Immune system diseases

For Debate Disease control in the information era Robert M Douglas MJA 2001; 174: 241-243 Abstract - Information technology - Ownership, privacy and access - Aggregation of individual records - Conclusion - Acknowledgements - References - Authors' details - - More articles on Infectious diseases and parasitology Abstract As a result of advances in information technology, there is now a new capacity to manage, interpret and apply data for the benefit not only of individual patients but of the population as a whole. Population health information systems are currently inadequate to meet the needs of disease control. In a rapidly changing world, effective public health action requires timely and efficient data about what is happening in the whole population. As the national effort to harness information technology to the needs of individual patient care begins, it is desirable that the electronic patient record also becomes the building block for public health research and monitoring. Individual healthcare and population healthcare should be two sides of the one coin. Ownership, privacy and access to the contents of the electronic health record should now be addressed in the context that disease control in the whole population will increasingly depend upon an efficient "real time" information system. In the past 50 years, vaccination and antibiotics have transformed our capacity to manage human infections. Biotechnology is now opening up new possibilities for managing the human genome. Our capacity to change individual patient outcomes through modern clinical treatment rightly commands headlines and attracts public resources. But control of disease in the population as a whole requires more than individual clinical action. Last1 has emphasised that the systematic control of any disease requires a consensus that a particular disease problem exists; an understanding of its cause; the ability to control its cause; a belief that the problem matters; and the political will to control it. Good information systems are essential to support all of these requirements. The relevance of information to disease control is well illustrated by the contrast in management of two communicable disease groups, HIV and respiratory infections. HIV incidence rates are declining in Australia2 at a time when those in other nations, particularly African countries,3are rising. This apparent success is believed to be at least partly attributable to a widely supported national control program that was begun in 1989.4 The program promoted broad community understanding of the nature of the disease and a shared commitment by stakeholders and governments to contain the problem. Unlikely coalitions were formed between scientists, risk groups and community representatives, and the entire community was involved in approaches that were pragmatic as well as innovative. As the epidemic progressed, research focused not only on the behaviour of the virus, but also on the behaviour of the humans who transmitted it. A central ingredient of the HIV public health strategy was the development of an excellent information system at a time when information about other diseases was (and continues to be) in disarray. The data system developed by the National Centre for HIV Epidemiology and Clinical Research helped the nation to view the HIV epidemic as a population problem rather than an individual issue, and enabled the public health community to monitor its progress, and modulate the public health response accordingly. In stark contrast, infections of the respiratory tract, which dominate the clinical experience of primary care practitioners everywhere5 and cause extensive morbidity and absenteeism, are not matched by any systematic national effort to contain them. Perhaps, as they now rarely cause death, we have become complacent about them. Yet, on average, all Australians experience two to three acute respiratory episodes per year and in early childhood the average is five to eight. Apart from the misery they cause, these infections result in widespread misuse of antibiotics and the serious threat of antibiotic ineffectiveness in the longer term.6 It is remarkable that in this field Australia has no public health strategy, no national commitment to the problem, inadequate preventive effort, and no program of either social or biological research. Common respiratory infections are left to patients, clinicians and pharmacists, despite the magnitude of the problem and the negative impact of antibiotic abuse. We tolerate a level of morbidity and misapplication of resources to respiratory infections that does not make public health sense. We collect no systematic information about the problem, and can only guess at its cost to the community. The lack of available information means that the public health perspective is not addressed. Information technology Unlike the banking and tourism sectors, the healthcare sector has not yet harnessed the electronic information revolution to the needs of either individuals or populations. It is time we re-examined the issue of information in healthcare in the light of the new opportunities created by modern technology. Australian health ministers have recently agreed to establish a national health information network built on electronic health records that, through data linkage, can enhance the quality of individual patient care.7 For individual clinical care, which often involves many agencies and professionals, linkage of electronic records is essential to avoid duplication and to ensure that an individual's medical history is accessible and complete wherever the person presents for care (see Box). Because of modern transport and human mobility, fragments of a patient's history may be scattered in many places. Modern technology now permits linkage of data that are "warehoused" in multiple, geographically dispersed electronic sites. At this early developmental stage it is essential that the new system be designed to serve the needs not only of individual patients and their clinicians, but also of organisations concerned with public health monitoring, research and administration. The personal electronic health record, however it is stored and accessed, should also be the building block for "real time" public health surveillance. Improved efficiency of personal clinical care and improved management of public health both require the same data and should become two sides of the one coin. When a patient presents for care by a general practitioner for a respiratory infection or a manifestation of HIV, that information should also automatically become part of national public health monitoring activity. And when the laboratory reports to the GP that the respiratory infection is, or is not, a new strain of influenza that fact should, as well as informing the clinician instantly, feed into a national database that informs public health action. Ownership, privacy and access The development of a national integrated health record and information system poses a range of logistic, ethical, privacy and professional issues. These need to be resolved during the system design phase so that a "rail-gauge" problem (ie, one of incompatibility) does not develop between the States, between the public and private healthcare systems, or between the outputs to clinicians and public health practitioners. A well designed and protected retrieval system would offer major benefits for disease prevention and control in the population as a whole. We need to break out of the mentality that sees medical records as being "owned" and controlled by doctors or hospitals. When a patient contracts for medical care from a doctor, the record that is prepared is paid for jointly by the patient and the community. They, jointly, should be the owners and controllers of the electronic record. Because elements of individual experience are pertinent to the health of the whole community, and because the vast majority of healthcare costs are met by the community, it is important that individual experiences be aggregated to inform public health action. Privacy and confidentiality must be protected and respected, but so also must public good. One can not be allowed to drown out the other. Access to an individual patient record should be controlled by the patient using a unique identifier, such as a thumbprint. An individual's records could be linked by Medicare number with repositories of individual data stored in multiple data warehouses that are themselves linked by the Internet. Through the use of a thumbprint and an access command, patients could authorise different healthcare providers to access different parts of their medical record. While a GP or medical specialist might be given access to the entire record, pharmacists might simply be given access to medication records. Mechanisms to ensure that access to identifiable data is precisely limited and carefully monitored should be part of the system specification. Aggregation of individual records Having created a comprehensive linked record for each person, it is desirable that the individual records become instantly accessible building blocks for defined administrative, monitoring and research databases. Those who use the aggregated datasets to monitor the health of the community should be denied access to personal identifiers, and should not need informed consent to make use of the de-identified data. If analysis of de-identified data revealed new community threats, access to the identification of individuals would be required in the interests of those individuals and of the public. In these circumstances, access protocols would be needed, backed up by audit trails, the right of redress for consumers in the event of misuse, and legal protection for public health practitioners who operate within carefully defined parameters. There are thoroughly reasonable concerns that in the process of aggregation privacy and confidentiality might be compromised. These concerns would need to be addressed in system design. Nevertheless, few systems are absolutely foolproof, and the design would need to include audit trails and monitoring systems to ensure that abuse could be traced and dealt with. Imperfection in this area has not prevented the banking industry from capitalising on the benefits of the new technology, and it should not justify inaction in the sphere of healthcare. Conclusion Currently, Australia's healthcare information systems are inadequate and, partly as a consequence, public health action is seriously deficient. Efficient, real-time information systems are a starting point for effective public health. Public health action can profoundly benefit the whole community by reducing the incidence of disease and the need for clinical care. It makes no more sense to plan public health action without high quality data than it does to prescribe a drug for hypertension without measuring blood pressure. It is essential that as we move towards electronic storage of health records we simultaneously address the public health need for a vastly improved body of data. Acknowledgements This is an edited version of the Sidney Sax Oration, presented to the ACT Branch of the Public Health Association of Australia, 10 August 2000. I am grateful to Dr Chris Mount for comments on the manuscript and for collaboration on many of the ideas discussed in this article, and to Jacquie Steele for preparation of the manuscript. References Last, J. Fouling and cleansing our nest: human-induced ecological determinants of infectious disease. Perspect Hum Biol 1999; 4: 145-147. Law MG, Li Y, McDonald AM, et al. Estimating the population impact in Australia of improved antiretroviral treatment for HIV infection. AIDS 2000; 14: 197-201. Ziegler JB, Ffrench RA. XIII International AIDS Conference, Durban, 9-14 July, 2000 [conference report]. Med J Aust 2000; 173: 572-574. Commonwealth of Australia. AIDS. A time to care: a time to act. Towards a strategy for Australians. Canberra: AGPS, 1988. Douglas RM. Respiratory tract infections as a public health challenge. Clin Infect Dis 1999; 28: 192-194. Schwartz, B. Preventing the spread of antimicrobial resistance among bacterial respiratory pathogens in industrialized countries: the case for judicious antimicrobial use. Clin Infect Dis 1999; 28: 211-218. National Electronic Health Records Taskforce. A health information network for Australia. Canberra: Commonwealth of Australia, 2000. Authors' details National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT. Robert M Douglas, MD, FRACP, FAFPHM, Visiting Fellow. Reprints will not be available from the author. Correspondence: Professor R M Douglas, National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT 0200. Bob. DouglasATanu.edu.au Electronic health records as the building blocks for a national health information system Future electronic health records are likely to include the following information on a patient: -- summary of previous medical history; -- current problems; - medications prescribed and dispensed; -- laboratory and radiological results; -- hospital discharge summaries; -- care plans and record of use of community care; -- allergies and adverse reactions; -- elements of social and demographic history. All data for an individual patient should be linked by a common identifier to ensure accuracy and improve safety. Clinical access to the electronic record should be authorised by the patient, and the national system should make it deliverable anywhere in Australia. Patient data should automatically feed into specifically designed national datasets that monitor various elements of the nation's health and can provide information for public health action. Protection of privacy and confidentiality must be designed into the system. Back to text

Robert M Douglas

Healthcare Adverse events associated with rush Hymenoptera venom immunotherapy Glen P Westall, Frank C K Thien, Dan Czarny, Robyn E O'Hehir and Jo A Douglass MJA 2001; 174: 227-230 Abstract - Methods - Results - Discussion - References - Authors' details - - More articles on Immunology and allergy Abstract Objectives: To determine the incidence and nature of adverse events associated with the induction of rush Hymenoptera venom immunotherapy. Design: Retrospective descriptive case study. Setting: The asthma and allergy unit at a major metropolitan teaching hospital, between 1 January 1989 and 30 June 1999. Patients: All patients with anaphylaxis to stings of Hymenoptera insects who received rush venom immunotherapy as inpatients. Outcome measures: Hypersensitivity reactions to venom administration, including angioedema, skin rashes, hypotension and asthma, as well as any other adverse events related to the inpatient stay. Results: 68 venom-allergic patients received 73 courses of rush immunotherapy; 89% were desensitised to honey bee venom, 10% to yellow jacket wasp venom, and one to paper wasp venom. Hypersensitivity reactions occurred after 36 subcutaneous injections (3.8% of all injections given) in 26 patients (38%). Conclusion: In our cohort, immunotherapy was accompanied by a high incidence of adverse systemic events during the induction phase. Immunotherapy should only be given by experienced staff in centres where there are facilities for resuscitation. Stinging-insect anaphylaxis is most often caused by bee and wasp stings, but may also occur as a reaction to ants, march flies, ticks and other insects.1 The insect order Hymenoptera includes the vespids (yellow jacket or European wasp, and paper wasps) and the apids (honey bees). Clinical manifestations after wasp and bee stings include hypersensitivity reactions that can be fatal. There is a minimal degree of immunogenic cross-reactivity between bee and wasp venoms.2 Australian Bureau of Statistics mortality figures after bee stings give a rate of 0.086 per million population per year, or approximately one death per year.3An anaphylactic reaction to insect venom is an absolute indication for venom immunotherapy (see Box 1), as this is protective in more than 80%-90% of individuals in preventing future severe reactions.4 The first commercial venom extracts became available in 1979 and since then indications and treatment schedules have been refined. A number of different dosing schedules for immunotherapy are used, including conventional (induction immunotherapy over several weeks as an outpatient), rush (induction over several days) and ultrarush (induction over several hours) immunotherapy.5-7 In rush protocols, patients are given higher venom doses in a shorter period of time compared with conventional protocols, reaching maintenance dose (100 µg) more quickly and thus offering the patient earlier protection.8 At our allergy clinic, patients usually receive rush immunotherapy. We performed a retrospective analysis of case records of insect-allergic patients to describe and ascertain the incidence of adverse events associated with inpatient rush Hymenoptera immunotherapy. Methods We chose the period 1 January 1989 to 30 June 1999 for our retrospective, descriptive study. Patients were identified by searching hospital records of discharge diagnosis, and we reviewed the records of all patients admitted to the Alfred Asthma and Allergy Unit for rush venom immunotherapy. The cohort therefore represented a highly selected group of venom-allergic individuals. The field sting that caused anaphylaxis was classified according to the system proposed by Mueller (Box 2).9 The causative insect was identified from the history and subsequently confirmed by detection of serum-specific IgE by skin-prick tests or blood-specific IgE serological testing.10 If blood-specific IgE tests were negative or unavailable, venom-specific IgE was sought by skin-prick tests with 100 µg/mL of honey bee, yellow jacket wasp and paper wasp venom; if these tests were negative patients underwent intradermal testing to serial 10-fold dilutions of venom. For diagnosis and immunotherapy, a freeze-dried venom of honey bees (Apis mellifera), paper wasps (Polistes sp.), or yellow jacket wasps (Vespula sp.) was reconstituted in albumin-saline (Bayer Australia Ltd, Pymble, NSW). Patients then had immunotherapy with the venoms corresponding to their sensitivity. Patients were treated over five days as inpatients at the Alfred Hospital, where full emergency resuscitation facilities were available, and with intravenous access being maintained at all times. Escalating doses of venom (0.1 µg to 100 µg) were injected subcutaneously. A total of 13 injections were given 60 minutes apart, and a nurse closely observed the patient after each injection. The patient's general practitioner continued maintenance immunotherapy according to a protocol provided by the Asthma and Allergy Unit. For patients who were unable to attain the recommended maintenance dose of 100 µg of venom, the patient's GP was provided with a treatment schedule on how to increase the dose, up to the maintenance dose. We compared the group of patients who developed hypersensitivity reactions to venom during the course of their induction immunotherapy with a group of patients who had no such reaction to look for any predictive variables. For each group, mean age, sex, stinging insect, severity of initial reaction, atopic status, presence of asthma, and blood-specific IgE to stinging insect was compared. Statistical analysis Statistical analysis was performed with the SAS software package.11 Means and proportions were compared by standard tests (χ2, t tests and Wilcoxon 2-sample test). The 0.05 level of significance was used throughout the analysis and all P values reported are two-sided. Ethical approval The study was approved by the Alfred Hospital Ethics Committee. Results Clinical features Patient demographics and clinical features are shown in Box 2. During the study period, 68 venom-allergic patients received a total of 73 courses of rush immunotherapy (949 injections). When asked about the causative stinging insect, 58 patients identified honey bee, six identified yellow jacket wasp and one identified the paper wasp. All of these responses were confirmed with either positive skinprick tests or blood-specific IgE testing to the same insect. Only three patients could not identify the stinging insect. Of the five patients who received two courses of immunotherapy, two initially complied poorly with the initial course and developed severe anaphylaxis when they were stung again, and three patients ran out of maintenance bee venom during a national shortage. One patient who was taking a β-blocker (a contraindication to immunotherapy) changed to an alternative antihypertensive medication before beginning immunotherapy. Immunotherapy Complications during treatment were recorded as being either IgE mediated (hypersensitivity reaction) or non-IgE mediated (no hypersensitivity reaction); details are shown in Box 3. Allergic complications occurred at all stages of the rush protocol. All patients developed local reactions at the site of injection. Systemic hypersensitivity reactions occurred after 36 of the 949 injections (3.8%) in 26 of the 68 patients (38%). Recurrent adverse reactions prevented 14% of individuals attaining the recommended maintenance dose (100 mg) during their hospital admission. Among patients who had non-IgE-mediated complications, two developed gram-negative sepsis, possibly from infected intravenous sites, and one was initially incorrectly given paper wasp rather than yellow jacket wasp venom. Discussion We found that allergic adverse events during rush immunotherapy were common, occurring in 38% of patients treated, with a risk of allergic reaction per immunotherapy injection of 3.8%. There are very few Australian reports looking at the management of insect venom allergy;1,3,12,13 most such reports come from the United States and Europe.6,14-17 The most striking difference between our findings and those of overseas studies was in the causative insect. In the US and Europe, most courses of insect immunotherapy are prescribed for wasp allergy, while we found that almost 90% of people assessed for desensitisation in our unit had honey bee allergy. This marked difference most likely reflects Australia's geographical location and thus differing local fauna. In particular, the European (yellow jacket) wasp has only been common in Australia in the past 10 years. The importance of this observation relates to marked differences in the efficacy and the rates of adverse events of bee and wasp immunotherapy.18 In our study, the risk of an allergic adverse event and the rate of administration of adrenaline per injection (1.4%) are higher than those reported in other centres that use rapid immunotherapy regimens.6,14-19 However, we treated a considerably higher proportion of patients with honey bee venom than these centres. This is relevant because previous reports have described a higher incidence of side effects in patients treated with honey bee venom owing to its greater potency,4 and our findings support these conclusions. A second explanation for the increased use of adrenaline may lie in our unit's policy of early identification and aggressive treatment of any allergic reactions to venom preparations. Previous investigators have shown that there is a strong correlation between a severe initial sting (Mueller grade IV) and subsequent propensity to develop hypersensitivity reactions after deliberate sting challenges.20 We found no correlation between an initial Mueller grade IV sting and subsequent likelihood of developing anaphylaxis during immunotherapy (P = 0.63). As in other studies looking at predictors of side-effects during treatment,18 we found no association with atopic status or the serum level of venom-specific IgE. The trend for increased adverse events in females that we observed has been previously reported,4,18 despite a predominance of males receiving desensitisation therapy. The finding that two patients developed gram-negative septicaemia led us to introduce a policy of moving the intravenous cannula every 48 hours. One problem with treating insect stings described in the literature is the importance of correctly identifying the stinging insect. This was not a significant problem with our cohort, with only three patients being unsure of the insect at their initial assessment. This may reflect the presence of a "stinger" at the sting site being indicative of honey bee stings and thus aiding identification.21 Over the period examined, 68 patients were treated with a rush immunotherapy protocol, with 86% of patients reaching maintenance dose by the time they were discharged. The maintenance dose is reached within a few days with rush therapy, compared with three months with conventional regimens. The safety and cost-effectiveness of rush therapy have been previously documented,22 and tolerance to rush immunotherapy has been reported to be equal to or better than that for conventional protocols.7 Because allergic reactions occurred within one hour of each injection, we advise general practitioners who administer maintenance injections to observe patients for an hour after each injection. In conclusion, our retrospective review of rush immunotherapy shows a large proportion of reactions to honey bees in Australia compared with Europe and the USA. However, there are only minimal differences in diagnosis, investigation and management compared with overseas practice. The incidence of adverse events during induction was more common with bee venom immunotherapy. Our rush protocol is convenient for the patients who often live in rural areas and would find weekly trips to our unit for outpatient immunotherapy disruptive. Our results support the recommendations that Hymenoptera venom immunotherapy should only be given by experienced staff, in centres where there are facilities for resuscitation.23 References Solley GO. Allergy to sting and biting insects in Queensland. Med J Aust 1990; 153: 650-654. Reisman RE, Mueller UR, Wypych JI, Lazell MI. Studies of co-existing honeybee and vespid venom sensitivity. J Allergy Clin Immunol 1984; 73: 246-252. Harvey P, Sperber S, Kettle F, et al. Bee sting mortality in Australia. Med J Aust 1984; 140: 209-211. Müller U, Helbling A, Berchtold E. Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety. J Allergy Clin Immunol 1992; 89: 529-535. Golden DBK, Valentine MD, Kagay-Sobolka A, Lichtenstein LM. Regimens of hymenoptera venom immunotherapy. Ann Intern Med 1980; 92: 620-624. Nataf P, Guinnepain MT, Herman D. Rush-venom immunotherapy: a 3-day programme for hymenoptera sting allergy. Clin Allergy 1984; 14: 269-275. Van der Zwan JC, Flinterrman J, Jankowski IJ, Kerckhaert JA. Hyposensitisation to wasp venom in six hours. Br Med J 1983; 287: 1329-1331. Gillman SA, Cummins LH, Kozak PP, Hoffman DR. Venom immunotherapy: comparison of "rush" vs "conventional" schedules. Annals of Allergy 1980; 45: 351-354. Mueller HL. Diagnosis and treatment of insect sensitivity. J Asthma Res 1966; 3: 331-333. American Academy of Allergy Committee on Insects. In: Levine MI, Lockey RF, editors. Monograph on insect allergy. Library of Congress Catalog Publication Data. Hartland, Wis: Parker Printing of Hartland, 1981. SAS statistical package [computer program]. Version 6.12. Cary, NC: SAS Institute, 1996. Roberts-Thompson PJ, Harvey P, Sperber S, et al. Bee sting anaphylaxis in an urban population of South Australia. Asia Pac J Allergy Immunol 1985; 3: 161-164. Lui CL, Heddle RJ, Kupa A, et al. Bee venom hypersensitivity and its management: patients perception of venom desensitisation. Asia Pac J Allergy Immunol 1995; 13: 95-100. Birnbaum J, Charpin D, Verloet D. Rapid Hymenoptera venom immunotherapy. Comparative safety of three protocols. Clin Exp Allergy 1993; 23: 226-230. Thurnheer U, Müller U, Stoller R, et al. Venom immunotherapy in Hymenoptera sting allergy. Comparison of rush and conventional hyposensitization and observations during long-term treatment. Allergy 1983; 38: 465-475. Bousquet J, Muller UR, Dreborg S, et al. Immunotherapy with Hymenoptera venoms. Allergy 1987; 42: 401-413. Bernstein DI, Mittman RJ, Kagan SL, et al. Clinical and immunologic studies of rapid venom immunotherapy in Hymenoptera-sensitive patients. J Allergy Clin Immunol 1989; 84: 951-959. Youlten LJ, Atkinson BA, Lee TH. The incidence and nature of adverse reactions to injection immunotherapy in bee and wasp venom allergy. Clin Exp Allergy 1995; 25: 159-165. Yunginger JW, Paull BR, Jones RT, Santrach PJ. Rush immunotherapy programs for honeybee sting sensitivity. J Allergy Clin Immunol 1979; 63: 340-347. van der Linden PW, Struyvenberg A, Kraaijenhagen RJ, et al. Anaphylactic shock after insect-sting challenge in 138 persons with a previous insect-sting reaction. Ann Intern Med 1993, 118: 161-168. Visscher PK, Vetter RS, Camazine S. Removing bee stings. Lancet 1996; 348: 301-302. Bernstein JA, Kagen SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with hymenoptera anaphylaxis. Ann Allergy 1994; 73: 423-428. Committee on the Safety of Medicines. CSM update: desensitising vaccines. BMJ 1986; 293: 948. (Received 11 Sep 2000, accepted 18 Jan 2001) Authors' details Department of Allergy, Asthma and Clinical Immunology, The Alfred and Monash University, Melbourne, VIC. Glen P Westall, MRCP, MB BS, Registrar; Frank C K Thien, FRACP, MD, Physician; Dan Czarny, FRACP, FRCP, Physician and Associate Professor; Robyn E O'Hehir, FRACP, PhD, Professor and Director; Jo A Douglass, FRACP, MD, Head, Asthma and Allergy Unit. Reprints will not be available from the authors. Correspondence: Dr J A Douglass, Department of Allergy, Asthma and Clinical Immunology, The Alfred and Monash University, Commercial Road, Prahran, VIC 3181. j.douglassATalfred.org.au 1: Indications for venom immunotherapy (adults) Type of reaction Venom- specific IgE Venom immunotherapy Severe systemic life-threatening Positive Yes Moderate systemic (angioedema, asthma, etc) Positive Allergist review Mild systemic (urticaria, pruritus) Positive No Large local Positive No Any type of reaction Negative* No *Blood-specific IgE tests to venom have a false negative rate of approximately 10%, so patients whose blood test results are negative but who have histories suggestive of venom allergy should have appropriate skin tests. Back to text 2: Clinical data of patients who received stings Bee Wasp Number of patients 60 (88%) 8 (12%) Sex Males 47 (78%) 4 (50%) Females 13 (22%) 4 (50%) Median age (years) 37 45.5 Range (years) (13-66) (22-71) Atopic 23 (38%) 1 (12.5%) Asthmatic 10 (17%) 0 Blood-specific IgE test score (mean of 4)* 2.8 2.2 Grade of sting† I 2 (3%) 0 II 11 (18%) 0 III 15 (25%) 4 (50%) IV 32 (53%) 4 (50%) No. of immunotherapy injections 845 104 Hypersensitivity reactions Number of injections 35 (4.1%) 1 (1%) Number of patients 25 (42%) 1 (12.5%) Grade of hypersensitivity reaction* I 21 0 II 4 0 III 7 0 IV 3 1 Adrenaline required Number of injections 12 (1%) 1 (1%) Number of patients 11 (18%) 1 (12.5%) *Blood-specific IgE scored as class 0, 1, 2, 3 or 4. †Mueller et al:9 Grade I - urticaria, pruritus, malaise; Grade II - angioedema, chest tightness, nausea, vomiting, abdominal pain, dizziness; Grade III - dyspnoea, wheeze, stridor, dysphagia, hoarseness; Grade IV - hypotension, collapse, loss of consciousness, incontinence, cyanosis. Back to text 3: Clinical data on patients who developed hypersensitivity reactions (HR) compared with those who had no adverse reactions Cohort with HR Cohort with no HR P Number 26 47 Mean age (years) 33.5 40.3 < 0.05 Sex Males 18 (69%) 36 (77%) NS Females 8 (31%) 11 (23%) Grade of sting (mean of 4) 3.3 3.3 NS Atopic 10 (38%) 10 (21%) NS Blood-specific IgE test (mean of 4)* 2.7 2.9 NS Bee immunotherapy 25 (42%) 35 (58%) NS Wasp immunotherapy 1 (12.5%) 7 (87.5%) NS NS=not significant. *Blood-specific IgE scored as class 0, 1, 2, 3 or 4. Back to text

Glen P Westall · Dan Czarny · Robyn E O'Hehir · Jo A Douglass

The Research Enterprise Exploring the unknown: the challenges of a career in biomedical research Gordon L Ada Gordon Ada reminisces on his career as a researcher and a facilitator MJA 2000; 173: 612-615 Getting started - Walter and Eliza Hall Institute, Melbourne - John Curtain School of Medical Research, Canberra - World Health Organization, Geneva - Retirement projects - The take-home message? - References - Authors' details - - More articles on Immunology and allergy The attractions of a career in research are many, but first among these is the opportunity to be involved in important discoveries, either personally or though close association with other researchers. Experimenting first with viruses and then in immunology at the Walter and Eliza Hall Institute (1948-1968) was a great start. Later, by becoming head of a world-class microbiology department at the John Curtin School of Medical Research at the Australian National University, I was able to establish an environment that spawned important discoveries in medical science. Getting started I had a happy childhood. I was the fourth in a family of six children -- three boys and three girls. My father studied electrical engineering at Sydney University and later became a senior executive with the New South Wales Railways, but my mother had to leave school early when her mother died. When I entered Sydney University in 1940, my aim was to study biochemistry, having received a fascinating book the previous Christmas -- The science of life, by H G Wells, Julian S Huxley and G P Wells. My years at university might not have been so enjoyable if Jack Still had not returned to Sydney University in 1941 from Gowland Hopkins' Biochemistry Department at Cambridge. He enthused us with stories about the exciting research being done there. My first research position at the Commonwealth Serum Laboratories (CSL) (1944-1946), studying ways of stabilising human serum and avoiding denaturation, convinced me of the need for new techniques to isolate and study individual proteins. I applied for leave from CSL to work at the National Institute of Medical Research in London, where moving-boundary electrophoresis and ultracentrifugation were being used for this purpose. This request, although supported by the Director of CSL, Frederick G Morgan, was refused at a higher level, so I resigned, travelled to England, and worked unpaid at the Institute with Arthur S McFarlane, Head of the Biophysics Department. After a few months, McFarlane recommended my paid appointment to the research staff. Walter and Eliza Hall Institute, Melbourne In the early 1940s, Macfarlane Burnet, Director of the Walter and Eliza Hall Institute (WEHI), on a visit to Harvard University to give the Dunham Lectures, saw the need for his institute to gain these new techniques for studying proteins. He obtained a government grant of £20 000 to establish the technologies (including, later, electron microscopy) at the WEHI. As there was no expertise in Australia, Burnet invited me to join the staff at the WEHI and, with the senior biochemist, Henry Holden, to set up moving-boundary electrophoresis and ultracentrifugation. I arrived back in Australia in August 1948. Fortunately, Holden did much of the establishing and I was able to spend most of my time on research. I became a virologist, working mainly with influenza and later Murray Valley encephalitis viruses, studying their composition and biological properties. I crystallised the Vibrio cholerae neuraminidase. In 1957, after publication of his clonal selection theory,1 Burnet decided to phase out virology in favour of immunology at the Institute. In 1962, I decided to make the switch and, after much reading, began studying immune responses, in particular the fate of tiny amounts of antigen (using the highly immunogenic Salmonella flagella and flagellin labelled with radioactive iodine) to establish the nature and location of cells which bind antigen. Because of my general ignorance of this field, I asked Gus Nossal, then the Deputy Director (Immunology) at the Institute, to help me get started. He kindly agreed, but, when the first autoradiographs showing localisation of antigen over rat primary lymphoid follicles (Box 1) were so striking, Gus decided to collaborate full-time. When presented at a meeting in the United States, our findings ranked a column in the New York Times. The next six years studying the fate and role of antigen during primary and secondary immune responses were like a taste of researcher's heaven, and Gus was a great colleague. We studied the role of antibody in antigen localisation and demonstrated the absence of antigen in antibody-forming cells. Burnet later wrote: What I can be certain about however, is the immense importance of the work on the cellular localisation of antigen led by Ada and Nossal in the 1962-5 period.2 All these findings, together with studies on the influence of antigen structure on immunogenicity with a new PhD student, Chris Parish, were published individually and then finally woven into a monograph.3 John Curtain School of Medical Research, Canberra Despite the attractions of working at WEHI, an invitation to head a department with an international reputation in virology was too exciting to refuse, and in 1968 I succeeded Frank Fenner as Head of the Department of Microbiology at the John Curtin School of Medical Research. Although much was known about the humoral response to viral infections, knowledge about cell-mediated immune responses was almost non-existent. I reasoned that research projects combining both virological and immunological approaches, supported by basic research in both these fields, would surely lead to some exciting findings. This turned out to be the case. For example: In 1972 Chris Parish was the first to show the inverse relationship between antibody and cell-mediated immune responses, which led others to describe two classes of helper T cells. Bruce Stillman's studies on adenovirus in 1978 started him on the road to becoming Director of the renowned Cold Spring Harbor Laboratories in New York State. Robert Blanden was to lay the foundations for a major finding. Our department was acknowledged as a world leader in poxvirus research,4 and Blanden was studying the immune response to ectromelia, a poxvirus pathogenic for mice. In the next few years, using technology for assaying the newly discovered cytotoxic T cells gleaned from overseas meetings, Blanden, in late 1972, became the first to show that cytotoxic T cells would kill cells infected with ectromelia virus. But how did these cells recognise virus-infected cells? Early indications were that major histocompatibility (MHC) antigens were involved in some way, so some inbred mouse strains (members of the same strain having identical MHC antigen specificities) were imported to facilitate further studies. Peter Doherty came to the department as a postdoctoral fellow in 1972, and started work on lymphocytic choriomeningitis (LCM) virus infections of mice. In early 1973, Rolf Zinkernagel, a Swiss medical graduate, worked for a while with Blanden to learn about assaying cytotoxic T cell activity. I then asked Doherty and Zinkernagel to share the same laboratory, as they clearly had similar research interests. In some very elegant experiments, they found that cytotoxic T cells formed during an LCM viral infection would only lyse infected target cells if effector and target cells shared at least some MHC antigen specificities (ie, the T cell lytic activity was "MHC restricted"). They suggested that the cytotoxic T cell receptor recognised at the infected cell surface some virus-induced alteration of the MHC molecule, possibly caused by complexing with a viral antigen.5 They proposed the fundamental concept -- that a central function of MHC antigens on cells was to signal changes in "self", to what they now called "altered self", to the immune system.6 Once identified, such a cell would be lysed. This finding stimulated much research both in the department and elsewhere, and studies investigating the details of MHC restriction of T cell responses became a leading immunological topic internationally. Needless to say, Zinkernagel was awarded a PhD scholarship and graduated in record time. Both he and Doherty left to work overseas in the mid-1970s. Subsequently, analysis of crystals of MHC molecules, isolated from the surface of infected cells by US researchers, showed a viral peptide occupying a cleft in the MHC molecule so that parts of each were recognised by the cytotoxic lymphocyte receptor (Box 2). The award of the 1996 Nobel Prize in Physiology or Medicine to Rolf Zinkernagel and Peter Doherty (Box 3) recognised the importance of their original discovery, as it was the first description of the molecular mechanism used by vertebrates for the control and clearance of most intracellular infectious agents, especially viruses. World Health Organization, Geneva For 20 years, from 1971, I became associated with different World Health Organization programs, concerned mostly with the development and use of vaccines (Box 4). I was the first Chairman of the Programme for Vaccine Development (1984-1989), which is now a much larger WHO program with Gus Nossal as Chairman. These experiences focused my own research towards defining the roles of different components of the immune response to viral infections. Retirement projects As I approached retirement (December 1987), I was invited to do a six-month consultancy at WHO (to plan for a major review of studies on developing a vaccine to control pregnancy in women), to spend my retirement at Johns Hopkins School of Hygiene and Public Health in Baltimore, and to give the plenary lecture on The prospects for HIV vaccines at the Fourth International AIDS Congress in Stockholm in May 1988. I had never worked with HIV, but the Swedes apparently wanted an "independent" opinion. Stockholm By 1986, HIV RNA had been largely sequenced, and there was great optimism that a vaccine could be developed quickly. However, in the next two years, several disturbing findings were made, especially the very great sequence variation of the envelope antigen in different HIV isolates. There are three desirable properties of an infectious agent which can facilitate vaccine development (Box 5). At the Stockholm lecture,7 I listed seven reasons why it would be very difficult to develop an HIV vaccine based primarily on strong infectivity-neutralising antibody formation (Box 5). I then drew on recent research by two of my colleagues, David Boyle and Ian Ramshaw, at the John Curtin School of Medical Research. They had shown that DNA, coding for antigens of other infectious agents and of cytokines, could be inserted into the DNA of a poxvirus, such as vaccinia virus. Vaccination with this "chimeric" virus could protect against infection by the agent which was the source of the inserted DNA. I therefore suggested that, because the internal antigens of HIV (which are the source of many T cell epitopes) showed considerably less variation, a vaccine might be developed based on vaccinia virus containing the genes coding for the internal HIV antigens, gag and pol, as well as for the cytokine, interferon gamma.7 In mice, such a construct generated a strong cytotoxic T cell response; in man, this might be sufficient to better control, if not clear, an HIV infection. The 8000-strong audience was largely stunned by my assessment of the situation, although none subsequently disputed it. However, major vaccine manufacturers ignored it, determined to make an antibody-inducing subunit vaccine based on the HIV envelope antigen, a strategy driven by the success of the hepatitis B viral vaccine which contains the surface antigen of that virus. Baltimore and Washington On arrival in Baltimore in July 1988, I was warmly welcomed, made Associate Director of a new Center for AIDS Research and later became Director. In Washington, I was asked to participate in meetings and activities of the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Disease. In 1991, after three years in the United States, my wife and I decided to return to Australia, but I was invited to continue the relationship with DAIDS and to join a new HIV Vaccine Working Group. The crunch came in 1995, when the Director of the US National Institute of Allergy and Infectious Disease refused to support a Phase III clinical trial of the then leading HIV candidate vaccine, based on the envelope antigen. Many reasons were given, but two critical ones were: Antibody from volunteers immunised with this candidate vaccine did not prevent infection by newly isolated HIV field strains; and The vaccine did not induce cytotoxic T cell formation in the volunteers. This was a major turning point in international HIV vaccine research. The National Institute of Allergy and Infectious Disease completely revamped its HIV vaccine development program, and my hectic travel schedule to and from the United States came to an end. My last task for the Working Group was to review the evidence supporting a role for cytotoxic T cells in controlling HIV infections.8 Return to Canberra In 1991, I was appointed Visiting Fellow in the (now) Division of Immunology and Cell Biology at the John Curtin School and Chairman of the HIV Vaccine Working Group, one of the committees of the National Centre in HIV Epidemiology and Clinical Research in Sydney. Ian Ramshaw had recently shown that a vaccination schedule involving priming with plasmids containing DNA coding for selected antigens, followed by boosting with chimeric fowlpox virus coding for the same antigens, gave a greatly enhanced immune response in mice. Stephen Kent (now at the University of Melbourne) and Ramshaw and their colleagues showed that Macaca nemestrina monkeys immunised in this way developed a strong cytotoxic T cell response and rapidly cleared a subsequent HIV infection.9 Any antibody induced was irrelevant. Supporting findings for this approach were later reported from the United States. Now Australia was set to develop an HIV vaccine initiative based on this vaccination technology. At a meeting of the HIV Vaccine Working Group, David Cooper, Head of the National Centre in HIV Epidemiology and Clinical Research, was elected to head an Australian HIV Vaccine Consortium. In June this year, out of 20 international applications received, the National Institute of Allergy and Infectious Disease awarded four contracts, three to US groups and the fourth to the Australian consortium ($27 million over five years) to carry out clinical trials of their vaccine formulation. It is anticipated that a strong immune capability based on cytotoxic T lymphocyte activity will greatly reduce viral titres. Thus, those infected by HIV will live longer and be much less likely to infect others. If this vaccination technology can be shown to generate strong cytotoxic lymphocyte responses in humans, it heralds a new approach to controlling other difficult infectious diseases, such as malaria, trachoma and pelvic inflammatory disease, and even pandemic influenza. The take-home message? From a career path in biochemistry, I switched to virology, then to immunology and became an enthusiastic supporter for the application of immunisation technology, not only for the more difficult infectious diseases but also for non-communicable diseases. Young researchers should jump at the chance to switch fields when exciting opportunities arise. Acknowledgement: I wish to acknowledge with gratitude the great support of my wife, Jean Ada, during my career. References Burnet FH. A modification of Jerne's theory of antibody production using the concept of clonal selection. Aust J Sci 1957: 20; 67-69. Macfarlane Burnet I. Walter and Eliza Hall Institute, 1915-65. Melbourne: Melbourne University Press, 1971. Nossal GJV, Ada GL. Antigens, lymphoid cells and the immune response. New York: Academic Press, 1971. Fenner F. Nature, nuture and my experience with smallpox eradication. Med J Aust 1999; 171: 638-641. Zinkernagel RM, Doherty PC. Restriction of in vitro cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semi-allogeneic system. Nature 1974; 248: 701-702. Doherty PC, Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet 1975; 1: 1406-1409. Ada GL. Prospects for HIV vaccines. J Acquir Immune Defic Syndr 1988; 1: 295-303. Ada GL, McElrath MJ. Perspectives. HIV type-1 vaccine-induced cytotoxic T cell responses: potential role in vaccine efficacy. AIDS Res Hum Retoviruses 1997; 13: 243-248. Kent SJ, Zhao A, Best SJ, et al. Enhanced T-cell immunogenicity and protective efficacy of a human immunodeficiency virus type 1 vaccine regimen consisting of consecutive priming with DNA and boosting with recombinant fowlpox virus. J Virol 1998; 72: 10180-10188. Authors' details John Curtin School of Medical Research, Australian National University, Canberra, ACT. Gordon L Ada, AO, DSc, FAA, Emeritus Professor, and Visiting Fellow in the Division of Immunology and Cell Biology. Correspondence: Professor G L Ada, John Curtin School of Medical Research, P O Box 334, Canberra, ACT 2601. Make a comment 1: Antigen in the immune response Autoradiograph showing localisation of antigen over primary lymphoid follicles of rat popliteal lymph nodes, after footpad injection of Salmonella flagellin labelled with radioactive iodine. Back to text 2: The function of major histocompatibility antigens Schematic diagram of the cytotoxic T lymphocyte receptor recognition of the complex between the major histocompatibility antigen molecule and a nonapeptide derived from an infectious agent protein expressed on the surface of the infected cell. Back to text 3: At the 1996 Nobel Prize awards Evening banquet after the awarding of Nobel Prizes, Stockholm, December 1996. From left to right: Gordon Ada, Peter Doherty and Frank Fenner at the display of Nobel Prize medals and citations (photograph courtesy of Peter Pockley). Back to text 4: Involvement with World Health Organization programs 1971-1973 Member, Fellowship Selection Committee 1973-1976 Member, then Chairman (1975-1976), Scientific Council, International Agency for Research on Cancer, Lyons, France 1978-1984 Member, Scientific and Technical Advisory Committee, Tropical Diseases Research 1981-1984 Member, Global Advisory Committee on Medical (Health) Research 1984-1989 Chairman, Scientific Advisory Group of Experts, Programme for Vaccine Development. Member and later Consultant (1988), Vaccination Committee, Human Reproduction Programme 1985-1988 Member, Regional (Western Pacific) Advisory Committee on Health Research 1987-1989 Member, Research and Development Group, Expanded Programme on Immunization Back to text 5: Factors for and against the development of an effective vaccine Factors favouring the development of an effective vaccine Only one or a few strains of the infective agent exist; little or preferably no antigenic variation within a strain. Infective agent causes an acute infection; host completely recovers from a sublethal dose of the agent; agent does not persist. Agent is moderately (rather than highly) infectious. Factors militating against development of an effective vaccine (all these factors apply to HIV) Great antigenic variation; antigenic drift. Integration of viral DNA/cDNA into the host cell genome. Infection may be transmitted by cells which are latently infected. Immune enhancement: antibody can enhance infection of macrophages/monocytes if these cells are susceptible to infection. Agent infects cells in immunoprivileged sites in the host. Crucial cells of the immune system are infected, and either destroyed or their function is impaired. Failure to produce protective antibody and/or persisting cell-mediated immunity responses. Back to text

Gordon L Ada

Editorial Illness or disease? The case of chronic fatigue syndrome Not every illness can be defined as a disease before care and treatment should commence MJA 2000; 172: 471-472 Few disorders in modern medical practice generate such uncertainty and controversy as the enigmatic clinical condition known as chronic fatigue syndrome (CFS). Much of the difficulty surrounds the dominant reductionist paradigm of medical practice, which emphasises diagnostic tests, recognised pathophysiology, and established pharmacological and other physical treatments. Broader paradigms, incorporating other cultural and psychosocial perspectives, are crucial for clinicians who treat patients with this challenging disorder. Prolonged fatigue is reported by about 25% of all patients presenting to Australian general practice.1 Such fatigue states represent a continuum of severity ranging from the mild and transient symptoms generally attributable to intercurrent infection or minor mental disorder through to the more rare, severe and prolonged fatigue disorders. In about 1% of patients attending general practice, the fatigue state will meet diagnostic criteria for CFS (Box). Although most people present to their doctors with characteristic symptom patterns, current clinical practice relies heavily on diagnostic tests for accurate recognition of almost all disease states. Consequently, doctors frequently explain the patient's suffering in pathophysiological terms based on test results, and treatments are often provided to "fix the numbers" rather than the problem identified by the patient. While doctors readily provide specific treatments that have a firm evidence base, many have little interest in the kind of medicine that maximises non-specific therapeutic benefits, such as providing complex or aversive treatments and encouraging adherence to non-pharmacological interventions. This makes it difficult for patients with poorly defined disorders, or disorders without simple treatment options, to find suitable care. In addition, the increasing specialisation of medicine creates problems for those patients whose disorders do not fit within distinct subspecialty boundaries. Each of these issues contributes to the current dilemmas in managing people with CFS. Syndromal diagnoses were once common in clinical medicine and still persist in situations where disease processes are complex or obscure, such as systemic lupus erythematosus. Syndromal diagnoses are common in neurology (eg, migraine and other headache syndromes), and in psychiatry (eg, major depression), where there is a strong reliance on patient self-report rather than clinical signs or laboratory markers. Many clinical specialties identify syndromes closely related to CFS, but with varied emphasis on a particular symptom feature, such as musculoskeletal pain in fibromyalgia and gastrointestinal disturbance in irritable bowel syndrome. Clinically, CFS has the characteristics of a neuropsychiatric disorder. Its major symptoms (disturbed perception of fatigue and pain, sleep disturbance, neurocognitive difficulties and mood disturbances) suggest a non-localised disturbance of central nervous system function. However, its pathophysiological basis remains obscure. A diverse array of aetiologies has been proposed (including immunological, infective, metabolic, neuroendocrine and psychiatric hypotheses), but no simple explanatory model has been supported by well-controlled studies. Indeed, the heterogeneity within patient groups labelled as having CFS makes it likely that more than one process is operative.3 Thus, CFS challenges the standard concept of discrete disease categories linked to specific aetiologies. The practitioner is confronted with the challenge of explaining the patient's symptoms without reference to a coherent biomedical model. In these circumstances, doctors often fall back on outdated notions of "psychosomatic disease", which patients generally interpret as "imaginary illness". In the face of medical disinterest or scepticism, patients are frequently driven to seek simplistic "alternative" explanations to legitimise their illness experience, and may be tempted to pursue useless or harmful unproven therapies. How can patients and practitioners engage in a more productive dialogue? To begin with, doctors should be prepared to acknowledge the limitations of our current state of knowledge. In the absence of a clear understanding of the underlying pathophysiology, CFS is best described as an illness rather than a disease.4 Illness is a subjective state of suffering -- physical, psychological and social -- and can only be understood and defined with reference to the sick individual.5 Disability arises when illness interferes with the individual's ability to function normally. People with CFS are clearly ill, and are often disabled, even though an underlying disease process has not yet been identified. Our goal as medical practitioners is not only to identify and treat disease, but also to help relieve suffering and disability, whatever the cause. Unfortunately, medical conditions for which there are limited therapeutic approaches are rarely popular territories for practitioners. Various antiviral, immunoregulatory, metabolic, and antidepressive drug treatments for CFS have been subjected to randomised controlled trials, but none has demonstrated definite efficacy. In disorders associated with broad disturbances of central nervous system function there is commonly an interplay between cultural, personal and biomedical factors. Thus, it is not surprising that cognitive-behavioural approaches have shown benefit in clinical trials,6 but it is not yet clear how generally applicable these findings are. A recent evaluation of patients with chronic fatigue in Hong Kong may provide an important insight for our "Western" medical practice.7 For these patients the notion of having a "medical" versus "psychiatric", or "biomedical" versus "psychosocial", cause of their illness made little sense. Their perception was that, while they were clearly unwell, the potential causes of that suffering could lie across a broad domain of personal, social or medical factors. If Australian patients and their doctors could rediscover this basic concept, and could also accept prolonged fatigue as a legitimate illness experience, there would be no need for the polarisation of aetiological models (and political views) that has become characteristic of medical practice in relation to CFS in the USA and UK. This unnecessary polarisation is intellectually shallow and harmful to patients. To build an effective therapeutic alliance, doctors should endeavour to maximise non-specific treatment effects by adopting an empathic and non-judgemental style, by displaying acceptance of their patient's suffering, and by demonstrating a commitment to continued care. Rejecting the patient's illness experience is likely to promote feelings of alienation and to perpetuate ill-health. The cornerstones of good management include providing information about the illness and its natural history; empirical treatment of disturbances of mood and sleep which commonly co-occur in CFS; and encouraging a rehabilitative approach to the illness, including graded physical activity as well as psychological and social support. Andrew R Lloyd Associate Professor, Inflammation Research Unit School of Pathology, University of New South Wales Ian B Hickie Professor, School of Psychiatry, University of New South Wales Robert H Loblay Associate Professor, Department of Clinical Immunology Royal Prince Alfred Hospital, Sydney Hickie I, Hooker AW, Hadzi-Pavlovic D, et al. Fatigue in selected primary care settings: sociodemographic and psychiatric correlates. Med J Aust 1996; 164: 585-588. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994; 121: 953-959. Hickie I, Lloyd A, Hadzi-Pavlovic D, et al. Can the chronic fatigue syndrome be defined by distinct clinical features? Psychol Med 1995; 25: 925-935. Jennings D. The confusion between disease and illness in clinical medicine. Can Med Assoc J 1986; 135: 865-870. Cassell EJ. The nature of suffering and the goals of medicine. New York: Oxford University Press, 1991. Wessely S, Hotopf M, Sharpe M. Chronic fatigue and its syndromes. New York: Oxford University Press, 1998. Lee S, Yu H, Wing YK, et al. Psychiatric morbidity and illness experience of primary care patients with chronic fatigue in Hong Kong. Am J Psychiatry 2000; 157: 380-384. Make a comment Diagnostic criteria for chronic fatigue syndrome2A. Clinically evaluated, unexplained, persistent or relapsing fatigue persistent for six months or more that is of new or definite onset; is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social or personal activities;andB. Four or more of the following symptoms are concurrent, persistent for six months or more, and must not have predated the fatigue: Impaired short term memory or concentration Sore throat Tender cervical or axillary lymph nodes Muscle pain Multijoint pain without arthritis Headaches of a new type, pattern, or severity Unrefreshing sleep Postexertional malaise lasting more than 24 hours. Back to text

Andrew R Lloyd · Ian B Hickie · Robert H Loblay

Notable Cases Echinacea-associated anaphylaxis Raymond J Mullins A woman with atopy experienced anaphylaxis after taking, among other dietary supplements, a commercial extract of echinacea. Hypersensitivity was confirmed by skinprick and RAST testing. Regular ingestion of echinacea by up to 5% of surveyed patients with atopy, combined with detection of echinacea-binding IgE in atopic subjects (19% by skin testing; 20% with moderate to strong reactivity by RAST testing), raises the possibility of severe allergic reactions, even with first-time use, due to cross-reactivity with other structurally similar allergens. Patients with atopy should be cautioned about the risk of developing life-threatening reactions to complementary medicines, including echinacea. MJA 1998; 168: 170-171 For the full text of this article, see the pdf version

Raymond J Mullins

Asthma and other atopic diseases in Australian children Australian arm of the International Study of Asthma and Allergy in Childhood Colin F Robertson, Marita F Dalton, Jennifer K Peat, Michelle M Haby, Adrian Bauman, J Declan Kennedy and Louis I Landau MJA 1998; 168: 434-438 Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - ©MJA1998 Abstract Objective: To determine the prevalence of asthma, eczema and allergic rhinitis in Australian schoolchildren using the protocol of the International Study of Asthma and Allergy in Childhood (ISAAC). Design: Questionnaire-based survey. Setting: Melbourne, Sydney, Adelaide (in winter-spring, 1993) and Perth (in winter-spring, 1994). Subjects: All children in school years 1 and 2 (ages 6-7 years) or in year 8 (ages 13-14 years), attending a random sample of 272 schools, stratified by age and city. Main outcome measures: Parent-reported (for 6-7 year olds) or self-reported (for 13-14 year olds) symptoms of atopic disease in the previous 12 months, or ever; treatment of asthma; and country of birth. Results: 10 914 questionnaires were completed for 6-7 year olds and 12 280 for 13-14 year olds (84% and 94% response rates, respectively). Prevalence of wheeze in the past 12 months was 24.6% for the 6-7 year olds and 29.4% for the 13-14 year olds, and, among 6-7 year olds, was significantly higher in boys (27.4%) than girls (21.7%). Children born in Australia were more likely to report current wheeze than those born elsewhere (6-7 year olds: odds ratio [OR], 1.82; 95% confidence interval [CI], 1.55-2.15; and 13-14 year olds: OR, 1.88; 95% CI, 1.68-2.11). Prevalences of current eczema and allergic rhinitis were 10.9% and 12.0%, respectively, for the 6-7 year olds, and 9.7% and 19.6%, respectively, for the 13-14 year olds. Asthma, eczema and rhinitis coexisted in 1.8% of 6-7 year olds and 2.8% of 13-14 year olds. Conclusion: This study provides evidence that asthma prevalence in Australian schoolchildren is continuing to increase and is higher among Australian-born children than among those born elsewhere. Asthma, eczema and allergic rhinitis coexist to a lesser extent than expected. These results form the basis for future Australian and international comparisons. Introduction There is now substantial evidence that the prevalence of asthma and other atopic disorders is increasing worldwide.1,2 While the prevalence of asthma has been documented in the past 30 years, variation in methods and lack of uniform diagnostic criteria make direct comparison between studies difficult. Little is known about the prevalence of the other atopic disorders -- eczema and allergic rhinitis -- both throughout the world and particularly in Australia. The International Study of Asthma and Allergy in Childhood (ISAAC) is a collaborative project which has developed a standardised methodology to describe the prevalence and severity of asthma, rhinitis and eczema in children throughout the world.3 Such data will provide a framework for aetiological research into lifestyle, environmental and genetic factors affecting these disorders. Phase 1 of ISAAC is to determine the prevalence of the disorders throughout the world. Phases 2 and 3 will be more comprehensive, using more detailed questionnaires and objective measures to confirm the differences seen in Phase 1 and to identify important aetiological factors. Our study was part of Phase 1 of ISAAC. It aimed to determine the prevalence of asthma and other atopic diseases in Australian schoolchildren, to determine the burden of atopic disease in this country, and to provide a basis for international comparison. Methods We used the protocol of ISAAC3 to survey two age groups: 6-7 year olds (school years 1 and 2) and 13-14 year olds (school year 8). Subjects were all children in the relevant years of a random sample of primary and secondary schools. The sample comprised about 10% of all government, Catholic and independent schools in the metropolitan areas of Adelaide and Perth; the area within a radius of 20 km from the GPO in Melbourne; the area within a radius of 10 km from the GPO in Sydney for primary schools (school years 1 and 2); and the Western Region of Sydney for secondary schools (school year 8). Previous studies have shown these areas of Sydney and Melbourne to be representative of the metropolitan areas of these cities.4,5 A five-page questionnaire was issued by teachers for completion by parents of the 6-7 year olds, and by the 13-14 year olds in the classroom under examination conditions. The questionnaires contained the three standard ISAAC modules, asking about symptoms of asthma, eczema and allergic rhinitis3 (see Box 1 for definitions), an additional module about treatment of asthma, and two extra questions about the children's and mothers' country of birth. No translations were provided. If the first questionnaire was not returned by the 6-7 year olds, a second was issued. A second visit was made to the secondary schools, if necessary, to recruit students absent at the initial visit. Data were analysed with the statistical package SPSS-X.9 Results were adjusted for cluster effect, and chi-squared tests were used to compare prevalences, while significance of odds ratios (OR) was assessed with 95% confidence intervals (CIs). Results Details of schools and subjects surveyed are shown in Box 2; 201 primary schools and 71 secondary schools participated, comprising 7%-42% of schools in the sampling area; 9% of schools selected declined to participate. A total of 12 952 questionnaires were issued to the 6-7 years age group (response rate, 84%) and 13 078 to the 13-14 years age group (response rate, 94%). Prevalence of atopic diseases in the two age groups is shown in Box 3. Asthma Prevalence of current wheeze was 24.6% for the 6-7 year olds (95% CI, 23.8-25.4), and 29.4% for the 13-14 year olds (95% CI, 29.1-29.7) (Box 3). In the younger group, current wheeze was significantly more common in boys than in girls (OR, 1.36; 95% CI, 1.25-1.49), but this sex difference was reversed in the older group (OR 0.82; 95% CI, 0.76-0.89). Figure 1 (below) compares the prevalence of atopic diseases between the four cities. For the 6-7 year olds, there was no significant difference in prevalence of current wheeze between cities, but for the 13-14 year olds prevalence was slightly higher in the western cities (Adelaide and Perth: 32.3%) than in the eastern cities (Sydney and Melbourne: 25.9%) (OR, 1.37; 95% CI, 1.26-1.48). There was a similar difference between west and east in percentage of 13-14 year olds who had had more than 12 episodes of wheeze per year (4.1% versus 3.1%) and who had attended the emergency department (3.5% versus 2.9%) (data not shown). The prevalence of current wheeze was generally higher in the older age group. The spectrum of asthma among children who reported current wheeze is shown in Box 4. While most children in both age groups reported only one to three asthma episodes in the previous 12 months, 8.0% of 6-7 year olds and 12.2% of 13-14 year olds reported more than 12 episodes. Sleep disturbance due to asthma was common, with 11.2% of 6-7 year olds and 9.8% of 13-14 year olds reporting sleep disturbance on one or more nights per week. About 7% of both age groups reported a hospital admission for asthma in the previous 12 months. Patterns of asthma treatment are shown in Box 5. Regular b2-agonists were taken as sole therapy by 5.5% of 6-7 year olds and 7.4% of 13-14 year olds with current wheeze, while regular inhaled steroids were taken by 21.1% of 6-7 year olds and 14.6% of 13-14 year olds, rising to 49.7% and 36.9% for those with more than 12 episodes per year. While overall 26.5% of 6-7 year olds with current wheeze and 15.8% of 13-14 year olds had a written asthma management plan, this increased to 46.5% and 25.9% in those who reported 12 or more attacks in the past 12 months. Most children attended a doctor at least once during a wheezy episode throughout the year, but only 42.2% of 6-7 year olds and 31.3% of 13-14 year olds visited a doctor for a regular check-up. Eczema Prevalence of current eczema did not vary significantly between the cities (Box 3). Eczema was less common in boys than in girls in both age groups (6-7 year olds: OR, 0.81; 95% CI, 0.72-0.92; 13-14 year olds: OR, 0.57; 95% CI, 0.51-0.65). Sleep disturbance due to itching was common among those with current eczema; it was reported to occur at least weekly by 7.9% of 6-7 year olds and 13.4% of 13-14 year olds, and at a lesser frequency by 27% of 6-7 year olds and 30.4% of 13-14 year olds. Allergic rhinitis The prevalence of current allergic rhinitis was significantly higher in Adelaide and Perth than in Sydney and Melbourne (6-7 year olds: OR, 1.62; 95% CI, 1.44-1.82; 13-14 year olds: OR, 1.53; 95% CI, 1.40-1.68). Like wheeze, rhinitis was more common in boys than girls in the younger group (boys versus girls: OR, 1.19; 95% CI, 1.06-1.33), while this sex difference was reversed in the older group (boys versus girls: OR, 0.64; 95% CI, 1.40-1.68). Among those with current rhinitis, 71% of 6-7 year olds and 76% of 13-14 year olds reported that it interfered with their daily activity to some extent (troublesome rhinitis), while 18.5% of 6-7 year olds and 19.1% of 13-14 year olds described this interference as moderate to "a lot". Atopic disease and country of birth Children born in Australia were more likely to report current wheeze than those born elsewhere (6-7 year olds: OR, 1.81; 95% CI, 1.54-2.14; 13-14 year olds: OR 1.89; 95% CI, 1.69-2.12). This trend was similar for children whose mothers were born in Australia compared with those whose mothers were born elsewhere (6-7 year olds: OR, 1.29; 95% CI, 1.18-1.42; 13-14 year olds: OR, 1.58; 95% CI, 1.45-1.71). When children born outside Australia were analysed by region of birth (United Kingdom, Central Europe, South-East Asia or the Middle East), there was no difference in the prevalence of wheeze between regions. Eczema and rhinitis were also more common in children born in Australia than those born elsewhere. For eczema the OR was 1.31 (95% CI, 1.06-1.63) for 6-7 year olds and 1.36 (95% CI, 1.14-1.61) for 13-14 year olds. For rhinitis, the OR was 1.79 (95% CI, 1.42-2.26) for 6-7 year olds and 1.5 (95% CI, 1.32-1.70) for 13-14 year olds. The proportion of children born outside Australia was higher in the eastern cities among 13-14 year olds (23%) than in the western cities (15%). Similarly, the proportion of mothers born outside Australia was higher in the eastern cities (54%) than in the western cities (39%). When the odds ratio comparing prevalence of wheeze among 13-14 year olds in western versus eastern cities was adjusted for child's country of birth, it fell from 1.37 to 1.25 (95% CI, 1.15-1.36). Interrelations of atopic diseases Figure 2 (below) shows the overlap of asthma, eczema and allergic rhinitis. While 35.2% of 6-7 year olds reported having at least one of these conditions in the past 12 months, only 1.8% reported having all three. Corresponding figures for 13-14 year olds were 41% with at least one condition and 2.8% with all three. Among those with current wheeze, only 19% of 6-7 year olds and 18% of 13-14 year olds reported coexistent current eczema, with no apparent age effect in the relationship. Discussion This study describes the burden of atopic disease in Australian schoolchildren. The prevalence of current wheeze was similar to that reported in recent epidemiological studies in Australia.10 However, comparison with results of a similar questionnaire given to Melbourne schoolchildren in 1990 suggests that, although the spectrum of asthma remains unchanged, the prevalence of recent wheeze has increased from 23.1% in 1990 (95% CI, 21.7-24.5)4 to 27.2% in 1993 (95% CI, 25.6-28.8) (P < 0.01). The rate of increase (1.4% per annum) is similar to that reported in an earlier Australian study (1.24%)10 and higher than that reported in European studies (0.1%-0.4%).1 Morbidity due to asthma remains significant, with high levels of symptoms, emergency department attendances and hospital admissions. Asthma is the second most common reason for admission to a paediatric hospital bed in Victoria (after otolaryngological conditions), with a rate in children of 738 per 100 000 population in 1994-1995.11 The total annual cost to the community associated with asthma management in Australia was estimated in 1989 as $627 million, or $769 per asthmatic person.12 These costs are likely to have increased because of the increases in medication costs and asthma prevalence. There was a significant difference in the prevalence of current wheeze and current rhinitis between the eastern and western States. A possible explanation is the difference in patterns of immigration, with more children in the eastern cities born outside Australia than in the western cities. Indeed, the odds ratio comparing prevalence of wheeze among 13-14 year olds in western versus eastern cities fell from 1.37 to 1.25 after adjustment for country of birth. Internationally, ISAAC has collected data on over half a million children from 120 centres in 48 countries. Australia ranks third-highest in prevalence of current wheeze for 13-14 year olds and second-highest for 6-7 year olds.13 For "current rhinitis", Australia ranks fifth and, for eczema, eleventh. Australia's high ranking for asthma prevalence is supported by data for asthma mortality. This was not collected by ISAAC, but comparison of available data from 11 developed countries shows Australia had the highest mortality rate due to asthma in 1990.14 We found evidence from throughout Australia for continuing lack of effective treatment of asthma. Among children with more than 12 episodes of wheeze per year, only 64% of 6-7 year olds and 43% of 13-14 year olds were taking regular preventive treatment. Further, 5.5% and 7.4% of those reporting "current wheeze" used regular b -agonists in the absence of any preventive therapy, despite the cumulative evidence against the practice. Sodium cromoglycate was used by 19% of the 6-7 year olds and 11% of the 13-14 year olds who reported taking regular preventive therapy, showing some support for the Australian paediatric asthma guidelines, which recommend cromoglycate as first-line therapy for mild to moderate persistent asthma.15 We also found eczema and rhinitis to be common and to cause significant morbidity among Australian schoolchildren. Eczema was less common in boys than in girls in both age groups, a trend seen throughout the world.16 It is not life-threatening, but may cause considerable physical and psychological disability (including discomfort from itching, which may result in sleep loss and secondary infection, as well as the psychological effects of a visible skin disease). Treatment can be expensive and time consuming. Recent Australian estimates of the cost to the family were $330 to $1255 a year, depending on eczema severity.17 Additional costs to the community for consultations ranged from $209 to $642 a year for each child. Allergic rhinitis also carries significant morbidity. The effect on quality of life of perennial rhinitis has been estimated to be similar to, or worse than, mild to moderate asthma.18 In adults, hayfever is estimated to cause, on average, the loss of a third of a day from work each year, in addition to loss of productivity through symptoms or the sedating effects of some drug treatments.18 There are no precise estimates for the cost of therapy, as many sufferers do not consult a medical practitioner,8 and most treatment is available "over the counter". The higher prevalence of "current wheeze" found among 13-14 year olds compared with 6-7 year olds should be interpreted with caution, as the respondents differed between the two groups (parents for the 6-7 year olds and the children themselves for the 13-14 year olds). In an earlier study of Melbourne 7-year-olds and 15-year-olds, in which parents completed the questionnaire for both age groups, prevalence of "current wheeze" was lower among the 15-year-olds (18.6%) than among the 7-year-olds (23.1%).4 Further, comparison of adolescent and parent responses to an Australian asthma morbidity questionnaire showed that the adolescents reported a higher incidence of symptoms than their parents.19 The correlation between the three atopic diseases was less than anticipated. Atopy is usually associated with increased serum levels of IgE and positive skin reactivity to common allergens and has a strong genetic basis. The factors that determine the phenotypic expression of atopy and direct it to asthma, eczema or hayfever are unclear. This diverse expression of the genotype needs to be considered when studying the genetics of asthma. In conclusion, Australia has a high prevalence of atopic disorders, ranking among the highest in the world. Our study, part of a much larger international study, provides an opportunity to gain new insights into the causes and natural history of these disorders. Acknowledgements We would like to thank the schools, parents and children who participated, the research assistants who helped collect the data, and the State departments of education that approved the study. In Adelaide, the study was supported by Rotary, in Perth by the Asthma Foundation of Western Australia, and in Melbourne and Sydney by internal department funds. References Magnus P, Jaakkola JJK. Secular trends in the occurrence of asthma among children and young adults: critical appraisal of repeated cross sectional surveys. BMJ 1997; 314: 1795-1799. Wuthrich B. Epidemiology and natural history of atopic dermatitis. Allergy Clin Immunol Int 1996; 83: 77-82. Asher I, Kiel U, Anderson HR, et al. International study of asthma and allergies in childhood (ISAAC): rationale and methods. Eur Resp J 1995; 8: 483-491. Robertson CF, Heycock E, Bishop J, et al. Changes in prevalence of asthma in Melbourne schoolchildren over 26 years. BMJ 1991; 302: 1116-1118. Peat JK, Toelle BG, Gray EJ, et al. Prevalence and severity of childhood asthma and allergic sensitisation is seven regions of New South Wales. Med J Aust 1995; 163: 22-26. Jenkins MA, Clarke JR, Carlin JB, et al. Validation of questionnaire and bronchial hyperresponsiveness against respiratory physician assessment in the diagnosis of asthma. Int J Epidemiol 1996; 25: 609-616. Williams HC, Burney PGJ, Pembroke AC, Hay RJ. Validation of the UK diagnostic criteria for atopic dermatitis in a population setting. Br J Dermatol 1996; 135: 12-17. Sibbald B, Strachan DP. Epidemiology of rhinitis. In: Busse WW, Holgate ST, editors. Mechanisms in asthma and rhinitis: implications for diagnosis and treatment. Oxford: Blackwell Scientific Publications, 1994: 32-43. Norusis MJ. SPSS/PC+ Advanced Statistics. V5.0 [computer program]. Chicago, Ill:SPSS Inc, 1992. Peat JK, van den Berg RH, Green WF, et al. Changing prevalence of asthma in Australian children. BMJ 1994; 308: 1591-1596. Information Analysis Unit, Acute Health, Victorian Department of Human Services. Victorian inpatient mordibity database. Melbourne: Department of Human Services. Sighted Oct 1997. Toelle BG, Peat JK, Mellis CM, Woolcock AJ. The cost of childhood asthma to Australian families. Pediatr Pulmonol 1995; 19: 330-335. Beasley R, Keil U, von Mutius E, et al. Worldwide variation in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema: the international study of asthma and allergies in childhood (ISAAC). Lancet 1998. In press. Robertson CF, Sennhauser F, Mallol J. The change in prevalence and severity of asthma in developed and developing countries. Phelan PD (ed). Baillieres Clin Paediatr 1995; 3: 253-275. National Asthma Campaign. Asthma management handbook. 3rd edition. Melbourne: National Asthma Campaign, 1996. Williams HC, Robertson CF, Stewart AW, et al. Worldwide variation in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1998. In press. Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family and financial cost. Arch Dis Child 1997; 76: 159-162. Juniper EF. Measuring health-related quality of life in rhinitis. J Allergy Clin Immunol 1997; 99: S742-S749. Bishop J, Robertson CF, Caust J, et al. Concordance between adolescent and parent response to an asthma morbidity questionnaire. Am Rev Respir Dis 1993; 147: A373. Received 30 Oct 1997, accepted 10 Mar 1998 Authors' details Department of Thoracic Medicine, Royal Children's Hospital, Melbourne. Colin F Robertson, MSc, FRACP, Deputy Director; Marita F Dalton, Assoc Dip Med Rec, Research Assistant. Department of Medicine, University of Sydney, Sydney. Jennifer K Peat, PhD, Senior Research Fellow; Michelle M Haby, MAppSc, Research Assistant. School of Community Medicine, University of New South Wales, Sydney. Adrian Bauman, PhD, FAFPHM, Associate Professor. Department of Respiratory Medicine, Women's and Children's Hospital, Adelaide. J Declan Kennedy, MD, FRCP, Physician. Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth. Louis I Landau, MD, FRACP, Professor of Paediatrics. Reprints will not be available from the authors. Correspondence: Dr C F Robertson, Department of Thoracic Medicine, Royal Children's Hospital, Flemington Road, Parkville, VIC 3054. E-mail: cfrobATcryptic.rch.unimelb.edu.au 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>". <URL: http://www.mja.com.au/> © 1998 Medical Journal of Australia.

Colin F Robertson · Marita F Dalton · Jennifer K Peat · Michelle M Haby · Adrian Bauman · Louis I Landau

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.

Prevalence of latex allergy in a dental school Constance H Katelaris, Richard P Widmer and Ross M Lazarus 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 - Acknowledgements - References - Authors' details - ©MJA1997 Abstract Objective: To determine the prevalence of latex allergy in dental workers. Design: Questionnaire survey of staff of a dental school. Setting: The Westmead Dental School, a large dental facility in western Sydney. Participants: 230 staff members of the Westmead Dental School (consisting of general and specialist dentists, chairside assistants and registered nurses, laboratory technicians, dental therapists and hygienists) received questionnaires. Main outcome measures: The prevalence of latex allergy, defined by prompt onset of hand urticaria with or without generalised symptoms, and the prevalence of hand dermatitis and other glove-related symptoms. Also, the relationship between latex allergy and associated atopic status. Results: 177 staff (77%) responded by the set collection date; 33% reported symptoms related to wearing gloves and 22% satisfied the criteria for glove dermatitis. Sixteen respondents (9%) reported characteristics suggestive of latex- glove allergy. Conclusions: Confirmation of the 9% prevalence of latex allergy among dental workers will require further studies incorporating an objective measure of IgE-mediated hypersensitivity. MJA 1996; 164: 711-714 Introduction Adverse reactions to rubber products have been recognised for many years, and irritant reactions and cell-mediated hypersensitivity reactions such as contact dermatitis are well described. The latter are thought to be caused by one or more low-molecular-weight chemical compounds added in the rubber-making process.1 It is now recognised that latex allergy is a particular problem for certain "at risk" groups, including health care workers, patients with spina bifida or other spinal cord abnormalities and patients who have had multiple operations. In addition, atopic individuals are more likely to develop IgE antibodies to latex protein with increased exposure.2 The clinical manifestations of type I hypersensitivity reactions to latex protein are wide ranging, from contact urticaria to life-threatening anaphylaxis and death. There is now little doubt that at least some episodes of intraoperative anaphylaxis have occurred because the patient has been sensitised by latex and reacts after mucosal contact with the operating staff's gloves. This has led to some institutions providing latex-free operating suites. No studies of latex allergy in Australia have been published. In this study, we examined the prevalence of latex glove-associated symptoms in the staff of a dental institution. Dental workers are an excellent group for studying the question of latex glove-related symptoms as they may wear gloves for 8-10 hours daily, 4-5 days a week, giving them a much greater degree of exposure to latex than most other health care workers. Methods All 230 staff of the Westmead Dental School, a large dental facility in western Sydney, New South Wales, were surveyed by anonymous questionnaire distributed during Feburary 1995, with a three-week collection time allocated. Personnel surveyed included general and specialist dentists, chairside assistants, dental technicians and dental hygienists. Questionnaire details The questionnaire was divided into four sections. Section A dealt with dental practice and contained questions on demographic characteristics, including age, gender, job description and years in present occupation. Section B sought information about glove use and working habits, including the number of patients seen per day, duration that each pair of gloves was worn, information about hand washing and glove changing and the type of gloves worn. Section C sought information about symptoms or problems on contact with surgical gloves. Respondents who acknowledged glove-related problems then answered detailed questions about symptoms, the time course of symptom development, non-hand-related symptoms such as rhinoconjunctivitis, asthma, angioedema, hypotension, symptoms on contact with other dipped-rubber products such as balloons, domestic gloves and condoms, and specific interventions sought by the respondent because of the symptoms. Section D was directed at all respondents and dealt with history of other allergies, including other contact dermatitis, food allergies (with specific foods listed), animal and drug allergies. Also included were questions for eliciting a history of asthma, allergic rhinitis and eczema, both directly, by symptoms, and by requesting information about medications used. Definitions Glove dermatitis: Report of the presence of two or more symptoms of itching, redness and rash (excluding hives) which had been present long term. Latex hypersensitivity: Report of the prompt onset (within 30 minutes of wearing gloves) of hand urticaria with or without the occurrence of allergic rhinoconjunctivitis, lower respiratory tract symptoms such as cough, wheeze or chest tightness, generalised cutaneous itch or urticaria, or upper-airway oedema, hypotension, dizziness or collapse. Atopy: Present if the respondent gave positive answers to any two or more questions on a history of asthma, allergic rhinitis or atopic dermatitis. Statistical analysis All statistical analysis was performed using the SAS package.3 Fisher's exact test was used to test for marginal association in all two-way tables. For other contingency tables, the chi-squared statistic was used to test for marginal association unless otherwise specified. The distribution of demographic characteristics of the staff of the Dental School was used to estimate response rates in order to test for sampling (volunteer) bias. Ethical approval Ethics approval was obtained from the Westmead Hospital Human Research Ethics Committee. Results Completed questionnaires were received from 177 of the 230 staff (77%) by the closing date. Table 1 (below) shows the distribution of non-response from the population, sampled by age group, by sex and by job category. Not all respondents answered all the demographic questions and the response rates are slightly underestimated because 2.3% of age, 8.5% of sex and 14.1% of job category data were missing. It was not possible to compare non-respondents with respondents as the questionnaires contained no personal identifying data. Year of graduation was the question most frequently not answered (32 of 177 questionnaires [18%]). Almost all of the youngest staff responded, whereas among older individuals response rates were as low as 32% for age 51 or 60. As three cells of this Table had expected counts of less than five, we used Fisher's exact test, which showed a significant association (P < 0.00001) between non-response and age group. Men were significantly more likely to respond than women (chi-squared = 26.1; P < 0.00001). The job categories with the highest non-response rates were the small group of registered nurses (58.3%) and the general dentists (43.9%). Evidence that response rate was associated with job category was weak (chi-squared = 11.1; P = 0.05), and this question was not answered by a substantial proportion of respondents. Two-thirds of the study group spent more than half their working day wearing gloves. Symptoms attributed to glove use were reported by one-third of subjects, with itch and redness being the commonest symptoms reported. Table 2 (above) compares selected demographic and allergic characteristics of the 39 subjects (22%) who satisfied the criteria for glove dermatitis with the 16 subjects (9%) fulfilling the criteria set for latex hypersensitivity. Other symptomatic and allergic characteristics of the 16 dental workers with latex hypersensitivity are compared with those of the rest of the respondents in Table 3 (below). Almost all of the individuals reporting latex-allergic symptoms also met the criteria for glove dermatitis. Nineteen per cent of the latex-allergic group reported food allergy, although none reported symptoms with foods such as avocado, banana, nuts or soy products, foods which have been described previously as cross-reacting with latex protein. Fisher's exact test was used to test the hypothesis that atopic diathesis was associated with latex hypersensitivity and glove dermatitis. Atopy was associated with both latex hypersensitivity (P = 0.014) and with glove dermatitis (P = 0.006). Subjects who reported experiencing symptoms of either glove dermatitis or latex-allergic symptoms were asked to indicate any action they had taken; of those with glove dermatitis 59% had never sought professional help and one-third of the latex hypersensitivity group had not sought medical attention. Discussion Our findings indicate a significant occupational health problem among dental personnel wearing latex gloves. In our study, 33% of those surveyed reported some symptoms with glove use; 22% met criteria for glove dermatitis and 9% for latex allergy. The distribution of non-response rates by demographic characteristics shown in Table 1 indicates that the volunteer sample was not fully representative of the study population. In particular, female staff, older staff, general dentists and registered nurses were less likely to respond. As a result of these sampling biases, our findings may not be fully generalisable to dental workers. For example, if staff experiencing symptoms were more likely to volunteer for the survey, then our rates will be overestimates of true prevalences. Our results should be interpreted with caution, and future surveys should aim to obtain more representative samples. Relying on questionnaire data alone to determine hypersensitivity reactions has obvious shortcomings. Contact urticaria with glove use may be caused by non-IgE-mediated mechanisms, so our findings may overestimate the prevalence of latex allergy. However, the occurrence of symptoms in other organ systems soon after gloves are used is highly suggestive of an IgE-mediated allergic reaction. Confirmation of this prevalence rate will require some objective measure of IgE-mediated hypersensitivity such as skin testing with appropriate extracts, or in-vitro assay of specific IgE antibodies to the latex allergens. Our prevalence rate of 9% for latex allergy among dental personnel is comparable with, although lower than, rates reported elsewhere. In a similar questionnaire survey without objective testing, Berky et al.4 reported "symptoms of an allergic nature" in 13.7% of 1043 United States Army dental officers. However, this figure included those reporting delayed symptoms as well as those reporting localised contact urticaria or generalised urticarial reactions. Furthermore, a third of those reporting symptoms were unable to be classified as having either contact dermatitis or latex allergy from their questionnaire responses. Only 25% of those reporting latex allergy in the Berky study had consulted a physician. Rankin et al.5 also conducted a questionnaire survey in a large dental facility in the US, obtaining a 15% prevalence of adverse reactions to latex gloves (Table 4). A number of studies4-6 have confirmed a relationship between atopy and latex allergy (Table 4). We also found a significant association when atopy was defined by our criteria (reported presence of any two of asthma, allergic rhinitis or atopic dermatitis). Walsh et al.7 examined factors influencing the wearing of protective gloves in general dental practice in Brisbane. Of 201 dentists who replied to a survey, 84.6% (170) reported that they routinely used gloves in their practice, compared with 13.9% (28) who reported that they did not. Reasons given for not wearing gloves included reduced sensation, reduced movement, low infection risk, skin reaction, patient acceptance and cost. Our results imply that there is a high rate of glove-related symptoms, particularly of glove dermatitis, in this dental workforce. This indicates a need to educate this occupational group about proper hand care as repeated washing, scrubbing and numerous glove changes contribute to hand irritation. Latex allergy has many implications for health care workers which extend beyond the occupational setting. Most reports of life-threatening anaphylactic reactions during surgery and other procedures have involved sensitised health care workers.8 These individuals need to know the risk they run when they themselves are patients. Mucosal contact with latex appears to be a far more potent trigger for anaphylactic reactions than cutaneous contact. People with latex allergy must be given anaesthesia and surgery in a totally latex-free environment. Atopic individuals appear to be especially at risk for sensitisation to the latex protein. Adequate counselling about occupational exposure and advice about methods of minimising the risk need to be considered in view of this and other studies. Latex gloves from different sources vary in the amount of latex protein detectable on the surface.9 Presumably, those with less cause less sensitisation and should be preferred in a workplace where glove use is mandatory. Acknowledgements We would like to thank Maggie Melink for valuable assistance and the staff of the Westmead Dental School for their cooperation. References Toner JS. Rubber. In: Fisher AA, editor. Contact dermatitis. 3rd ed. Philadelphia, Pa: Lea & Febiger, 1986: 603-643. Slater JE. Rubber anaphylaxis. N Engl J Med 1989; 320: 1126-1130. PC SAS [computer program], version 6.04. Cary, NC: SAS Institute Inc, 1991. Berky ZT, Luciano J, James WD. Latex glove allergy. A survey of the US Army Dental Corps. JAMA 1992; 268: 2695-2697. Rankin KV, Jones DL, Rees TD. Latex glove reactions found in a dental school. J Am Dent Assoc 1993; 124: 67-71. Turjanmaa K. Incidence of immediate allergy to latex gloves in hospital personnel. Contact Derm 1987; 17: 270-275. Walsh LJ, Lange P, Savage MW. Factors influencing the wearing of protective gloves in general dental practice. Quintessence Int 1995; 26: 203-209. Leynadier S, Pecquet C, Dry J. Anaphylaxis to latex during surgery. Anesthesia 1989; 44: 547-550. Yunginger JW, Jones RT, Fransway AS, et al. Extractable latex allergens and proteins in disposable medical gloves and other rubber products. J Allergy Clin Immunol 1994; 93: 836-842. (Received 19 Sep 1995, accepted 6 Apr 1996) Authors' details Department of Immunology, Westmead Hospital, Sydney, NSW. Constance H Katelaris, PhD, FRACP, Senior Consultant. Department of Paediatric Dentistry, Westmead Dental School, Sydney, NSW. Richard P Widmer, MDSc, FRACDS, Associate Professor. Department of Public Health and Community Medicine, University of Sydney, Sydney, NSW. Ross M Lazarus, MB BS, FAFPHM, Lecturer. Reprints: Dr C H Katelaris, Department of Immunology, Westmead Hospital, Westmead, NSW 2145. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Editorial Oily fish and asthma - a fishy story? Further studies are required before claims can be made of a beneficial effect of oily fish consumption on asthma Interest in the possible health benefits of dietary fish lipids followed observations that populations with a high dietary intake of fish, such as Greenland Inuit and the Japanese, had low incidences of atherosclerotic disorders and of inflammatory conditions such as rheumatoid arthritis. Our recent understanding of asthma as a chronic inflammatory airway disease has led to speculation that a diet rich in fish oil may also ameliorate asthma. The potential anti-inflammatory effect of fish oil stems from its active ingredient, eicosapentaenoic acid (EPA), which is a competitive substrate with arachidonic acid for the generation of inflammatory mediators. The derivatives of arachidonic acid (an n-6 fatty acid) are leukotriene B4 (LTB4), a potent neutrophil chemoattractant and pro- inflammatory mediator, and the cysteinyl series of leukotrienes (LTC4, LTD4 and LTE4), which produce potent smooth muscle contraction and bronchoconstriction. In contrast, EPA (an n-3 fatty acid), as well as inhibiting arachidonic acid metabolism, is a substrate for the less active prostanoids (e.g., thromboxane A3) and leukotrienes (e.g., LTB5), and so has the potential to reduce airway inflammation and reverse bronchoconstriction. As the most profound anti-inflammatory actions of fish oil are on neutrophil function and mediator generation, it is not surprising that clinical trials of dietary fish oil have been beneficial in diseases where there is a neutrophilic inflammation, such as rheumatoid arthritis, psoriasis, cystic fibrosis and inflammatory bowel disease. However, in asthma the role of neutrophils is much less certain. Eosinophils and mast cells are thought to be the predominant effector cells in asthma (through the release of mediators), with T lymphocytes, macrophages and, possibly, mast cells having initiating and immunomodulatory roles through cytokine secretion. Placebo-controlled interventional studies of high dose fish oil supplementation in patients with asthma have been disappointing. Early short term trials (eight weeks) of up to 4 g/day of EPA in severe asthmatics showed no clinical benefit, despite demonstrating profound suppression of neutrophil chemotaxis and mediator generation.1 In a study in aspirin-intolerant subjects asthma control worsened after six weeks of 3 g/day of EPA, 2 consistent with the known aspirin-like effect of cyclooxygenase inhibition by EPA. Further studies in milder asthmatics with 3.2 g/day for 10 weeks showed no benefit in either clinical symptoms or bronchial hyperresponsiveness,3 despite demonstrating attenuation of allergen-induced late-phase bronchoconstriction induced in the laboratory.4 A more prolonged trial for six months with 3.2 g/day of EPA also showed no clinical benefit in patients with pollen-induced asthma and seasonal hayfever.5 These disappointing results are consistent with in-vitro evidence that EPA does not inhibit eosinophils and mast cells. In contrast to its dampening effect on neutrophils, EPA incubated with cultured murine mast cells produced a marked increase in production of platelet-activating factor, without an effect on histamine release.6 Similarly, stimulated human eosinophils incubated with EPA generated significantly greater amounts of leukotrienes than those incubated with arachidonic acid.7 Furthermore, in asthma there is a complex interaction between cells, cytokines, nerves and lipid and other mediators. Although of the lipid mediators leukotrienes may have the most influential role in asthma, modulating any one group of inflammatory mediators alone may not be sufficient to produce clinical improvement. The only interventional study which has shown positive results was a small placebo-controlled trial of low-dose EPA (1 g/day) for 12 months in 12 adult asthmatic subjects (six taking fish oil and six taking placebo). After nine months a small but significant improvement was found in forced expiratory volume at one second (FEV1).8 However, no details were given of concurrent medication use or assessment of compliance with therapy by leukocyte membrane phospholipid analysis, and there have been no follow-up data since 1991. The question of fish diet and respiratory health has also been investigated from an epidemiological perspective in recent American studies. In a survey of 2526 adult subjects aged 30-70 years, the first National Health and Nutrition Survey found eating fish more than once a week, compared with less than once a week, was associated with a higher level of lung function. However, only 2.9% of subjects in this survey were asthmatic, so no conclusion could be drawn about the effect of fish consumption on asthma.9 The Atherosclerosis Risk in Communities (ARIC) study surveyed 8960 adult current and former smokers10 and reported that a high dietary intake of n-3 fatty acids was inversely related to the risk of chronic obstructive pulmonary disease (COPD). This apparent protective effect is biologically plausible as neutrophilic inflammation is a feature of COPD. The Nurses' Health Study, possibly the largest prospective study of its type, reporting the incidence of adult-onset asthma in 77 866 women aged 34-68 years, found no relationship between dietary intake of fatty acids and the incidence of doctor-diagnosed asthma over a 10-year period.11 With this background, what interpretation can be put on the study by Hodge et al. in this issue of the Journal (page 137)? The novel aspects of this epidemiological survey are that the study population consisted of Australian children aged 8-11, and that the diagnosis of asthma was based both on symptoms and measurement of bronchial hyperresponsiveness. The investigators found an inverse relationship between weekly oily fish intake and prevalence of asthma in 574 schoolchildren. A number of salient points may be made. Firstly, the investigators previously reported an inverse relationship between weekly total fish intake and asthma, which is not evident in this study. This may reflect the inherent variability of food frequency questionnaire data or the different sample sizes of the two studies, but it does raise doubts about the primary hypothesis being tested. Secondly, the estimated mean intake of EPA from a weekly serve of fish10 is about 0.2-0.8 g, which is much lower than the amount that would be expected to have anti-inflammatory effects on leukocyte mediator and cytokine generation. It is possible that it is not the oil in the fish per se but some other dietary or social component associated with families who eat fish which is responsible for these results. Thirdly, a much larger prospective study in adults did not find a similar relationship between dietary fish intake and asthma prevalence.11 Can this discrepancy be explained by subtle effects of low-dose fish oil on the immunological development of asthma in childhood, which are no longer relevant in adulthood? There is currently insufficient understanding of the mechanisms involved to put forward a biologically plausible hypothesis. Finally, the study of Hodge et al. is a cross-sectional study, and thus cannot establish a temporal relationship between oily fish intake and asthma. Nevertheless, these are very interesting data but they need to be confirmed in larger studies. Placebo-controlled prospective intervention studies with dietary manipulation for prolonged periods in childhood are also required before any claim can be substantiated. Until then, unwarranted speculation about the relationship between dietary fats and asthma12 should be avoided as this may have a negative impact on other health outcomes, cause even more confusion about diet and health in the general population and undermine an evidence-based approach to public health initiatives. Francis C K Thien Senior Lecturer Rosalie K Woods Research Fellow E Haydn WaltersProfessor/Director Department of Respiratory Medicine, Alfred Healthcare Group Melbourne, VIC (©MJA 1996; 164: 135-136) Kirsch CM, Payan DG, Wong MYS, et al. Effect of eicosapentaenoic acid in asthma. Clin Allergy 1988; 18: 177-187. Picado C, Castillo JA, Schinca N, et al. Effects of a fish oil enriched diet on aspirin intolerant asthmatic patients: a pilot study. Thorax 1988; 43: 93-97. Arm JP, Horton CE, Mencia-Huerta J-M, et al. Effect of dietary supplementation with fish oil lipids on mild asthma. Thorax 1988; 43: 84-92. Arm JP, Horton CE, Spur BW, et al. The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 1989; 139: 1395-1400. Thien FCK, Mencia-Huerta J-M, Lee TH. Dietary fish oil effects on seasonal hay fever and asthma in pollen-sensitive subjects. Am Rev Respir Dis 1993; 147: 1138-1143. Triggiani M, Connell TR, Chilton FH. Evidence that increasing the cellular content of eicosapentaenoic acid does not reduce the biosynthesis of platelet-activating factor. J Immunol 1990; 145: 2241-2248. Thien FCK, Hallsworth MP, Soh C, Lee TH. Effects of exogenous eicosapentaenoic acid on generation of leukotriene C4 and leukotriene C5 by calcium ionophore-activated human eosinophils in vitro. J Immunol 1993; 150: 3546-3552. Dry J, Vincent D. Effect of a fish oil diet on asthma: results of a 1-year double-blind study. Int Arch Allergy Appl Immunol 1991; 95: 156-157. Schwartz J, Weiss ST. The relationship of dietary fish intake to level of pulmonary function in the first National Health and Nutrition Survey (NHANES I). Eur Resp J 1994; 7: 1821-1824. Shahar E, Folsom AR, Melnick SL, et al. Dietary n-3 polyunsaturated fatty acids and smoking-related chronic obstructive pulmonary disease. N Engl J Med 1994; 331: 228-233. Troisi RJ, Willett WC, Weiss ST, et al. A prospective study of diet and adult-onset asthma. Am J Respir Crit Care Med 1995; 151: 1401-1408. Hodge L, Peat JK, Salome C. Increased consumption of polyunsaturated oils may be a cause of increased prevalence of childhood asthma. Aust N Z J Med 1994; 24: 727. (©MJA 1996; 164: 135-136)

Rosalie K Woods

Research Consumption of oily fish and childhood asthma risk Linda Hodge, Cheryl M Salome, Jennifer K Peat, Michelle M Haby, Wei Xuan and Ann J Woolcock For editorial comment, see Thien et al. Abstract - Authors' details - Introduction - Methods - Results - Discussion - Appendix - Acknowledgements - References - Box 1 - Box 2 - Box 3 - Figure - © MJA 1996 - Abstract Objective: To investigate the association between diet and airway disease in children in the light of epidemiological studies suggesting that consumption of fish more than once a week reduces the risk of developing airway hyperresponsiveness (AHR). Design: Diet was assessed by a detailed food frequency questionnaire and airway disease by respiratory symptoms or airway responsiveness to exercise. Methods: A questionnaire, containing questions about the frequency of eating more than 200 foods, was sent to the parents of 574 children in whom we had measured recent wheeze (by questionnaire), AHR (by exercise) and atopy (by skin prick tests) six months before this study. We defined current asthma as the presence of both recent wheeze and AHR. Results: Response rate to the questionnaire was 81.5% (n = 468). After adjusting for confounders such as sex, ethnicity, country of birth, atopy, respiratory infection in the first two years of life and a parental history of asthma or smoking, children who ate fresh, oily fish (> 2% fat) had a significantly reduced risk of current asthma (odds ratio, 0.26; 95% confidence interval, 0.09-0.72; P < 0.01). No other food groups or nutrients were significantly associated with either an increased or reduced risk of current asthma. Conclusion: These data suggest that consumption of oily fish may protect against asthma in childhood. MJA 1996; 164: 137-140 Introduction The substantial increase in the prevalence of childhood asthma in the past 20 years has affected both rural and urban communities of westernised countries,1,2 suggesting that local environmental factors, such as exposure to allergens or industrial air pollutants, are not the cause. However, the widespread changes in diet may be responsible. Seaton et al.3 have postulated that increases in the prevalence of asthma may be due to a reduced intake of antioxidant vitamins (beta-carotene, vitamins A, C and E) and mineral cofactors essential for antioxidant defence mechanisms (selenium, zinc and copper) as a result of reduced consumption of meat, fresh fish, fruit and vegetables in Western diets. Reduced consumption of magnesium4 and increased consumption of salt5 have been implicated as risk factors for airway hyperresponsiveness (AHR). Our own epidemiological studies of Australian schoolchildren have shown that children who eat fish more than once a week have a third the risk of AHR of children who do not eat fish regularly.6 However, these studies did not include other dietary questions, so that fish consumption may have been a marker for another dietary characteristic. Here, we investigate the association between diet, as assessed by a detailed dietary questionnaire, and airway disease, assessed by respiratory symptoms or airway responsiveness to exercise. Methods Subjects In June 1993, a cross-section of 808 children aged 8-11 years from schools randomly selected from all schools within a 10 km radius of Sydney General Post Office had airway responsiveness to exercise, respiratory symptoms and atopy measured and frequency of fish consumption assessed.7 In October 1993, 584 children were selected from this group in a stratified case-control design and their parents were asked to complete a detailed food frequency questionnaire about their child's eating habits. The selection criteria included all children with AHR, all children who had had wheeze in the last 12 months (recent wheeze) and a three-in-five sample of children with normal airways (no AHR or recent wheeze), who were chosen by excluding two children after every three from numerically ordered lists of children identified by number. The study coordinator who collected the food frequency questionnaires was blind to the respiratory symptom and AHR status of the subjects. Ethical approval for the study was obtained from the Ethics Review Committee of the University of Sydney. Permission to approach schools was obtained from the New South Wales Department of School Education and the Catholic Education Office. Respiratory questionnaire In June 1993 the parents or guardians of the children completed a standard respiratory questionnaire, with questions on age, sex, ethnicity, country of birth, history of asthma or wheeze in the last 12 months, medication use, and also parents' occupations, history of asthma and smoking. The questionnaire included the question used in previous studies about the dietary consumption of fish - "How often does your child eat a meal that contains fish?" - with the options of replying "never or rarely", "once a week", or "more than once a week". Dietary questionnaire In October 1993, a food frequency questionnaire (adapted from that developed and validated by the Commonwealth Scientific and Industrial Research Organisation [CSIRO], Division of Human Nutrition, South Australia8,9) was distributed to the selected children, whose parents were asked to complete this for their child's usual eating habits over the last year. The questionnaire identified consumption patterns (daily, weekly, monthly, rarely or never) of more than two hundred foods commonly consumed in Australia. Additional questions on the type of fresh fish consumed and regular consumption of vitamin, mineral or herbal supplements were included. Estimates of sodium intake included naturally occurring sodium in foods, salt added in cooking, at the table and from processed foods. If questionnaires were not returned after one month the parents were contacted by telephone and offers were made to replace the questionnaires, or to provide assistance. In 11 cases, where neither parent spoke fluent English, an interpreter was commissioned to complete the questionnaire with the parents over the telephone. Returned dietary questionnaires were checked for missing or obviously erroneous information. Parents were contacted by telephone to complete omitted sections or to clarify erroneous information. Each food in the dietary questionnaire was allocated to one of 23 different food groups (see Appendix). Diets were analysed for energy, fibre and 39 nutrients (see Appendix). Definitions of respiratory categories, atopy, and categories of fish, plus a list of fish with more than 2% fat, are given in Box 1. Statistical analyses The questionnaires were analysed by the Division of Human Nutrition, CSIRO, South Australia, using Australian tables of nutrient composition12 for energy, protein, fat, carbohydrates, vitamins and minerals. The total quantity of food in each food group for every child was converted to a common base of weekly serves with Clinical Reporting Systems software.13 Data were analysed with the statistical package SAS.14The association between fish, food or nutrient intake and respiratory category was analysed categorically using chi-squared tests, and continuously using Student's t tests and analysis of variance. Some values obtained from the nutrient analysis were well outside what could reasonably be expected in children of this age group. These outliers were excluded from the statistical analysis. The number of exclusions never exceeded nine subjects in any analysis and were not significantly associated with any of the respiratory groups. Logistic regression was used to adjust estimates for the effects of known confounders for the effect of fish consumption on AHR and symptoms of asthma (e.g., sex, race, country of birth, atopy, early respiratory infection, parental smoking and parental asthma). Only those confounding factors found to be significant or approaching significance (P < 0.1) (atopy, parental asthma, early respiratory infection, country of birth) were included in the model. Results Of the 584 children selected 574 received the dietary questionnaire and 468 completed questionnaires were returned (81.5%). Non-responders were not significantly different from responders in the prevalence of AHR (26.0% v. 27.1%) or fish consumption (46.2% v. 52.1%). Box 2 shows details of the children studied. Children with current asthma did not differ significantly from children with normal airways in the consumption of any nutrient or food group. (Tables showing mean weekly intake in standard serves of food groups and mean daily intake [SD] of nutrients for children with normal airways and children with current asthma are available from the authors.) Children with wheeze only had a significantly higher intake of red meat (P < 0.05), offal meat (P < 0.001) and vitamin B12 (P < 0.03) and a significantly lower intake of mixed vegetables (P < 0.05) than children with normal airways. Children with AHR only consumed significantly more offal meat (P = 0.001) and high fat/high sugar foods (P < 0.001) than children with normal airways. They also had higher intakes of nitrogen, protein, total sugar, cholesterol, potassium nicotinamide, total nicotinamide, calcium, copper, zinc, vitamin B12 (P < 0.05) and refined sugar (P < 0.01). Total fish intake per week did not differ significantly between children with normal airways (1.2 serves per week; 95% confidence interval [CI], 1.0-1.3), AHR only (1.2 serves; CI, 0.9-1.5), wheeze only (1.2 serves; CI, 0.8-1.5) and current asthma (1.0 serve; CI, 0.8-1.2). Fresh fish was eaten by 84% (CI, 79.6%-88.4%) of children with normal airways, and by 72% (CI, 61.6%-82.4%) of children with current asthma. When fresh fish was divided into oily and non-oily types, significantly fewer children with current asthma (15.5%; CI, 7.1%-23.9%) included oily fish in their diet than did children with normal airways (30.8%; CI, 25.2%-36.4%; P < 0.05). There were no significant differences in the proportions of children with current asthma (56.3%; CI, 44.8%-67.8%) and normal children (52.9%; CI, 46.9%-58.9%) who ate exclusively non-oily fish. Neither fresh fish consumption nor respiratory disease was significantly associated with socioeconomic status, as defined by the father's occupation, or with the consumption of vitamin, mineral or other dietary supplements (including fish oil). The unadjusted risk (odds ratio) for children having current asthma was significantly lower in those who consumed any fresh fish or oily fresh fish (Box 3). Current asthma was found in only 8.8% (CI, 3.8%-13.8%) of children who ate oily fish, but in 15.6% (CI, 11.2%-20.0%) of those who ate non-oily fish only and 23% (CI, 14.2%-31.8%) of those who never ate fresh fish (Figure). When the results were adjusted for the effects of other known risk factors such as atopy, parental asthma, parental smoking, ethnicity, country of birth, early respiratory illness and sex, only children who ate oily fresh fish had a significantly reduced risk of current asthma. In these children, the risk was almost a quarter that of children who did not eat oily fish (odds ratio, 0.26; CI, 0.09-0.72) (Box 3). Consumption of any fresh fish, whether or not it was separated into oily fresh fish and non-oily fresh fish, did not significantly reduce the risk of AHR only or wheeze only either before or after adjustment for other risk factors. Discussion Our study shows that regular consumption of fresh, oily fish is associated with a reduced risk of current asthma. This reduced risk remained significant after adjustment for other known risk factors for asthma, including sex, atopy, parental asthma, parental smoking, early respiratory infection, ethnicity and place of birth. The subjects were selected from a random cross-sectional sample of children which was stratified (on the basis of recent respiratory symptoms and AHR to exercise) to increase the proportion of cases in the study group. The response rate was high (81.5%) and non-responders were not different from responders with respect to AHR or fish consumption. Socioeconomic status was not a confounder for either respiratory illness or fish consumption. Current asthma was defined as recent wheeze plus AHR to exercise. We have shown previously that current asthma, defined as recent wheeze plus AHR to histamine, identifies a group with severe, ongoing respiratory impairment, while those with AHR only and wheeze only have a milder condition which differs only slightly from the normal group.15 The diets of children with current asthma differed from those of the normal group only in the consumption of fresh, oily fish. In our previous study, more than one serve of fish per week was associated with a reduced risk of asthma,6 but in that study it was not possible to distinguish the effects of oily and non-oily fish. In the study reported here we were unable to detect differences in total fish consumption, possibly because of the smaller sample size. There were no significant differences between respiratory groups in the consumption of non-oily fish, suggesting that parents had not selectively withheld fish from the diets of asthmatic children. It is unclear why consumption of canned and processed fish was not associated with reduced risk of asthma. Processing may alter the integrity or activity of the fatty acids in fish oils. Several foods and nutrients in the diets of children with AHR only and wheeze only differed significantly from those of the normal group. However, none of these factors differed between the asthmatic and normal groups, suggesting that they are unlikely to have an aetiological role. Intake of offal meats was higher in both the AHR-only and wheeze-only groups, but, as offal meats are eaten by very few children, this may be a type I error. Vitamin B12 intake was also higher in both the AHR-only and wheeze-only groups, but the mechanism by which this could affect respiratory symptoms or AHR is unclear. There were no significant differences between any of the respiratory groups in consumption of sodium, vitamin C, vitamin E, selenium or magnesium. These findings do not support previous evidence that these dietary factors are important in the aetiology of asthma.4,5,16 Reduced risk of current asthma was associated with the consumption of oily fish, but not with non-oily fish. Fish oil contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have anti-inflammatory effects.17 Theoretically, EPA could either prevent the development of asthma or reduce its severity by altering two of the cardinal features of asthma, namely airway inflammation and AHR. Supplementation with EPA reduces production of leukotriene B4,18 a chemical mediator responsible for the recruitment of inflammatory cells, such as neutrophils, into the airways. It also reduces production of the cytokine tumour necrosis factor (TNF),19 which increases airway responsiveness.20 Fish oil supplements given over 6-10 weeks cause a substantial uptake of EPA in neutrophil membrane phospholipids.18,21 In asthmatics, this may reduce the allergen-induced late asthmatic response,22 but does not change severity of asthma.21,22 However, a recent study suggests that a longer period of supplementation may be required to reduce asthma severity.23 Data of recent fish consumption (during the last 12 months) were used in our study, but may also reflect lifetime dietary habits. In conclusion, we have shown that consumption of oily fish is associated with a reduced risk of asthma in childhood. Although further studies are required to confirm these benefits, public health interventions to increase the consumption of oily fish may reduce the morbidity and prevalence of asthma in children. Appendix The 23 food groups were: cereals; dairy products; eggs; red, white, preserved meat and offal; seafood, fried, steamed, canned fish and fish fingers; red, green, white, mixed and other vegetables; legumes; high and low vitamin C fruit and other fruit; high sugar or fat content; and other. The 39 nutrients were: nitrogen; protein; starch; refined, natural and total sugar; total carbohydrate; saturated, monounsaturated, polyunsaturated and total fat; cholesterol; carotene; retinol; vitamin A; thiamine; riboflavin; potassium nicotinic acid and total nicotinic acid; niacin; vitamins B6 and B12; pantothenic acid; biotin; free and total folate; vitamins C, D, E; calcium; copper; iron; magnesium; manganese; phosphorus; potassium; selenium; sodium; and zinc. Acknowledgements This study was supported by the Fisheries Research and Development Corporation, Australia. The authors thank Dr Katrine Baghurst for allowing us to use the dietary questionnaire, Sally Record and Kay Pender for their help with the nutritional analyses, Elena Belooussova for data organisation and Suzanne Gray for her assistance with collecting the questionnaires. We are grateful for the support of the New South Wales Department of School Education, the Catholic Education Office and the Principals and teachers of all the schools involved. We are especially grateful to the parents and the children who participated in the survey. (©MJA 1996; 164: 137-140) References Robertson CF, Bishop J, Sennhauser FH, Mallol J. International comparison of asthma prevalence in children: Australia, Switzerland, Chile. Pediatr Pulmonol 1993; 16: 219-226. Burney P, Chinn S, Rona RJ. Has the prevalence of asthma increased in children? Evidence from the national study of health and growth 1973-86. BMJ 1990; 300: 1306-1310. Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994; 49: 171-174. Britton J, Pavord I, Richards K, et al. Dietary magnesium, lung function, wheezing, and airway hyperreactivity in a random adult population sample. Lancet 1994; 344: 357-362. Burney PG, Neild JE, Twort CHC, et al. Effect of changing dietary sodium on the airway response to histamine. Thorax 1989; 44: 36-41. Peat JK, Salome CM, Woolcock AJ. Factors associated with bronchial hyperresponsiveness in Australian adults and children. Eur Respir J 1992; 5: 921-929. Haby MM, Peat JK, Mellis CM, et al. An exercise challenge for epidemiological studies of childhood asthma: validity and repeatability. Eur Respir J 1995; 8: 729-736. Baghurst KI, Record SJ. Intake and sources in selected Australian subpopulations of dietary constituents implicated in the etiology of chronic diseases. J Food Nutr 1983; 40: 1-15. Rohan TE, Record SJ, Cook MG. Repeatability of estimates of nutrient and energy intake: the quantitative food frequency approach. Nutr Res 1987; 7: 125-137. Analyses of NSW fish and shellfish. Sydney: Australian Government Analytical Laboratory, 1989. Sinclair A, Dunstan GA, Naughton JM, et al. The lipid content and fatty acid composition of commercial marine and freshwater fish and molluscs from temperate Australian waters. Aust J Nutr Diet 1992; 49: 77-83. English R, Lewis J. Composition of foods Australia. 1st ed. Vols 1-5. Canberra: AGPS, 1989-1990. Clinical Reporting Systems [computer program], version 3.0. Sydney: Clinical Reporting Systems Pty Ltd. 1992. SAS [computer program], version 5. Cary, NC: SAS Institute, 1984. Toelle BG, Peat JK, Salome CM, et al. Toward a definition of asthma for epidemiology. Am Rev Respir Dis 1992; 146: 633-637. Stone J, Hinks LJ, Beasley R, et al. Reduced selenium status of patients with asthma. Clin Sci 1989; 77: 495-500. Kremer JM, Jubiz W, Michalek A, et al. Fish-oil fatty acid supplementation in active rheumatoid arthritis. Ann Intern Med 1987; 106: 497-503. Lee TH, Hoover RL, Williams JD, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med 1985; 312: 1217-1224. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320: 265-271. Thomas PS, Yates DH, Barnes PJ. Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 1995; 152: 76-80. Arm JP, Horton CE, Mencia-Huerta J-M, et al. Effect of dietary supplementation with fish oil lipids on mild asthma. Thorax 1988; 43: 84-92. Arm JP, Horton CE, Spur BW, et al. The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 1989; 139: 1395-1400. Dry J, Vincent D. Effects of fish oil diet on asthma: results of a 1-year double blind study. Int Arch Appl Immunol 1991; 95: 156-157. (Received 31 May, accepted 28 Nov 1995) Authors' details Institute of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW. Linda Hodge, MSc(Med), GradDipNutr&Diet, Dietitian. Department of Medicine, University of Sydney, Sydney, NSW. Cheryl M Salome, BSc, Senior Research Officer. Jennifer K Peat, PhD, Senior Research Officer. Michelle M Haby, MSc, Research Assistant. Wei Xuan, MSc, MApplStat, Statistician. Ann J Woolcock, MD, FRACP, Professor in Respiratory Medicine. Reprints: Professor A J Woolcock, Institute of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, NSW 2050. (©MJA 1996; 164: 137-140)

Linda Hodge · Cheryl M Salome · Jennifer K Peat · Michelle M Haby · Wei Xuan · Ann J Woolcock

Vaccine-preventable childhood diseases in Australia Too much disease, not enough vaccination: what more can we do? MJA 1996; 164: 61 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/>". - ©MJA1997 In 1994, there were 17 442 notifications of vaccine- preventable diseases in Australia.1 This disgraceful situation exists despite the ready availability of free, safe and effective vaccines. Particularly damning were the 8661 cases of pertussis, measles, mumps, rubella and Haemophilus influenzae type b notified in children up to school leaving age (19 years old) -- all diseases for which a national immunisation program has been in place for many years! Why do we still have so much disease despite good vaccines and good delivery systems? While there is a lack of uniform reliable data on vaccination coverage, it would seem our national childhood vaccination rates are inadequate. The Australian Bureau of Statistics' 1989-90 National Health Survey reported that, according to parental recall, 53% of children up to six years of age had been vaccinated in accord with the National Health and Medical Research Council (NHMRC) vaccination schedules.2 Unpublished data from State health departments include the report of a 1991 cluster survey in Victoria of 630 children aged 18 months to 3 years which found that 88% were fully vaccinated against diphtheria, pertussis, tetanus, polio and measles (John Carnie, Manager, Infectious Diseases Unit, Victorian Department of Health and Community Services, Melbourne, personal communication); a 1994 ACT report found that only 67% of 236 children at school entry (aged about five years) were fully vaccinated (Ms Ann Kempe, Immunisation Coordinator, ACT Department of Health and Community Care, Canberra, personal communication). Whatever the true vaccination coverage, continuing notifications (in the thousands) of cases of measles, with its well-known risks of encephalitis, bronchopneumonia and subacute sclerosing panencephalitis (SSPE), highlight how much still needs to be done. In the United Kingdom a recent national measles-rubella immunisation program has successfully terminated measles virus circulation in schools; in March and April 1995, there were four confirmed cases of measles in England and Wales; three cases had recently arrived in the country, and the other occurred in an unvaccinated 15-month-old child.3 In Australia there were 229 measles notifications for the same period (National Notifiable Diseases Surveillance System, personal communication). there is still a lack of awareness on the part of parents and even some health practitioners of the benefit-risk equation for vaccination On the other hand, notifications of invasive Haemophilus influenzae type b have decreased from at least 3.5 cases per 100 000 population in 19911 to 1 case per 100 000 in 1994.1 Within three years we may see less than a quarter the number of cases of childhood bacterial meningitis recorded in 1990 -- evidence of the benefit of effective vaccination. The National Childhood Immunisation Committee has implemented a number of initiatives over the past two years to increase vaccination coverage rates in line with the goals of the 1993 NHMRC National Childhood Immunisation Strategy.4 More than 30 000 copies of a kit, which included the fifth edition of the Australian immunisation procedures handbook,5 were distributed to general practitioners and other vaccination service providers. A parents' guide to immunisation, Understanding childhood immunisation,6 was also produced and widely distributed; a recent mass media awareness campaign offers this booklet free to enquirers through a toll-free telephone number (1800 671 811). Such initiatives have received broad professional and community support from organisations such as the Australian Medical Assocation, the Royal Australian College of General Practitioners, the Australian College of Paediatrics, the Australian Institute of Environmental Health, the Sudden Infant Death Association and the NHMRC. Technical considerations also play a role in ensuring the optimal efficacy of vaccines: guidelines and systems for cold-chain maintenance have been implemented (some local studies have suggested that some vaccine providers have difficulty maintaining vaccines at between 2-81/4C7,8 ); knowledge of the thermolability of reconstituted measles-mumps- rubella vaccines and of oral polio vaccine at room temp erature is another important consideration. The safety and efficacy of vaccines are apparent to all but a few. A scheme to record, follow-up and regularly publish significant adverse events following vaccination has been under way since March 1995 (general practitioners and other providers notifying respective State or Territory health authorities by telephone). The data are collated, reviewed and published monthly in Communicable Diseases Intelligence. Adverse event rates of less than 1% have been recorded, although the data are as yet incomplete. Nevertheless, there is still a lack of awareness on the part of parents and even some health practitioners of the benefit-risk equation for vaccination, at least for some vaccines. A few individuals who propagate tired myths of exaggerated vaccination harm, however sincerely, make it more difficult to provide concerned parents with balanced benefit-risk information. To address this problem Commonwealth funding of $24 million has been allocated towards childhood vaccination during 1995-96 and 1996-97. Most of this outlay is provided to the States and Territories to purchase NHMRC standard childhood immunisation schedule vaccines in return for their undertaking to provide a coordinated program. Some of this funding will be used to obtain better information about vaccination coverage via the Australian Childhood Immunisation Register, which commenced on 1 January 1996. Information from the Register will enable resources to be targeted effectively to assist areas with the lowest coverage rates. Combination 4-in-1 (tetravalent) and 5-in-1 (pentavalent) vaccines (e.g., against diphtheria, tetanus, polio, Haemophilus influenzae type b and hepatitis B), less reactogenic acellular pertussis vaccines, as well as a varicella vaccine, are soon to appear on local markets. On the eve of the third millennium, once again we as a nation will need to debate the cost-benefit of disease prevention. In this debate we must acknowledge how far we have come in the two hundred years since Jenner's successful inoculations against smallpox, and how far we have yet to go. Gavin W Frost Senior Medical Adviser, AIDS/Communicable Diseases Branch Commonwealth Department of Human Services and Health, Canberra, ACT Monica Johns Senior Project Officer, National Childhood Immunisation Program Commonwealth Department of Human Services and Health, Canberra, ACT Hargreaves J, Longbottom H, Myint H, et al. Annual Report of the National Notifiable Diseases Surveillance System 1994. Commun Dis Intell 1995; 19: 542-574. Australian Bureau of Statistics. 1989-90 National Health Survey Children's Immunisation Survey, Australia. Canberra: ABS, 1992. (Catalogue No. 4379.0.) Interruption of measles transmission in school schildren, 1995. Wkly Epidemiol Rec 1995; 70: 215-216. National Health and Medical Research Council. National Immunisation Strategy. Canberra: NHMRC/AGPS, 1993. National Health and Medical Research Council. The Australian immunisation procedures handbook. 5th ed. Canberra: AGPS, 1995. Herceg A, Shelley S. Understanding childhood immunisation. Canberra: Commonwealth Department of Human Services and Health, 1995. Liddle JL, Harris MF. How general practitioners store vaccines. A survey in south-western Sydney. Med J Aust 1995; 162: 366-368. Herceg A, Longbottom H. A national immunisation provider survey. Canberra: Commonwealth Department of Human Services and Health, 1995. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Gavin W Frost · Monica Johns