Connect
MJA
MJA

Pulmonary physiology, airway responsiveness and asthma

Stephen M Stick
Med J Aust 2002; 177 (6): S55. || doi: 10.5694/j.1326-5377.2002.tb04818.x
Published online: 16 September 2002

Abstract

What we know

What we need to know

Challenge tests for assessing airway responsiveness

A variety of methods have been used to assess airway responsiveness, including both direct and indirect stimuli to bronchoconstriction.1,2 Examples of direct stimuli are inhaled methacholine or histamine, while exercise, voluntary hyperventilation, cold air, and inhalation of adenosine monophosphate, hypertonic saline or mannitol are indirect stimuli. Most challenge tests require an outcome measure that reflects airway function, although indirect outcome measures — transcutaneous oxygen levels and pulse oximetry — have been reported.

The ability to determine airway responsiveness in infants was made possible by advances in methods of testing lung function, most importantly forced expiratory flow rate. Early studies made use of the rapid thoracoabdominal compression technique for producing passive forced expiration — an inflatable jacket fitted around the thorax and abdomen, which was rapidly inflated at end-inspiration.3 This technique was used to measure the maximum flow at functional residual capacity, at baseline and in response to cold air or to increasing concentrations of histamine or methacholine. More recently, the raised-volume rapid thoracoabdominal compression technique has been used during challenge tests4 to obtain timed forced expiratory volumes (FEVt) as outcome variables (ie, measures analogous to forced expiratory volume in one second [FEV1] in cooperative subjects).

A limitation of these types of studies in infants is the requirement for sedation. Clearly, exercise testing is not possible in infants and the hypersalivation that occurs with hypertonic saline challenges makes this type of challenge unsafe in sedated infants. The airway response to exercise appears to be mediated by changes in the tonicity of the airway lining fluid, and therefore a test in infants based on the inhalation of mannitol powder might be feasible and provide information similar to that from exercise challenges in cooperative older children.

There have been few reports of adenosine monophosphate challenges in infants or preschool children,5 and none that have used direct measures of lung function to determine outcome. However, in cooperative older children and adults with asthma, adenosine monophosphate challenges appear to better reflect ongoing airway inflammation than histamine or methacholine challenges, and might be useful in identifying asthma in infants with wheeze.

Airway responsiveness in infants

Most infants show a response to histamine3 or methacholine challenge.8 Although underlying physiological or structural factors may determine this relative increase in responsiveness in infants compared with older children, the most likely explanation is that infants receive a relatively larger dose of inhaled challenge agent than older children. Thus, when a correction is made for this dose effect, infants and older children appear to have a similar response to inhaled histamine.9

The importance of this observation is that absolute values of airway responsiveness cannot be used to compare airway responsiveness at different ages. However, airway responsiveness can be tracked over time within populations using z-scores, or, alternatively, by using non-parametric analyses based on ranking individuals at each time point. Such analyses have been used in birth-cohort studies to investigate the role of airway responsiveness in the early genesis of asthma.

A unique birth-cohort study has shown that airway responsiveness at one month is a predictor of lung function at six years.10 Data from this study also show that the genetic determinants of atopy and airway responsiveness are independent.11 In another study of infants with wheeze, persistence of airway responsiveness was associated with persistence of symptoms, although airway responsiveness at one month of age was neither a sensitive nor a specific predictor of outcome.12

These studies imply that airway responsiveness is a key factor in asthma, but it is not clear whether the factors that are important for the manifestation of airway responsiveness in early life are related to inflammation, structure or physiology of the airways. Furthermore, it is not clear how viruses, allergens and irritants in the environment modify innate airway responses.13

What we need to know

Observations of the importance of airway responsiveness in early life need to be extended to include investigations shedding light on the mechanisms involved. These should include an examination of possible genetic, immunological, infective and environmental influences. Observations that lung function in later life is predicted by early airway responsiveness, and that persistent airway responsiveness is associated with persistence of asthma symptoms, suggest that more information is required about the role of airway remodelling in the early stages of childhood asthma.

Evidence is emerging that various challenge agents can be used to provide different information about the processes taking place in airways that result in airway responsiveness.14 However, very few data are available from infants exploiting these response differences. Therefore, further studies in infants are needed to investigate responses to the different challenges in relation to measurements of airway inflammation and the other physiological and structural factors known to contribute to airway responsiveness in older subjects.

A better understanding of the factors that underpin an individual's response to a given airway challenge could result in tests to predict outcomes at an early age and to monitor interventions.

  • Stephen M Stick

  • Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, WA.



  • 1. Anderson SD. Challenge tests to assess airway hyperresponsiveness and efficacy of drugs used in the treatment of asthma. J Aerosol Med 1996; 9: 95-109.
  • 2. Polosa R, Holgate S. Adenosine bronchoprovocation: a promising marker of allergic inflammation in asthma? Thorax 1997; 52: 919-923.
  • 3. Le Souëf PN, Geelhoed GC, Turner DJ, et al. Response of normal infants to inhaled histamine. Am Rev Respir Dis 1989; 139: 62-66.
  • 4. Hayden M, Devadason SG, Sly PD, et al. Methacholine responsiveness using the raised volume forced expiration technique in infants. Am J Respir Crit Care Med 1997; 155: 1670-1675.
  • 5. Avital A, Picard E, Uwyyed K, Springer C. Comparison of adenosine 5'-monophosphate and methacholine for the differentiation of asthma from chronic airway diseases with the use of the auscultative method in very young children. J Pediatr 1995; 127: 438-440.
  • 6. Sears MR, Jones DT, Holdaway MD, et al. Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children. Thorax 1986; 41: 283-289.
  • 7. O'Connor GT, Sparrow D, Weiss ST. A prospective longitudinal study of methacholine airway responsiveness as a predictor of pulmonary-function decline: the Normative Aging Study. Am J Respir Crit Care Med 1995; 152: 87-92.
  • 8. Tepper RS. Airway reactivity in infants: a positive response to methacholine and metaproterenol. J Appl Physiol 1987; 62: 1155-1159.
  • 9. Stick SM, Turnbull S, Chua HL, et al. Bronchial responsiveness to histamine in infants and older children. Am Rev Respir Dis 1990; 142: 1143-1146.
  • 10. Palmer LJ, Rye PJ, Gibson NA, et al. Airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age. Am J Respir Crit Care Med 2001; 163: 37-42.
  • 11. Palmer LJ, Burton PR, Faux JA, et al. Independent inheritance of serum immunoglobulin E concentrations and airway responsiveness. Am J Respir Crit Care Med 2000; 161: 1836-1842.
  • 12. Delacourt C, Benoist MR, Waernessyckle S, et al. Relationship between bronchial responsiveness and clinical evolution in infants who wheeze. A four-year prospective study. Am J Respir Crit Care Med 2001; 164: 1382-1386.
  • 13. Holt PG, Macaubas C, Stumbles PA, Sly PD. The role of allergy in the development of asthma. Nature 1999; 402(Suppl 25): B12-B16.
  • 14. Avital A, Springer C, Bar-Yishay E, Godfrey S. Adenosine, methacholine, and exercise challenges in children with asthma or paediatric chronic obstructive pulmonary disease. Thorax 1995; 50: 511-516.

Author

remove_circle_outline Delete Author
add_circle_outline Add Author

Comment
Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Online responses are no longer available. Please refer to our instructions for authors page for more information.