Volume 167 Issue 10

Mammographic screening: results from the 1996 National Breast Health Survey Alexandra L Barratt, Jill Cockburn, Sally Redman, Christine Paul and Janice Perkins For editorial comment, see Glasziou & Irwig This article has been cited in Rodger A, Kavanagh AM, Outcome measures of an Australian breast-screening program, MJA 1998; 169: 179-180 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - - ©MJA1997 Abstract Objective: To establish the extent of women's knowledge of mammographic screening, particularly in relation to the national screening program, BreastScreen Australia, and to estimate the proportion of women who are participating in screening both within and outside BreastScreen Australia. Design and setting: Validated prospective telephone survey of women aged 30-69 years selected at random from across Australia. Participants: 2935 women with no previous breast cancer diagnosis. Results: The adjusted response rate was 64%. Almost 90% of women had heard of the national program; only 1% correctly stated that screening is for asymptomatic women. 60% correctly identified the current recommended age of starting screening is about 50 years of age; 26% thought screening should begin at about 40 years of age. Approximately 60% correctly reported that the recommended screening interval is every two years; 27% thought screening should be done annually. 55% reported ever having had a mammogram, and 37% reported having had at least one screening mammogram. Among women in the target age group (50-69 years) about 70% reported ever having had a screening mammogram, and about 50% reported having had a screening mammogram within the national program in the last two years. Among women aged 40-49 years, 29% reported ever having had a screening mammogram, and 22% reported having been screened in the last two years. Conclusions: Awareness of the national screening program is high, but some women do not know the purpose of screening, the target age group and the recommended screening interval. Compliance with screening is good among women in the target age group; many women in their 40s are also participating in screening. MJA 1997; 167: 521-524 Introduction Breast cancer is the most common cause of cancer death in Australian women, with approximately 7000 new cases and over 2500 deaths annually.1 Evidence from randomised controlled trials shows that mammographic screening can substantially reduce mortality from breast cancer among women aged 50-69 years,2,3 but high rates of compliance with screening are necessary to achieve these benefits. Since 1991 the Commonwealth and State governments have funded a national program of mammographic screening, BreastScreen Australia, which provides free mammographic screening for women aged 40-79 years, but specifically targets women aged 50-69 years. Clearly, if women are to participate, they need to know about mammographic screening generally, and about the service provided by the national program in particular. In 1996, we undertook a national survey on behalf of the National Health and Medical Research Council National Breast Cancer Centre (NBCC) to establish baseline information about women's knowledge of, and participation in, screening mammography. Limited data about participation within the national program are available from the national program's own evaluation reports. Little is known about participation in screening outside the national program. Our aims were, firstly, to determine Australian women's knowledge of mammographic screening and the national program, and whether knowledge differs by area of residence or education. Secondly, we aimed to estimate the proportion of women who are participating in screening both within and outside BreastScreen Australia. Methods The survey was conducted by telephone by a market research company on behalf of the NBCC in April 1996. The questionnaire was developed and pilot-tested by the NBCC; test-retest reliability was assessed by administering the questionnaire twice to a random sample of 100 women at a one-week interval, with good agreement for key items ( k = 0.89-1.00). Telephone numbers were chosen at random from the electronic white pages telephone directory. Up to five callbacks were made to contact eligible women (those aged 30-69 years whose English was sufficient to complete a telephone interview). The sampling frame was stratified to ensure participation by women in all States and Territories, and in urban and rural areas.4 The outcome of every phone call was recorded. Ethical approval for this study was obtained from the NSW Cancer Council Ethics Committee in March 1996. Validation A random sample of 150 women who reported having been screened by BreastScreen Australia were asked for consent to check their questionnaire answers against BreastScreen Australia records. For those who consented, identifying data and the estimated date of last screen within the program were forwarded to BreastScreen Australia for confirmation. To assess selection bias, one survey question (Have you ever had a mammogram?) was placed in the February 1996 Australian Bureau of Statistics (ABS) Population Survey Monitor, which is conducted quarterly by household interview. The question was asked only of women 30-69 years in the ABS sample, and the results were weighted as for our survey (described below) to give a comparable estimate. Statistical analysis Our data were weighted for area of residence and age based on ABS projected population estimates. As all percentages reported in this paper are weighted results, sample sizes are not routinely given in the results. Significance testing was done by chi-squared tests based on the sample size of the survey; P values of less than 0.05 were considered statistically significant. Ninety-five per cent confidence intervals were calculated from the standard error of the proportion, again based on the sample size of the survey. Education was coded according to ABS categories and collapsed to those with post-school qualifications and those without post-school qualifications.5 Age was classified as younger (30-49 years) and older (50-69 years) to differentiate women within and outside the target age range of the national program. Results The raw response rate was 70.2% (calculated as completed interviews [3014] over contacted eligible women [4291]). After inflating the denominator by the estimated number of eligible women among those who could not be contacted (n = 389), the response rate was 64.4%. Seventy-nine women who had previously been diagnosed with breast cancer were excluded. The demographic characteristics of the remaining women are shown in Box 1. Of the 150 women asked, 127 (85%) consented to having their screening records checked. Of 126 women who reported having been screened within BreastScreen Australia within the last two years, attendance was confirmed for 121 (96%). Twenty-six per cent of women were able to recall the mammogram date accurately to the day, and a further 38% accurately recalled the month. Ninety-two per cent of women reported the mammogram date accurately to within 12 months. The weighted ABS estimate for the question Have you ever had a mammogram? was 50% (95% CI, 46.9-53.2). Responses to specific questions Do you know any ways to detect breast cancer in the early stages? -- 63.2% of respondents nominated mammography without prompting. Those more likely to nominate mammography were older women (chi-squared = 14.99; P < 0.01) and women with post-school qualifications (chi-squared = 12.05; P< 0.01). The Commonwealth and State governments fund a mammographic screening program in Australia known as the National Program for the Early Detection of Breast Cancer. In [respondent's State] it is known as [program name in respondent's State] . Have you heard of this Program? -- 88.7% of women responded that they had heard of the national program. More women in rural areas than in urban areas had heard of the program (92.9% v. 87.0%; chi-squared = 14.82; P< 0.001). More older than younger women had heard of the program (93.1% v. 86.2%; chi-squared = 42.09; P< 0.001). There was no difference in the proportion who had heard of the program by educational level. Which women do you think should attend for mammographic screening; only women who have no symptoms of breast cancer ; only women who have symptoms of breast cancer ; or it doesn't matter whether women have symptoms or not? -- only 1.3% of women correctly replied that screening was for women without symptoms, 2.9% replied that it was for women with symptoms, and 94.8% replied that it didn't matter. Slightly more younger women than older women thought screening was for women with symptoms (3.6% v. 2.0%; chi-squared = 11.70; P< 0.009). There were no differences between women living in urban and rural areas or according to educational level. When does the government program recommend women should start (stop) having mammograms? -- 60.3% of women correctly reported that the recommended commencement age was 50-59 years; 26.0% reported it was 40-49 years (see Box 2). More younger women than older women reported that the recommended commencement age was 40-49 years (28.1% v. 22.5%; chi-squared = 58.73; P= 0.001). Again, there were no differences in these proportions between women living in urban and rural areas or according to educational level. Most women (55.5%) thought screening should never cease, and 19.5% of women were unable to say when screening should stop (Box 2). How often does the government screening program suggest women should have a screening mammogram? -- 58.7% correctly reported that the government program suggests screening should be done every two years, but 26.7% reported that annual screening is recommended. More younger women than older women reported that annual screening is recommended (32.1% v. 17.4%; chi-squared = 178.76; P< 0.001). Referral and access to the government program Of respondents in the target age group (50-69 years), 34.7% reported that their GP had suggested they have a mammogram as part of the government program. This proportion did not vary by area of residence or by education level. Among all respondents, almost all women (95.8%) reported having visited a GP within the last two years. Among women in the target age group, 84.0% knew that a screening mammogram within the national program was free. More women with post-school qualifications knew this (87.9% v. 80.9%; chi-squared = 9.30; P= 0.01), but the proportions did not vary according to area of residence. Most women in the target age group (65.8%) reported being very confident of knowing how to make an appointment for a mammogram within the program, and this proportion did not differ according to area of residence or educational level. Participation in screening mammography A series of questions was used to determine whether women had had a mammogram within or outside the national program. To determine whether it had been a screening mammogram, they were then asked, When you had [that mammogram] was it because you already thought you had some problems with your breasts?. Overall, 55.0% of all women reported ever having had a mammogram (Box 3). The frequency of having had a mammogram rose steeply with age, peaking in the 50-59 years age group at 86.5%. Overall, 36.6% of women reported having had at least one screening mammogram (Box 3). Among women aged 30-39 years, approximately 6% reported having been screened, and this proportion rose to approximately 70% in the 50-69 years target age group. Having had a screening mammogram was not associated with area of residence or with education. In the target age group (50-69 years), 49.5% of women reported being screened in the national program within the last two years, and this was not influenced by area of residence or educational level. Another 12.1% reported having been screened outside the national program within the last two years. Among women 30-39 years of age, only 3% had been screened in the last two years, mostly outside the national program. In the older age groups, most women reported being screened within the national program (Box 4). Discussion Our findings are the first validated, baseline estimates of Australian women's knowledge of, and participation in, mammographic screening since the establishment of the national program. Our adjusted response rate of 64% compares well with those of similar reported surveys.6-8 The estimate by the ABS for the identical question Have you ever had a mammogram? was 50% (95% CI, 46.9-53.2) compared with ours of 55% (95% CI, 53.2-56.8), suggesting that our estimates are likely to be only minimally affected by selection bias. However, we excluded some women, notably non-English speakers and those living in homes without telephones. Also, as it is likely that women who chose to participate were more aware of breast cancer and screening mammography than those who refused, our data may overestimate both women's knowledge of, and participation in, such screening. Awareness of the national program was high (nearly 90%). Although asking a prompted question may have inflated this estimate, the result does suggest that the promotion of the program has been effective. The vast majority of women knew that the national program is free, and that it recommends women start screening at around 50 years of age and have a screening mammogram every two years. Most women also felt very confident in knowing how to access the program. The absence of significant variation in knowledge about screening mammography according to area of residence or educational level suggests that the national program has been successful in widely promoting screening. However, consistent with a previous study,9 most women were not aware that screening is intended only for asymptomatic women. Most women thought symptoms didn't matter, suggesting they appreciate to some extent that the national program is not designed for the evaluation of symptoms. While this may be encouraging, it is still of some concern as people who do not appreciate the distinction between diagnostic and screening tests may be more likely to seek compensation for missed diagnoses.9 As most women reported that their GPs had never recommended they attend the national program for screening, there is a greater opportunity for GPs to recruit more women to screening. Our findings indicate that attendance for mammography is becoming increasingly common. Surveys conducted in 1988 found that only 18% of women spontaneously mentioned mammography as a means of detecting breast cancer in the early stages, and 50% claimed to have heard of it when prompted.10 Only about 10%-20% of women had ever had a mammogram, about half for diagnostic and half for screening purposes.7,11 Clearly, this situation has changed dramatically, with 60% of women now nominating mammography as a means of early detection in an unprompted question, 55% of all women reporting having ever had a mammogram, and 37% of women reporting having had at least one screening mammogram. High proportions of women in the age group targeted by the national program reported having been screened at least once (70%) and having been screened in the last two years (about 60%). Many more of these women are being screened as part of the national program than outside it. Our finding that 49.8% of women in the target age group had been screened within the national program in the last two years is consistent with BreastScreen Victoria's estimated participation rate of 47.7%.12 Recent meta-analyses showing a small reduction in mortality after about 10 years of screening for women aged 40-49 years13 have prompted heated debate over whether younger women should also be targeted for screening. It is interesting to note that we found quite high screening rates among women aged 40-49 years, indicating that many women in this age group are, in fact, already being screened. References Taylor R, Smith D, Hoyer A, et al. Breast Cancer in New South Wales 1972-1991. Sydney: NSW Cancer Council, 1994. Kerlikowske K, Grady D, Rubin SM, et al. Efficacy of screening mammography. A meta-analysis. JAMA 1995; 273: 149-154. Glasziou P, Woodward AJ, Mahon CM. Mammographic screening trials for women aged under 50. A quality assessment and meta-analysis. Med J Aust 1995; 162: 625-629. Department of Primary Industries and Energy, Department of Human Services and Health. Rural, remote and metropolitan areas classification. Canberra: AGPS, 1994. Australian Bureau of Statistics. Labour force status and educational attainment, Australia. Canberra: Australian Bureau of Statistics, 1994. (Catalogue No. 6235.0.) Etzi S, Lane DS, Grimson R. The use of mammography vans by low-income women: the accuracy of self-reports. Am J Public Health 1994; 84: 107-109. Hill D, White V, Borland R, Cockburn J. Cancer-related beliefs and behaviours in Australia. Aust J Public Health 1991; 15: 14-23. Smith W, Chey T, Jalaludin B, et al. Increasing response rates in telephone surveys: a randomized trial. J Public Health Med 1995; 17: 33-38. Cockburn J, Redman S, Hill D, Henry E. Public understanding of medical screening. J Med Screening 1995; 2: 224-227. Cockburn J, Murphy B, Schofield P, et al. Development of a strategy to encourage attendance at screening mammography. Health Ed Res Theory Practice 1991; 6: 279-290. Irwig L, Cockburn J, Turnbull D, et al. Women's perceptions of screening mammography. Aust J Public Health 1991; 15: 24-32. BreastScreen Victoria: 1995 annual statistical report. Melbourne: BreastScreen Co-ordination Unit, 1996. Breast-cancer screening with mammography in women aged 40-49 years. Report of the Organizing Committee and Collaborators, Falun Meeting, Falun, Sweden 1996. Int J Cancer 1997; 68: 693-699. (Received 11 Mar, accepted 12 Aug, 1997) Authors' details Department of Public Health and Community Medicine, University of Sydney, NSW. Alexandra L Barratt, PhD, FAFPHM, Lecturer. Discipline of Behavioural Science in Relation to Medicine, University of Newcastle, NSW. Jill Cockburn, PhD, Head. National Health and Medical Research Council National Breast Cancer Centre, Sydney, NSW. Sally Redman, PhD, Director; Christine Paul, PhD, Consultant Behavioural Scientist. New South Wales Cancer Council Cancer Education Research Program, Wallsend, NSW. Janice Perkins, PhD, Research Associate. Currently at the Discipline of Behavioural Science in Relation to Medicine, University of Newcastle, NSW. No reprints will be available. Correspondence: Dr A L Barratt, Department of Public Health and Community Medicine, Building A27, University of Sydney, NSW 2006. - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

"Single use only" labelling of medical devices: always essential or sometimes spurious? Ian Stewart While the medical disposables industry may benefit from labelling devices as "single use only", we all bear the costs of subsequent disposal and pollution. MJA 1997; 167: 538-539 For editorial comment see Whitby & Looke Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/MJA/>". Introduction - Conclusion - References - Authors' details Make a comment - - ©MJA1997 Introduction Earlier this year, the National Health and Medical Research Council (NHMRC) released its final report on the reuse of medical devices labelled as "single use only". Australia's health ministers will now be expected to decide which of the report's two main recommendations is most appropriate: that either reuse of single-use devices should cease altogether or, if reuse is condoned, the practice should be subject to enforceable standards for cleaning, resterilisation and quality control. The medical disposables industry is likely to lobby politicians to adopt the former strategy, one which will require our health ministers to find up to an estimated $100 million annually.1 In their deliberations, another issue which ministers may wish to consider, which the NHMRC report did not examine, is the process by which devices come to bear the label "single use only". Most of the debate about reuse of single-use devices has focused on expensive disposables such as cardiac catheters. Currently, such instruments are routinely reprocessed in many hospitals because the cost of disposal after each use would necessitate a reduction of services. The single-use status of devices such as angioplasty balloon catheters appears to be warranted, in that they are invasive devices with narrow lumens which may be difficult to clean and inspect. However, a randomised, double-blind, controlled clinical trial,2 cohort studies,3,4 and a risk-benefit assessment5 suggest that cardiac catheters can be safely reused if sound protocols for reprocessing are observed. There is not even any anecdotal evidence for the transmission of viral disease from the reuse of cardiac electrode catheters.6 Therefore, the evidence supporting the single-use status of apparently high risk cardiac catheters is unconvincing. Given this situation, how should we view the broad array of devices labelled "single use only" where criteria for disposability are tenuous at best, and most often knowingly inappropriate? Consider just a few examples from a long list of devices that I believe are spuriously labelled as "single use only". Disposable PVC oxygen masks. Used and discarded in considerable quantities every day in postoperative recovery rooms, most of these masks have a working life of about 10 minutes. They are not supplied as a sterile item (nor should they be) but the accompanying directions-for-use insert says "for single use only". In comparison, multiple-use black rubber anaesthetic masks (which are probably thought to do the same job from a microbiologist's perspective) are deemed safe for many uses. Disposable pressure infuser. This consists of a bladder with an external sleeve and an inflating bulb. A plastic bag of sterile fluid for flushing an artery or other vessel is placed inside the infuser sleeve and the bladder is inflated. The inside of the sealed bag is sterile; the external surface which is in contact with the infuser sleeve does not need to be sterile. The potential for nosocomial infection from this device is probably less than that of a blood pressure cuff, which is washed periodically, or immediately if soiled (a practice which should also apply to pressure infusers). Disposable nasal oxygen prongs. Even if staff insist on throwing away the nosepiece (which could be cleaned and pasteurised for reuse), why do the two metres of oxygen tubing need to be discarded? The answer is that the product is sold only as a single unit. It is difficult to see how design efficiency could be claimed to drive marketing decisions in this case because the oxygen tubing is of a larger diameter than the nasal prongs -- the two parts are bonded and sold as one. Single-patient-use oxygen transducers. A non-invasive device which is fitted to a finger or toe, this is a recent addition to the throw-away stable, and expensive at $26 (adult) or $34 (neonatal) each. They were formerly multiple-use devices that were easy to clean in detergent or with an alcohol swab. Pill cups, kidney trays, suction tubing, sequential calf compression cuffs and arm splints for intravenous lines also have low potential for cross-infection and would be easy to clean, inspect and, if necessary, resterilise. Perhaps little consideration is given to the mass consumption and disposal of such instruments because they are seen to be low-cost items. Yet this low cost is somewhat artificial, especially on the disposal side. In most hospitals, waste disposal is not costed to individual departments, so there are few incentives to minimise waste. Many of the indirect costs of waste disposal are passed on to the wider community. Incineration of chlorinated plastic releases carbon dioxide, dioxins and acid vapours into the atmosphere. The incremental costs of pollution monitoring and greenhouse warming, as well as the negative health effects and declining aesthetic value of decreased air quality, are not accounted for in the purchase price of biomedical disposables. Further, if it were a simple matter of supply and demand, clinicians would not be concerned about the opportunity costs of enforced disposal after one use, and health workers would not be worried about the environmental impact of all this unnecessary consumption and disposal of energy and resources. If there was a demand for durable, multiple-use devices, then surely entrepreneurial suppliers would rise to the occasion! However, the situation is more complex. John Kenneth Galbraith showed how suppliers can manipulate demand to suit their own ends.7 His exposure of the supply-and-demand myth is well represented by the culture of disposability which has taken root in modern healthcare over the last three decades, driven by the fear of litigation, so that non-invasive devices labelled "single use only" are treated as such without question. The infection-risk bogey and the spectre of litigation are raised in articles in nursing journals,8,9 central sterilising journals,10 pronouncements of the medical disposables industry,11 and in the mass media.12,13 The latter forum has a far-reaching capacity to muddy the waters; at least one television program linked the reuse of single-use medical devices with the HIV cross-infection of four women in a Sydney surgery, yet there was no suggestion that the surgeon involved deliberately reprocessed single-use devices.14 The virus was thought to have been transmitted through some unidentified breach of infection control guidelines,15 which is an entirely different issue. The process of cleaning, disinfecting and resterilising needs to be brought out into the open so that the current, somewhat surreptitious, practice of reprocessing single-use items can be guided by clear, commonsense protocols, quality controls and reporting of adverse events. However, the process by which biomedical devices come to carry the stamp of "single use only" should also be scrutinised. At present, these three words could be seen to be a licence to print money -- to my knowledge, manufacturers of single-use products do not have to explain why any device deserves to be labelled "disposable". The Industry Commission's 1996 report on the medical and scientific equipment industries16 reported that manufacturers have a financial incentive to label as "single use only" devices which may be safe to reuse. The Industry Commission suggested that market forces -- competition, threatened competition and the countervailing market power of more circumspect purchasing policies -- should put the brakes on this practice. With so much public money at issue, if governments decide to enforce single use more accountability should be required from the industry. If the industry has no interest in writing a code of labelling practice, then perhaps use of the words "single use only" should be regulated and licensed. Conclusion The NHMRC report on the reuse of medical devices labelled as "single use only" examines a small part of a problem that deserves much wider scrutiny; whether devices labelled "single use only" are to be discarded or reused is only tinkering at the margins. The real agenda should be a more thorough and open analysis of the costs and benefits of using and reusing biomedical devices, including: The question of how biomedical devices come to be labelled "single use only"; How to support the manufacture and marketing of durable, sophisticated devices that are designed for multiple use; How to favour best practice cleaning and resterilisation of all biomedical devices, whether labelled "single use only" or intended for multiple use; and How to develop economic indicators to account for the hidden costs of disposables -- storage space, waste disposal and pollution. References National Health and Medical Research Council. Report of the NHMRC expert panel on re-use of medical devices labelled as single use. Canberra: AGPS, 1997. Burton J, Tymchak W, Dzavik V, et al. Randomized controlled trial of reuse of PTCA balloon catheters [abstract]. Circulation 1995; 92 Suppl 1: 661. Frank U, Herz L, Daschner FD. Infection risk of cardiac catheterization and arterial angiography with single and multiple use disposable catheters. Clin Cardiol 1988; 11: 785-787. Mak KH, Eisenberg MJ, Plante S. Absence of increased in-hospital complications with reused balloon catheters. Am J Cardiol 1996; 78: 717-719. Conseil d'evaluation des technologies de la sante du Quebec. The reuse of single-use cardiac catheters: safety, economical, ethical and legal issues. Can J Cardiol 1994; 10: 413-421. Ross DL. Re-use of electrode catheters labelled as single use for clinical cardiac electrophysiological studies [editorial]. Aust N Z J Med 1996; 26: 632-635. Galbraith JK. Economics and the public purpose. London: Pelican, 1975: 150-161. Pickersgill F. Disposables: the case against re-use. Nurs Times 1988; 84: 45-48. Langslow A. Legal liability and the re-use of disposables. Aust Nurs J 1994; 2: 22-24. Milligan J. Sterilizing services perspective. Sterilisation Aust 1992; 11: 6-8. Medical Industry Association of Australia. Statement of industry policy on the reuse of single-use medical devices. Sydney: MIAA, 1991. Robinson M. The patient's right to know. The Sydney Morning Herald 1996 Feb 22: 15 . Australian Broadcasting Corporation. 7:30 Report (television program). 1994: 8 Sep. Chant K, Lowe D, Rubin G, et al. Patient-to-patient transmission of HIV in private surgical consulting rooms [letter]. Lancet 1993; 342: 1548-1549. Penny R. HIV exposure in health care [editorial]. Med J Aust 1995; 162: 509. Industry Commission. Report No. 56: medical and scientific equipment industries. Canberra: AGPS, 1996: 89-91. Authors' details Health Professionals for Global Responsibility,* Sydney, NSW. Ian Stewart, RN, BAppBiol, Environmental Health Co-ordinator; also NSW Co-ordinator for Nursing The Environment (a special interest group of the Australian Nursing Federation). Reprints will not be available from the author. Correspondence: Mr I Stewart, PO Box 72, Erskineville, NSW 2043. E-mail: I. Stewart AT unsw.edu.au * Health Professionals for Global Responsibility is the NSW affiliate of the Medical Association for Prevention of War (Australia), affiliated with International Physicians for Prevention of Nuclear War. <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Specific allergen immunotherapy for asthma A Position Paper of the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Immunology and Allergy MJA 1997; 167: 540-544 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/MJA/>". Introduction - Atopy, allergens and asthma - Rationale for using immunotherapy for asthma - Clinical trials - Allergen extracts and route of administration - Adverse effects - Practical aspects of administering immunotherapy - References - Authors' details Make a comment - - ©MJA1997 Introduction Specific allergen immunotherapy (desensitisation, hyposensitisation) is the technique of treating IgE-mediated disease with increasing doses of an allergen in order to decrease sensitivity to that allergen. First used early this century, 60 million patients annually are now treated with immunotherapy throughout the world. The only absolute indication for immunotherapy is a life-threatening reaction after a Hymenoptera (bee or wasp) sting; all other indications are relative (see indications and contraindications for immunotherapy). Many randomised controlled trials have shown that hayfever caused by airborne pollens and house dust mite responds to this therapy.1 The use of specific allergen immunotherapy in asthma remains controversial. Despite this, the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Immunology and Allergy believe that all strategies which may impact on the morbidity and mortality of asthma should be assessed. The cost-effectiveness of this therapy also needs to be addressed in the context of the total cost of asthma in Australia, the mid-estimate of which in 1991 was $652 million (National Asthma Campaign, 1992). We present an overview and do not cover all aspects of this subject. Interested readers are referred to recent reviews.1-9 Atopy, allergens and asthma Allergy is best defined as an exaggerated response on exposure to an allergen following prior exposure, and mediated by an immune reaction involving IgE. The same clinical picture may result from non-immune mechanisms. Atopy is an increased tendency to IgE-based sensitivity resulting in production of specific IgE antibody to common environmental allergens, such as house dust mite, pollens, moulds or animal danders. This sensitisation occurs in genetically predisposed people after exposure to low concentrations of allergen; cigarette smoke and viral infections may assist in the sensitisation process. About 40% of the population is atopic, and about half of this group develop clinical disease ranging from trivial rhinitis to life-threatening asthma. After sensitisation, continuing exposure to allergens leads to a significant increase in the prevalence of asthma.10 Ninety per cent of children and 80% of adults with asthma are atopic.10 Once sensitisation has occurred, re-exposure to allergen is a risk factor for exacerbations of asthma.11 Effective management of allergic asthma includes pharmacological therapy and allergen avoidance. For example, avoiding dust mite allergen can reduce symptoms and the need for medication. Rationale for using immunotherapy for asthma Asthma is an inflammatory disease characterised by the presence of cells such as eosinophils, mast cells, basophils, and CD25+ T lymphocytes in the airway walls. There is close interaction between these cells, because of the activity of cytokines which have a variety of communication and biological effector properties. Chemokines attract cells to the site of inflammation and cytokines activate them, resulting in inflammation and damage to the mucosa.12 With chronicity of the process, secondary changes occur, such as thickening of basement membrane and fibrosis.13 An immunological reaction to allergen is the initiating event of airway inflammation in many cases of asthma.14 Continued exposure to allergen results in chronic inflammation. Current therapy aims to suppress this inflammation with inhaled corticosteroids, sodium cromoglycate, or nedocromil sodium, all of which interfere with the cellular and cytokine interactions by diverse mechanisms, but do not address the initiating event in allergic asthma. By withdrawing the allergen or altering the immune response to allergen, it is theoretically possible to control the allergic trigger of asthma. Immunological changes have been described after immunotherapy. These include an initial rise in specific serum IgE, followed by a fall, and a rise in specific IgG ("blocking antibody"). Specific IgG titres correlate poorly with the degree of protection. Immunotherapy leads to a reduction in mediator release from mast cells in vitro, alterations in lymphocyte subsets, and a downregulation of IL-4 production from T cells.15 Several studies have shown a reduction in inflammation and a decrease in bronchial hyperresponsiveness after immunotherapy.1,16,17 There are strong theoretical arguments why immunotherapy should be used early in the course of the disease, before irreversible secondary changes such as fibrosis have occurred. Further, data are emerging to suggest that immunotherapy may also influence the progression of clinical disease.3,7 Immunotherapy should not be regarded as an alternative to established forms of preventive therapy, as recommended by the National Asthma Campaign.18 A systematic cost-benefit analysis of immunotherapy has not yet been undertaken. Clinical trials There have been numerous randomised placebo- controlled double-blind trials of immunotherapy for asthma. Comparison of these trials is difficult, not only because of the inherent problems of trials involving asthma (such as standardisation of inclusion and outcome criteria), but also because of differences in allergen extracts and dosage regimens. A meta-analysis can address some of these difficulties, and has recently been applied to 20 randomised controlled trials of immunotherapy for asthma in both adults and children.19 This meta-analysis found a clinically useful improvement from immunotherapy with house dust mite and with other allergens (see Box below). It concluded that immunotherapy is a treatment option in highly selected patients (discussed more fully below) with allergic asthma. The reviews cited in this position paper,1-9 the meta-analysis19 and further controlled studies published in the last five years20-24 provide references to the most important trials of immunotherapy. Allergen extracts and route of administration Although several routes of allergen delivery have been used in immunotherapy, only subcutaneous injection has been studied in detail and shown to be effective. Giving allergen extract sublingually is not recommended as studies have failed to show long-term efficacy.25 Trials with giving birch pollen orally appeared promising, but large doses were required and there was a high incidence of side effects. Further studies of oral immunotherapy using modified preparations are under way. Intranasal administration of pollen extracts resulted in an unacceptable level of side effects. Local bronchial immunotherapy with mite extract in patients with asthma has been studied in a controlled trial but failed to produce significant clinical improvement.26 Most allergen extracts used in Australia for immuno therapy of inhalant allergy are alum-precipitated. Such preparation slows the absorption of allergen, reducing the risk of serious anaphylaxis and providing sustained immune stimulation. There is no reliable standardisation of biological activity for many allergen extracts used in Australia. Mass and concentration of active material are not useful guides to biological activity. The concentrations of the slow-release (alum-precipitated) preparations are expressed in "protein nitrogen units" and not biological activity. Aqueous preparations of some allergens, including Dermatophagoides pteronyssinus, are standardised against a WHO standard and are extremely potent. Their use in asthma should be restricted to specialist centres. Adverse effects Local reactions Mild swelling and erythema at the site of the injection is to be expected. It may persist for 24 hours or more and is not a cause for concern. A more severe reaction over 50 mm in diameter is an indication for reduction in the subsequent dose. Systemic reactions These include sneezing, bronchospasm, urticaria and, in more severe cases, anaphylaxis with hypotension and collapse. They must always be regarded seriously. Although they usually occur within 30 minutes of the injection, they may be delayed for several hours with the use of alum-precipitated preparations. Recent data from the UK estimate that the incidence of severe systemic reactions was 1 in 500 injections,1 but most occurred with aqueous extracts, and alum-precipitated extracts appeared to be much safer. The incidence of anaphylaxis with Allpyral (Bayer, Pymble, NSW), the alum-precipitated material available in Australia, was reported to be 1 in 27 854 courses of treatment, and of anaphylaxis and/or bronchospasm, 1 in 14 998 courses of treatment.27 The Committee on the Safety of Medicines, in the United Kingdom, reported in 1986 that in the 29 years from 1957 to 1986 during which 1 459 273 courses of treatment were given, there were 29 deaths from immunotherapy -- 16 in patients where the indication for therapy was asthma.27 Highly purified and potent aqueous extracts were involved in most of these deaths, and no deaths were reported with the Allpyral extract. Subsequent reports indicated a much lower incidence of anaphylaxis and deaths in France and the US,28,29 where one major difference in practice is that treatment is administered by specialists with expertise in the area. In Australia, five deaths from immunotherapy were reported to the Adverse Drug Reactions Advisory Committee in the 21 years from 1972 to 1993. Four were in patients with asthma, and in each case there was a divergence from recommended procedure. Long term adverse effects There is no increase in the prevalence of vasculitis, autoimmune disease or monoclonal gammopathies during or after immunotherapy.30 Further, there is no evidence that long term worsening of asthma occurs with immunotherapy. Practical aspects of administering immunotherapy These guidelines relate to specific allergen immunotherapy for the treatment of asthma in patients with clinical manifestations and/or need for treatment of ongoing bronchial hyperreactivity. The decision to prescribe immunotherapy is based on appropriate patient selection, appropriate antigen selection, and whether potential benefits outweigh associated risks. Only a practitioner or team with training and experience in the management of both asthma and immunotherapy should make the decision. Suitably qualified practitioners include thoracic physicians with training and expertise in allergy, or clinical immunologist/allergists with training and expertise in asthma. It is the responsibility of the supervising consultant to (a) decide whether a patient needs to be treated in a hospital, and (b) ensure that the medical practitioner giving immunotherapy receives written instructions on patient assessment and immunotherapy protocol. Informed consent according to currently accepted guidelines must be obtained from patients before starting immunotherapy. Immunotherapy should be given only by a medical practitioner familiar with immunotherapy, conversant with resuscitative procedures, and in a setting where the following resuscitation equipment is immediately available: adrenaline 1:1000 for intramuscular use (adrenaline is the drug of choice for the immediate management of systemic reactions to immunotherapy), oxygen, an inflatable bag and mask ventilator, a nebuliser and bronchodilator nebuliser solution, needles and tubing for intravenous access, intravenous fluids suitable for volume replacement, parenteral antihistamine, and parenteral corticosteroid. The practitioner and a second appropriately trained health care professional should be present during immunotherapy to assist if resuscitation is required. Each patient requires an individual dosage schedule according to the degree of sensitivity and clinical reaction to the injections. The principle of therapy is to start with a small dose and gradually increase it as tolerated. Supervising consultants will have the training and experience necessary to determine the starting dose and appropriate schedule. Flexibility in dosage is essential and rigid adherence to predetermined dosage schedules is inappropriate. Extracts should be stored in a refrigerator at 4°C , clearly marked with the patient's identifier(s) and replaced in the refrigerator immediately after use. Before injection, the extract should be examined visually and discarded if its appearance has changed. The contents of the bottle should be mixed well to avoid variation in dosage. When changing to a new batch of unstandardised extract (such as Allpyral), the first dose should be reduced by 25% to take account of possible variation in biological activity of the preparations. Each patient should have his or her own individual vial of extract -- laws in some States forbid multiple use of vials for different patients. Every patient should be assessed clinically on each occasion before an injection is given , with particular attention to stability of asthma as indicated by peak flow charts, intercurrent illness, reaction to the last injection and any change in medication. Spirometry or peak flow meter readings must be taken before injection and, if more than 20% below the best recent recorded reading for that patient, the injection should not be given. The readings should be repeated 30 minutes after the injection and immediately any lower respiratory symptoms arise during the period of observation -- a fall of 10% or more is an indication for reducing the dose of the next injection. The medical practitioner must be responsible for selecting the dose and having it checked by a second health professional. Injections are given subcutaneously, a suitable site being the tissue overlying the triceps muscle group. After introducing the needle, and before starting the injection, the plunger should be withdrawn gently to ensure that the needle is not placed intravenously. There is no consensus about the optimal time that a patient must remain under observation . However, we recommend 45 minutes, as serious reactions after that time are rare. Reactions may be delayed with alum-precipitated preparations but they are usually minor. Before discharge patients should be examined to record the size of the local reaction, ensure that there are no signs of a systemic reaction, and to repeat spirometry or peak flow readings. Patients must not engage in strenuous physical exercise or take hot baths or saunas for six hours after the injection. Patients should monitor their peak flow at home ; excessive variability would indicate a need for re-evaluation of asthma and immunotherapy. A local swelling larger than 50 mm requires a reduction in dosage. Patients should be instructed to measure the diameter of any local reaction should it increase in size after leaving medical supervision, and report this before the next injection. Some practitioners "cover" therapy by giving prophylactic antihistamines to reduce the local reactions. This practice may make it difficult to judge the effects of therapy, both locally and systemically, and to modify dosage accordingly. It may also block the initial manifestations of an anaphylactic reaction. Use of this practice is a matter of judgement, but if prophylactic drugs are used use must be consistent. Injection schedules vary with individual patients, but the Allpyral preparations are administered every 1-2 weeks until a maintenance dose is reached. Maintenance injections are administered every 2-4 weeks. It should be re-emphasised that immunotherapy schedules are individualised and fixed schedules are not recommended, particularly when aqueous extracts, which are becoming more readily available in Australia, are used. The duration of therapy for optimal management is unknown at present. With bee and wasp venom immunotherapy, there is evidence that five years of maintenance injections will provide long term protection in almost all patients. There is no corresponding evidence in inhalant allergy and practice varies. Dust mite injections are often continued for 2-3 years if there is a response, and preseasonal immunotherapy with grass pollen is repeated for 2-3 years. References Position paper on allergen immunotherapy. Report of a BSACI Working Party. Clin Exp Allergy 1993; 23 Suppl 3: 1-44. WHO/IUIS Working Group Report. Current status of allergen immunotherapy. Lancet 1989; 1: 259-261. Position paper: immunotherapy. The European Academy of Allergology and Clinical Immunology (EAACI). Allergy 1993; 48 (14 Suppl): 9-35. Platts-Mills TAE. Allergen-specific treatment for asthma. Am Rev Respir Dis 1993; 148: 553-555. Lockey RF, Bukantz SC, editors. Allergen immunotherapy. New York: Marcel Dekker, 1991. Walls RS. Desensitisation injections: do they have a role? Aust Prescriber 1989; 12: 90-92. Bousquet J, Michel F-B. Specific immunotherapy in asthma: is it effective? J Allergy Clin Immunol 1994; 94: 1-11. Malling H-J. Immunotherapy in Europe. Clin Exp Allergy 1994; 24: 515-521. Greenberger PA, editor. Immunotherapy of IgE-mediated disorders. Immunol Allergy Clin North Am 1992; 12: 1-203. Sporik RB, Chapman MD, Platts-Mills TAE. House dust mite exposure as a cause of asthma. Clin Exp Allergy 1992; 22: 897-906. Gelber LE, Seltzer LH, Bouzoukis JK, et al. Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital. Am Rev Respir Dis 1993; 147: 573-578. Corrigan CJ, Kay AB. T cells and eosinophils in the pathogenesis of asthma. Immunol Today 1992; 13: 501-506. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; 1: 520-524. Lenfant C. Global initiative for asthma: global strategy for asthma management and prevention. NHLBI/WHO Workshop Report. Bethesda, Md.: National Institutes of Health, January 1995. (Publication No. 95-3659.) O'Brien RM, Byron KA, Varigos GA, Thomas WR. House dust mite immunotherapy results in a decrease in Der p2-specific IFN- g and IL-4 expression by circulating T lymphocytes. Clin Exp Allergy 1997; 27: 46-51. Rak S, Bjornson A, Hakanson L, et al. The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure. J Allergy Clin Immunol 1991; 88: 878-888. Nagata M, Shibasaki M, Sakamoto Y, et al. Specific immunotherapy reduces the antigen-dependent production of eosinophil chemotactic activity from mononuclear cells in patients with atopic asthma. J Allergy Clin Immunol 1994; 94: 160-166. Asthma management handbook. 2nd ed. Melbourne: National Asthma Campaign, 1996. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of randomised controlled trials. Am J Resp Crit Care Med 1995; 151: 969-974. Bousquet J, Hejjaoui A, Soussana M, Michel F. Double-blind placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid. J Allergy Clin Immunol 1990; 85: 490-497. Haugard L, Dahl R. Immunotherapy in patients allergic to cat and dog dander. I. Clinical results. Allergy 1992; 47: 249-254. Alvarez-Cuesta EJ, Cuesta-Herranz J, Puyana-Ruiz J, et al. Monoclonal antibody-standardised cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. J Allergy Clin Immunol 1994; 93: 556-566. Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med 1996; 334: 501-506. Adkinson NF, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med 1997; 336: 324-331. Bjšrksten B. Local immunotherapy is not documented for clinical use. Allergy 1994; 49: 299-301. Crimi E, Voltolini S, Troise C, et al. Local immunotherapy with Dermatophagoides extract in asthma. J Allergy Clin Immunol 1991; 87: 721. Committee on Safety of Medicines. CSM update. Desensitising vaccines. BMJ 1986; 293: 948. Warner JO, Kerr JW. Hyposensitisation. BMJ 1987; 294: 1179-1180. Stewart GE, Lockey RF. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol 1992; 90: 567-578. Katelaris CH, Walls RS. A study of possible ill effects from prolonged immunotherapy in treatment of allergic diseases. Ann Allergy 1984; 53: 257-261. Authors' details The Thoracic Society of Australia and New Zealand, Melbourne, VIC. Reprints: Dr P I Field, Honorary Secretary, 145 Macquarie Street, Sydney, NSW 2000. Australasian Society of Clinical Immunology and Allergy, Melbourne, VIC. No reprints will be available. Correspondence: Dr D Gillis, Honorary Secretary, PO Box 204, Mt Albert, VIC 3127. <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.