R. E., and Lindsay, D. A. (1979), An evaluation of pharmacotherapy for exercise-induced asthma. J. Allergy Clin. Immunol. 64, 612–624.
Dahlén, B., O'Byrne, P. M., Watson, R. M., Roquet, A., Larsen, F., and Inman, M. D. (2001), The reproducibility and sample size requirements of exercise-induced bronchoconstriction measurements. Eur. Respir. J. 17, 581–588.
Hofstra, W. B., Sont, J. K., Sterk, P. J., Neijens, H. J., Kuethe, M. C., and Duiverman, E. J. (1997), Sample size estimation in studies monitoring exercise-induced bronchoconstriction in asthmatic children. Thorax 52, 739–741.
Nicolai, T., Mutius, E. V., Reitmeir, P., and Wjst, M. (1993), Reactivity to cold-air hyperventilation in normal and in asthmatic children in a survey of 5,697 schoolchildren in southern Bavaria. Am. Rev. Respir. Dis. 147, 565–572.
Anderson, S. D. and Holzer, K. (2000), Exercise-induced asthma: is it the right diagnosis in elite athletes?. J. Allergy Clin. Immunol. 106, 419–428.
Rosenthal, R. R. (1984), Simplified eucapnic voluntary hyperventilation. J. Allergy Clin. Immunol. 73, 676–685.
Eliasson, A. H., Phillips, Y. Y., and Rajagopal, K. R. (1992), Sensitivity and specificity of bronchial provocation testing. An evaluation of four techniques in exercise-induced bronchospasm. Chest 102, 347–355.
Anderson, S. D., Argyros, G. J., Magnussen, H., and Holzer, K. (2001), Provocation by eucapnic voluntary hyperpnoea to identify exercise-induced bronchoconstriction. Br. J. Sports Med. 35, 344–347.
Zeballos, R. J., Shturman-Ellestien, R., McNall, J. F., Hirsch, J. E., and Souhrada, J. F. (1978), The role of hyperventilation in exercise-induced bronchoconstriction. Am. Rev. Respir. Dis. 118, 877–884.
Smith, C. M. and Anderson, S. D. (1986), Hyperosmolarity as the stimulus to asthma induced by hyperventilation? J. Allergy Clin. Immunol. 77, 729–736.
Smith, C. M. and Anderson, S. D. (1989), A comparison between the airway response to isocapnic hyperventilation and hypertonic saline in subjects with asthma. Eur. Respir. J. 2, 36–43.
Argyros, G. J., Phillips, Y. Y., Rayburn, D. B., Rosenthal, R. R., and Jaeger, J. J. (1993), Water loss without heat flux in exercise-induced bronchospasm. Am. Rev. Respir. Dis. 147, 1419–1424.
Assoufi, B. K., Dally, M. B., Newman-Taylor, A. J., and Denison, D. M. (1986), Cold air test: a simplified standard method for airway reactivity. Bull. Eur. Physiopathol. Respir. 22, 349–357.
Blackie, S. P., Hilliam, C., Village, R., and Pare, P. D. (1990), The time course of bronchoconstriction in asthmatics during and after isocapnic hyperventilation. Am. Rev. Respir. Dis. 142, 1133–1136.
Smith, C. M., Anderson, S. D., and Seale, J. P. (1988), The duration of action of the combination of fenoterol hydrobromide and ipratropium bromide in protecting against asthma provoked by hyperpnea. Chest 94, 709–717.
Latimer, K. M., O'Byrne, P. M., Morris, M. M., Roberts, R., and Hargreave, F. E. (1983), Bronchoconstriction stimulated by airway cooling. Better protection with combined inhalation of terbutaline sulphate and cromolyn sodium than with either alone. Am. Rev. Respir. Dis. 128, 440–443.
Argyros, G. J., Roach, J. M., Hurwitz, K. M., Eliasson, A. H., and Phillips, Y. Y. (1995), The refractory period after eucapnic voluntary hyperventilation challenge and its effect on challenge technique. Chest 108, 419–424.
Argyros, G. J., Roach, J. M., Hurwitz, K. M., Eliasson, A. H., and Phillips, Y. Y. (1996), Eucapnic voluntary hyperventilation as a bronchoprovocation technique. Development of a standardized dosing schedule in asthmatics. Chest 109, 1520–1524.
Nielsen, K. G. and Bisgaard, H. (2000), Lung function response to cold air challenge in asthmatic and healthy children of 2–5 years of age. Am. J. Respir. Crit. Care Med. 161, 1805–1809.
Rodwell, L. T., Anderson, S. D., du Toit, J., and Seale, J. P. (1993), Different effects of inhaled amiloride and furosemide on airway responsiveness to dry air challenge in asthmatic subjects. Eur. Respir. J. 6, 855–861.
Koskela, H. and Tukiainen, H. (1995), Facial cooling, but not nasal breathing of cold air, induces bronchoconstriction: a study in asthmatic and healthy subjects. Eur. Respir. J. 8, 2088–2093.
Koskela, H. O., Räsänen, S. H. and Tukiainen, H. O. (1997), The diagnostic value of cold air hyperventilation in adults with suspected asthma. Respir. Med. 91, 470–478.
Ramsdale, E. H. Morris, M. M., Roberts, R. S., and Hargreave, F. E. (1984), Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow limitation and cold air responsiveness. Thorax 39, 912–918.
Deal, E. C., McFadden, E. R., Ingram, R. H., Breslin, F., and Jaeger, J. J. (1980), Airway responsiveness to cold air and hyperpnea in normal subjects and in those with hay fever and asthma. Am. Rev. Respir. Dis. 121, 621–628.
Weiss, S. T., Tager, I. B., Weiss, J. W., Munoz, A., Speizer, F. E., and Ingram, R. H., (1984), Airways responsiveness in a population sample of adults and children. Am. Rev. Respir. Dis. 129, 898–902.
Schoeffel, R. E., Anderson, S. D., and Altounyan, R. E. (1981), Bronchial hyperreactivity in response to inhalation of ultrasonically nebulised solutions of distilled water and saline. Br. Med. J. 283, 1285–1287.
Smith, C. M. and Anderson, S. D. (1989) Inhalation provocation tests using non-isotonic aerosols. J. Allergy Clin. Immunol. 84, 781–790.
Riedler, J., Reade, T., and Robertson, C. F. (1994), Repeatability of response to hypertonic saline aerosol in children with mild to severe asthma. Pediatr. Pulmonol. 18, 330–336.
Riedler, J. and Robertson, C. F. (1994), Effect of tidal volume on the output and particle size distribution of hypertonic saline from an ultrasonic nebuliser. Eur. Respir. J. 7, 998–1002.
in't Veen, J. C. C. M., de Gouw, H. W. F. M., Smits, H. H., Sont, J. K., Hiemstra, P. S., Sterk, P. J., et al. (1996), Repeatability of cellular and soluble markers of inflammation in induced sputum from patients with asthma. Eur. Respir. J. 9, 2441–2447.
Gibson, P. G., Wooley, K. L., Carty, K., MurreeAllen, K., and Saltos, N. (1998), Induced sputum eosinophil cationic protein (ECP) measurement in asthma and COPD. Clin. Exp. Allergy 28, 1081–1088.
Gibson, P. G., Saltos, N., and Borgas, T. (2000), Airway mast cells and eosinophils correlate with clinical severity and airway hyperresponsiveness in corticosteroid-treated asthma. J. Allergy Clin. Immunol. 105, 752–759.
Anderson, S. D. and Schoeffel, R. E.. The inhalation of ultrasonically nebulized aerosols as a provocation test for asthma, in Airway Responsiveness: Measurement and Interpretation. Hargreave, F. E., Woolcock A. J., ed., Astra Pharmaceuticals Canada Ltd, Ontario, Canada, 1985, pp. 39–50.
Brannan, J. D., Koskela, H., Anderson, S. D., and Chan, H. K., (1998), Inhaled corticosteroids reduce airway responsiveness to inhaled mannitol: a pilot study. Am. J. Respir. Crit. Care Med. 157, A407.
Barben, J., Roberts, M., Carlin, J. B., and Robertson, C. F. (2001), Repeatability of bronchial responsiveness to mannitol dry powder in children with asthma. Eur. Respir. J. 18, 493s.
Subbarao, P., Brannan, J. D., Ho, B., Anderson, S. D., Chan, H.-K., and Coates, A. L. (2000), Inhaled mannitol identifies methacholine-responsive children with active asthma. Pediatr. Pulmonol. 29, 291–298.
Gonda, I. (1986), Pharmaceutical developments in therapeutic and diagnostic aerosols. Pharm. Tech. Japan 2, 883–893.
O'Connor, G., Sparrow, D., Taylor, D., Segal, M., and Weiss, S. (1991), Analysis of dose-response curves to methacholine. An approach suitable for population studies. Am. Rev. Respir. Dis. 144, 663–667.
Peat, J. K., Salome, C. M., Berry, G., and Woolcock, A. J. (1992), Relation of dose-response slope to respiratory symptoms and lung function in a population study of adults living in Busselton, Western Australia. Am. Rev. Respir. Dis. 146, 860–865.
Lis, G. and Pietrzyk, J. J. (1998), Response-dose ratio as an index of bronchial responsiveness to hypertonic saline in an epidemiological survey of asthma in Polish children. Pediatr. Pulmonol. 25, 375–382.
Leuppi, J. D., Salome, C. M., Jenkins, C. R., Anderson, S. D., Xuan, W., Marks, G. B., et al. (2001), Predictive markers of asthma exacerbations during stepwise dose-reduction of inhaled corticosteroids. Am. J. Respir. Crit. Care Med. 163, 406–412.
O'Hickey, S. P., Arm, J. P., Rees, P. J., and Lee, T. H. (1989), Airway responsiveness to methacholine after inhalation of nebulized hypertonic saline in bronchial asthma. J. Allergy Clin. Immunol. 83, 472–476.
Rodwell, L. T., Anderson, S. D., Spring, J. F., Seale, J. P. (1993), Indomethacin & airway responsiveness to repeated 4.5% NaCl challenges. Eur. Respir. J. 6 (suppl 17), 200s.
Anderson, S. D., Brannan, J., Trevillion, L., and Young, I. H. (1995), Lung Function and Bronchial Provocation Tests for intending divers with a history of asthma. SPUMS 25, 233–248.
Wilson, N. M., Bridge, P., and Silverman, M. (1995), Bronchial responsiveness and symptoms in 5–6 year old children: a comparison of a direct and indirect challenge. Thorax 50, 339–345.
Gibson, P. G., Hargreave, F. E., Girgis-Gabardo, A., Morris, M., Denburg, J. A., and Dolovich, J. (1995), Chronic cough with eosinophilic bronchitis examination for variable airflow obstruction and response to corticosteroid. Clin. Exp. Allergy 25, 127–132.
Bjorck, T., Gustafsson, L. E., and Dahlen, S. E. (1992), Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am. Rev. Respir. Dis. 145, 1087–1091.
Avital, A., Springer, C., Bar-Yishay, E., and Godfrey, S. (1995), Adenosine, methacholine, and exercise challenges in children with asthma or paediatric chronic obstructive pulmonary disease. Thorax 50, 511–516.
Hancox, R. J., Subbarao, P., Kamada, D., Watson, R. M., Hargreave, F. E., and Inman, M. D. (2002), B2-agonist tolerance and exercise-induced bronchospasm. Am. J. Respir. Crit. Care Med. 165, 1068–1070.
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Anderson, S.D., Brannan, J.D. Methods for “Indirect” challenge tests including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols. Clinic Rev Allerg Immunol 24, 27–54 (2003). https://doi.org/10.1385/CRIAI:24:1:27
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DOI: https://doi.org/10.1385/CRIAI:24:1:27