What Is the Relationship between Airway Hyperresponsiveness and Atopy?

ANN J. WOOLCOCK and JENNIFER PEAT

Institute of Respiratory Medicine, Sydney, Australia

	INTRODUCTION

TOP INTRODUCTION DEFINITIONS WHAT IS KNOWN? WHAT IS PARTLY KNOWN? IMPORTANT QUESTIONS REFERENCES

The nature of the relationship between airway hyperresponsiveness (AHR) and atopy (specific IgE to aeroallergens) is unknown and one of the most important questions about asthma. Is AHR a consequence of airway inflammation caused by allergic or other responses or is it a separately inherited state? It is clear from epidemiological studies that these two abnormalities are linked. However, not all allergic (atopic) people have AHR and not all airway-hyperresponsive people are allergic. Furthermore, there is some suggestion that the risk factors for the two abnormalities are different. In Australian children, there has been little increase in the prevalence of atopy but AHR and symptoms have increased so that more of the atopic group now have asthma (1). The data suggest that over the years between 1982 and 1992 in atopic children, the risk factors for AHR have increased or that protective factors have been lost. There have been almost no other studies of atopic status and AHR in randomly selected populations over a period of time to determine if this is happening elsewhere. This article outlines what is known, what is partially known, and the important questions that need to be answered.

	DEFINITIONS

TOP INTRODUCTION DEFINITIONS WHAT IS KNOWN? WHAT IS PARTLY KNOWN? IMPORTANT QUESTIONS REFERENCES

For epidemiological purposes, atopic status can be defined either by skin prick tests (2) or by measurement of specific IgE. Usually, a battery of eight or more common aeroallergens are used and a wheal size, measured at 15 min, of 3 mm or more in children and 4 mm or more in adults is considered to be positive. If specific IgE in serum is measured then one plus reaction to one or more allergens is considered to denote an allergic status (3).

Airway hyperresponsiveness (AHR) is defined as a 20% fall in the FEV₁ in response to a provoking agent, such as histamine, methacholine, or hypertonic saline, and sometimes to exercise or cold air hyperventilation. The cutoff points to define AHR have variously been defined, using the concentration method, as a PC₂₀ of 8 mg/ml (4, 5) and 25 mg/ml (6) and a PC₁₀ of 16 mg/ml (7, 8) and, using the dose method, as a PD₂₀ of 3.9 mmol (9, 10), 7.8 mmol (11), and 1 mg (5 mmol) (14) or 2 mg (15) of methacholine. The reproducibility of the test varies from one doubling dose under ideal conditions (16, 17) to 1.5- 2.5 doubling doses under field conditions, or with naive subjects (18). In epidemiological studies, the methods for measuring both AHR and atopy have been well described by Peat and coworkers (10), Burrows and coworkers for children (21), and by Burney and coworkers for the European Community Respiratory Health Survey (ECRHS) in adults (22).

	WHAT IS KNOWN?

TOP INTRODUCTION DEFINITIONS WHAT IS KNOWN? WHAT IS PARTLY KNOWN? IMPORTANT QUESTIONS REFERENCES

Prevalence of Atopy in Adults and Children

Atopy has been measured by skin prick tests or specific IgE in adults and in children in many countries but there are few other than in Australia for which there have been at least two studies for the same population. On the whole, little is known about changes in the prevalence of atopy, but the prevalence did not change in Australia in the years 1982-1992. Large changes were seen in Tucson (23) but the studies may not have been typical since house dust mite allergens were not used and the later National Health and Nutrition Examination Survey (NHANES) showed a much lower prevalence (24). There are now large amounts of data from the European study (3), which show significant differences between populations within Europe and within countries, with low values in highly polluted cities such as Athens and the highest values in the most westernized populations in New Zealand, Australia, and Switzerland.

Prevalence of AHR

There are data for AHR measured by standardized methods in quite a number of populations of children (25) and more recently data for different populations within the European community for adults (14). There are large variations in AHR between and within communities that are unlikely to be caused by methodological differences. The data for children are less standardized and most are from the southern hemisphere. In children in Australia there have been studies that show an increase in the prevalence of AHR with time both within a cohort and between cohorts living in the same places. In Australia and New Zealand the prevalence of AHR is about 16-18% (27, 33).

Relationship between Atopy and AHR in Populations

When the data from the ECRHS are used to construct the relationship between AHR and atopy (as measured by specific IgE), for adult populations a close correlation is found where the prevalence of atopy is less than 40%. For populations with a high prevalence of atopy (> 40%) the prevalence of AHR varies widely from a low of 9.8% in Basel, Switzerland to a high of 27.8% in Hawkes Bay in New Zealand (14) and is even higher in a different study in Tristan da Cunha (34). It is not possible to construct the same figure for children because there are few studies of children in which both AHR and atopy have been measured by standardized methods and with similar age groups.

What Are the Risk Factors for Atopy?

Our group has examined the risk factors for atopy in preschool children (35) using logistic regressions and found family history of asthma and male sex as the main risks. In this study exposure to environmental tobacco smoke (ETS) and preterm status were not risk factors for atopy. Attendance at day care was protective but sibling numbers were not. In other studies sibling numbers have been shown to be protective for atopy (36, 37).

Risk Factors for AHR

In the Australian childhood population risk factors for AHR are atopy (especially to house dust mites if living in a high house mite area), parental asthma, early respiratory illness, and being born in Australia, while a fish diet has been shown to be protective (38). In adults living in Busselton, Western Australia, atopy, female sex, and increasing age are independent risk factors for AHR; but on the whole the risk factors for AHR in adults with asthma have not been studied.

	WHAT IS PARTLY KNOWN?

TOP INTRODUCTION DEFINITIONS WHAT IS KNOWN? WHAT IS PARTLY KNOWN? IMPORTANT QUESTIONS REFERENCES

The prevalence of both AHR and atopy vary greatly within some countries, for example, Spain (3, 14, 39). The reasons for this are not known. It is also suggested that the prevalence of allergy has increased in Western Europe (40). However, data from large randomized populations where exactly the same methods have been used are not available, except in Australian children, where little change has occurred (1).

Some emerging protective risk factors for atopy include contact with farm animals (41), particulate air pollution (42), exposure to endotoxin (43), parasitic gut infections (44), and perhaps a lactobacillus (45). However, these factors need to be confirmed. Additional risk factors for childhood asthma include low sibling numbers and Western life style (difficult to define!). The risk factors for AHR from the ECRHS have not yet been published.

	IMPORTANT QUESTIONS

TOP INTRODUCTION DEFINITIONS WHAT IS KNOWN? WHAT IS PARTLY KNOWN? IMPORTANT QUESTIONS REFERENCES

• Could appropriate studies help to resolve these important questions?
• What are the factors that protect against AHR in atopic children?
• Can segregation analysis for AHR in families that are nonatopic be doneare there sufficient numbers?
• Is atopy increasing in children in developing countries and is it related to better hygiene?
• In Guangzhou, has a greater proportion of atopic children developed asthma in the last 10 yr?
• Can diet and/or farm animal exposure in childhood explain the differences in prevalence of AHR (adult ECHRS study) and asthma (children ISAAC study) between Switzerland and New Zealand (where atopy is similar)?

	Footnotes

Correspondence and requests for reprints should be addressed to A. J. Woolcock, M.D., Institute of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.

	References

TOP INTRODUCTION DEFINITIONS WHAT IS KNOWN? WHAT IS PARTLY KNOWN? IMPORTANT QUESTIONS REFERENCES

1. Peat, J. K., R. H. van den Berg, W. F. Green, C. M. Mellis, S. R. Leeder, and A. J. Woolcock. 1994. Changing prevalence of asthma in Australian children. Br. Med. J. 308: 1591-1596 [Abstract/Free Full Text].

2. Pepys, J.. 1975. Skin testing. Br. J. Hosp. Med. 14: 412-417 .

3. Burney, P., E. Malmberg, S. Chinn, D. Jarvis, C. Luczynska, and E. Lai. 1997. The distribution of total and specific serum IgE in the European Community Respiratory Health Survey. J. Allergy Clin. Immunol. 99: 314-322 [Medline].

4. Backer, V., S. Groth, A. Dirksen, N. Bach-Mortensen, K. K. Hansen, E. M. Laursen, and D. Wendelboe. 1991. Sensitivity and specificity of the histamine challenge test for the diagnosis of asthma in an unselected sample of children and adolescents. Eur. Respir. J. 4: 1093-1100 [Abstract].

5. Cockcroft, D. W., K. Y. Murdock, B. A. Berschield, and B. P. Gore. 1992. Sensitivity and specificity of histamine PC20 determination in a random selection of young college students. J. Allergy Clin. Immunol. 89: 23-30 [Medline].

6. Burrows, B., M. R. Sears, E. M. Flannery, G. P. Herbison, M. D. Holdaway, and P. A. Silva. 1995. Relation of the course of bronchial responsiveness from age 9 to age 15 to allergy. Am. J. Respir. Crit. Care Med. 152: 1302-1308 [Abstract].

7. Rijcken, B., J. P. Schouten, S. T. Weiss, F. E. Speizer, and R. van der Lende. 1987. The relationship of nonspecific bronchial responsiveness to respiratory symptoms in a random population sample. Am. Rev. Respir. Dis. 136: 62-68 [Medline].

8. Rijcken, B., J. P. Schouten, S. T. Weiss, F. E. Speizer, and R. van der Lende. 1987. The association of airway responsiveness to respiratory symptom prevalence and to pulmonary function in a random population sample. Bull. Eur. Physiopathol. Respir. 23: 391-394 [Medline].

9. Peat, J. K., C. Mellis, S. R. Leeder, and A. J. Woolcock. 1994. Differences in airway responsiveness between children and adults living in the same environment: an epidemiological study in two regions of Australia. Eur. Respir. J. 7: 1805-1813 [Abstract].

10. Peat, J. K., B. Toelle, L. Gray, M. M. Haby, E. Belousova, C. M. Mellis, and A. J. Woolcock. 1995. Prevalence and severity of childhood asthma and allergic sensitisation in seven climatic regions of New South Wales. Med. J. Aust. 163: 22-26 [Medline].

11. Burney, P. G., S. Chinn, J. R. Britton, A. E. Tattersfield, and A. O. Papacosta. 1989. What symptoms predict the bronchial response to histamine? Evaluation in a community survey of the bronchial symptoms questionnaire (1984) of the International Union against Tuberculosis and Lung Disease. Int. J. Epidemiol. 18: 165-173 [Abstract/Free Full Text].

12. Salome, C. M., J. K. Peat, W. J. Britton, and A. J. Woolcock. 1987. Bronchial hyperresponsiveness in two populations of Australian schoolchildren: I. Relation to respiratory symptoms and diagnosed asthma. Clin. Allergy 17: 271-281 [Medline].

13. Toelle, B. G., J. K. Peat, C. M. Salome, C. M. Mellis, and A. J. Woolcock. 1992. Towards a definition of asthma for epidemiology. Am. Rev. Respir. Dis. 146: 633-637 [Medline].

14. Chinn, S., P. Burney, D. Jarvis, and C. Luczynska. 1997. Variation in bronchial responsiveness in the European Community Respiratory Health Survey (ECRHS). Eur. Respir. J. 10: 2495-2501 [Abstract].

15. Anonymous. 1998. ECRHS-I. Determinants of bronchial responsiveness in the European Community Respiratory Health Survey in Italy: evidence of an independent role of atopy, total serum IgE levels, and asthma symptoms. Allergy 53: 673-681 [Medline].

16. Ryan, G., M. B. Dolovich, R. S. Roberts, P. A. Frith, E. F. Juniper, F. E. Hargreave, and M. T. Newhouse. 1981. Standardization of inhalation provocation tests: two techniques of aerosol generation and inhalation compared. Am. Rev. Respir. Dis. 123: 195-199 [Medline].

17. Yan, K., C. Salome, and A. J. Woolcock. 1983. Rapid method for measurement of bronchial responsiveness. Thorax 38: 760-765 [Abstract/Free Full Text].

18. Clifford, R. D., M. Radford, J. B. Howell, and S. T. Holgate. 1989. Prevalence of respiratory symptoms among 7 and 11 year old schoolchildren and association with asthma. Arch. Dis. Child. 64: 1118-1125 [Abstract/Free Full Text].

19. Britton, J., A. Mortagy, and A. Tattersfield. 1986. Histamine challenge testing: comparison of three methods. Thorax 41: 128-132 [Abstract/Free Full Text].

20. Peat, J. K., C. M. Salome, A. Bauman, B. G. Toelle, S. L. Wachinger, and A. J. Woolcock. 1991. Repeatability of histamine bronchial challenge and comparability with methacholine bronchial challenge in a population of Australian school children. Am. Rev. Respir. Dis. 144: 338-343 [Medline].

21. Burrows, B., M. R. Sears, E. M. Flannery, G. P. Herbison, and M. D. Holdaway. 1995. Relations of bronchial responsiveness to allergy skin test reactivity, lung function, respiratory symptoms, and diagnoses in thirteen-year-old New Zealand children. J. Allergy Clin. Immunol. 95: 548-556 [Medline].

22. Burney, P. G. J., S. Luczynska, and C. D. Jarvis. 1994. The European Community Respiratory Health Survey. Eur. Respir. J. 7: 954-960 [Abstract].

23. Barbee, R. A., W. Kaltenborn, M. D. Lebowitz, and B. Burrows. 1987. Longitudinal changes in allergen skin test reactivity in a community population sample. J. Allergy Clin. Immunol. 79: 16-24 [Medline].

24. Gergen, P. J., P. C. Turkeltaub, and M. G. Kovar. 1987. The prevalence of allergic skin test reactivity to eight common aeroallergens in the U.S. population: results from the second National Health and Nutrition Examination Survey. J. Allergy Clin. Immunol. 80: 669-679 [Medline].

25. Peat, J. K., R. H. van den Berg, C. M. Mellis, S. R. Leeder, and A. J. Woolcock. 1993. Changes in the prevalence of asthma and allergy in Australian children 1982-1992 (abstract). Am. Rev. Respir. Dis. 147: A800 .

26. Hurry, V. M., J. K. Peat, and A. J. Woolcock. 1988. Prevalence of respiratory symptoms, bronchial hyperresponsiveness and atopy in schoolchildren living in the Villawood area of Sydney. Aust. N.Z. J. Med. 18: 745-752 [Medline].

27. Gray, E. J., J. K. Peat, C. M. Mellis, J. Harrington, and A. J. Woolcock. 1994. Asthma severity and morbidity in a population sample of Sydney schoolchildren: Part 1. Prevalence and effect of air pollutants in coastal regions. Aust. N.Z. J. Med. 24: 168-175 [Medline].

28. Flynn, M. G. L.. 1994. Respiratory symptoms, bronchial responsiveness, and atopy in Fijian and Indian children. Am. J. Respir. Crit. Care Med. 150: 415-420 [Abstract].

29. Pattemore, P. K., M. I. Asher, A. C. Harrison, E. A. Mitchell, H. H. Rea, and A. W. Stewart. 1989. Ethnic differences in prevalence of asthma symptoms and bronchial hyperresponsiveness in New Zealand schoolchildren. Thorax 44: 168-176 [Abstract/Free Full Text].

30. Turner, K. J., G. K. Dowse, G. A. Stewart, and M. P. Alpers. 1986. Studies on bronchial hyperreactivity, allergic responsiveness, and asthma in rural and urban children of the highlands of Papua New Guinea. J. Allergy Clin. Immunol. 77: 558-566 [Medline].

31. Zhong, N. S., R. C. Chen, M. O-yang, J. Y. Wu, W. X. Fu, and L. J. Shi. 1990. Bronchial hyperresponsiveness in young students of southern China: relation to respiratory symptoms, diagnosed asthma, and risk factors. Thorax 45: 860-865 [Abstract/Free Full Text].

32. Peat, J. K., and A. J. Woolcock. 1991. Sensitivity to common allergens: relation to respiratory symptoms and bronchial hyperresponsiveness in children from three different climatic areas of Australia. Clin. Exp. Allergy 21: 573-581 [Medline].

33. Sears, M. R., B. Burrows, G. P. Herbison, M. D. Holdaway, and E. M. Flannery. 1993. Atopy in childhood: 11. Relationship to airway responsiveness, hay fever and asthma. Clin. Exp. Allergy 23: 949-956 [Medline].

34. Zamel, M., P. A. McClean, P. R. Sandell, K. A. Siminovitch, and A. S. Slutsky. 1996. Asthma on Tristan da Cunha: looking for the genetic link. The University of Toronto Genetics of Asthma Research Group. Am. J. Respir. Crit. Care Med. 153: 1902-1906 [Abstract].

35. Haby De Sosa, M. M. 1998. Risk Factors for Asthma and Atopy in Preschool Children (Ph.D. thesis). Department of Public Health and Community Medicine, University of Sydney, Sydney, Australia.

36. von Mutius, E., F. D. Martinez, C. Fritzsch, T. Nicolai, P. Reitmeir, and H. H. Thiemann. 1994. Skin test reactivity and number of siblings. Br. Med. J. 308: 692-695 [Abstract/Free Full Text].

37. Jarvis, D., S. Chinn, C. Luczynska, and P. Burney. 1997. The association of family size with atopy and atopic disease. Clin. Exp. Allergy 27: 240-245 [Medline].

38. Peat, J. K., C. M. Salome, and A. J. Woolcock. 1992. Factors associated with bronchial hyperresponsiveness in Australian adults and children. Eur. Respir. J. 5: 921-929 [Abstract].

39. Sunyer, J., J. M. Anto, J. Sabria, J. Roca, F. Morell, R. Rodriguez-Roisin, and M. J. Rodrigo. 1995. Relationship between serum IgE and airway responsiveness in adults with asthma. J. Allergy Clin. Immunol. 95: 699-706 [Medline].

40. Jogi, R., C. Janson, E. Bjornsson, G. Boman, and B. Bjorksten. 1996. The prevalence of asthmatic respiratory symptoms among adults in Estonian and Swedish university cities. Allergy 51: 331-336 [Medline].

41. Braun-Fahrlaender, C., M. Gassner, L. Grize, U. Neu, F. H. Sennhauser, H. S. Varonier, J. C. Vuille, B. Wuethrich, and a. T. S. Team. 1999. Prevalence of hay fever and allergic sensitization in farmer's children and their peers living in the same rural community. Clin. Exp. Allergy 29: 28-34 [Medline].

42. Nowak, D., J. Heinrich, R. Jorres, G. Wassmer, J. Berger, E. Beck, S. Boczor, M. Claussen, H. E. Wichmann, and H. Magnussen. 1996. Prevalence of respiratory symptoms, bronchial hyperresponsiveness and atopy among adults: West and East Germany. Eur. Respir. J. 9: 2541-2552 [Abstract].

43. Preller, L., G. Doekes, D. Heederick, R. Vermeulen, P. F. Vogelzang, and J. S. Boleij. 1996. Disinfectant use as a risk factor for atopic sensitization and symptoms consistent with asthma: an epidemiological study. Eur. Respir. J. 9: 1407-1413 [Abstract].

44. Lynch, N. R., I. Hagel, M. Perez, M. C. Di Prisco, R. Lopez, and N. Alvarez. 1993. Effect of anthelmintic treatment on the allergic reactivity of children in a tropical slum. J. Allergy Clin. Immunol. 92: 404-411 [Medline].

45. Naaber, P., K. Klaus, E. Sepp, B. Bjorksten, and M. Mikelsaar. 1997. Colonization of infants and hospitalized patients with Clostridium difficile and lactobacilli. Clin. Infect. Dis. 25: S189-S190 .