Volume 185 Issue 4

Health professionals must create the climate to force politicians to act Australia is in the throes of an unprecedented epidemic of diabetes and obesity. The Australian Diabetes, Obesity and Lifestyle (AusDiab) study found that a million Australians are affected by diabetes, and it provided vital data on Australia’s obesity epidemic.1 Obesity is a driving force behind type 2 diabetes, which has cardiovascular and other complications, such as renal failure and blindness. The dominant effect of weight gain in precipitating glucose intolerance and its consequences suggests that reversal of the “diabesity” epidemic requires a public alert on the need to limit weight gain. The heightened risk of type 2 diabetes occurs at levels of abdominal or general obesity previously regarded as normal. For decades in affluent societies such as Australia, women have been obsessed with their shape and weight. They spend huge amounts of time and money desperately trying to slim, with little effect — men do no better. Meanwhile, the epidemic of both obesity and diabetes shows no sign of slowing. There is a biological component to persistence of the epidemic. The adaptation in hypothalamic control of appetite to reinforce higher food intakes and the endocrine and metabolic thermogenic adjustments with slow weight gain counteract attempts to lose weight.2 Coupled with the modern commercial drive to market unhealthy foods everywhere and seduce us into ever more sedentary leisure, this means we are facing a seemingly unstoppable juggernaut of obesity and diabetes. This epidemic is guaranteed to continue, unless we accept that the decades-long reliance on health promotion and intense media coverage of obesity have had virtually no effect. Dietary advice from doctors has induced only minimal reductions in blood pressure and cholesterol levels, and the results for weight control are probably worse.3 Meanwhile, politicians and health professionals confine themselves to promoting the value of health education. Evidence-based approaches now require us to discard our prejudices and preconceptions and consider converting policymakers and politicians. We must also recognise the influential commercial forces that contribute to an ever more obesogenic and diabetogenic environment. What, realistically, can our politicians do? Australia has a reputation for outstanding obesity research, ranging from public health and epidemiology to molecular biology. However, what is being done strategically about the problem? On the surface, Australia is making what are seen as major investments in promoting leisure time sports and other activities, especially for youth. Presumably, this is based on the recent advice that to cure the obesity problem we need only change input and output by a mere 100 kcal — which seems to be a minute change.4 This implies that all one has to do is get a pedometer to encourage walking, or eat one less slice of bread each day. Unfortunately, there is a dearth of evidence that this works. The current rates of weight gain, varying perhaps from 0.5 to 2 kg/year in the very susceptible, amount to about 10–40 kcal (ie, 0.3%–2% of energy turnover) in the average daily discrepancy between input and output. However, we need to walk briskly for 80–90 minutes daily (ie, about 350 kcal of daily effort) to maintain energy balance on current diets.5 This is a near impossible population goal for leisure time activity. Alternatively, given our current sedentary state, we would need to change to a diet of 20% fat intake with minimal sugary drinks.6 This implies that our hypothalamic regulatory system works to minimise energy imbalance, so the external environmental changes must be of a greater magnitude than the induced energy imbalance. It is ludicrous to expect the whole population — including the disadvantaged — to voluntarily become very active on an optimum diet. Thus, we need to change substantially our living conditions and environment. Our politicians need to accept that major legislative and other regulatory measures are required (see Box). We could arrest the development of obesity in children and adolescents within a year of introducing a coherent program. If the political will is there, then there is hope. The current pervasive marketing to children distorts their understanding, codifies their demands, and transforms their eating, drinking and exercise habits to generate obesity.7 Changing this requires legislative regulation of the marketing pressures (including television and other advertisements which now dominate children’s attention). Parliamentary enquiries in the United Kingdom have revealed that some food and advertising companies may be misleading consumers as blatantly as the tobacco industry did.7 Voluntary restrictions have never been shown to work. Health professionals and their peer organisations must demand that all junk foods and soft drinks be kept out of health institutions, schools and public institutions, as these products can induce as much illness as tobacco.8 They should also go public, demanding political change to transform the school environment and curriculum to improve physical and nutritional education, as well as the food and drink on the premises. In adults, the problem is greater. Nevertheless, a start could be made with statutory food labelling. Currently, labels cannot be understood by consumers nor converted into meaningful units for individuals with different energy needs. Furthermore, health claims are often misleading. Consumers’ views should dominate labelling design (eg, “traffic light” indicators of overall nutritional quality9). A universal display of nutritional health profiles of food products could dramatically change consumers’ choice. In Finland, the introduction of free vegetables and a salad bar with meals sold in canteens and restaurants was associated with a threefold increase in the population’s vegetable consumption. Standards are also needed for the nutritional content of all meals provided within the public sector. The food industry would respond rapidly to new requirements, to ensure continued sales and profits. It is natural that politicians focus on evident benefits within a short parliamentary cycle. But the result is that nothing will happen until health professionals, including the medical profession, engage politicians and media opinion leaders to create a climate that will force politicians to respond to public opinion. Targeting the protection of children’s health, presenting clear analyses of the financial cost of political inertia, and highlighting the need to resist short-term commercial interests is the way to engage high-level politicians. A great example was Tony Blair’s response within 24 hours when Jamie Oliver started soliciting potential votes unless British school dinners improved. The prevention of obesity and type 2 diabetes requires coordinated policy and legislative changes, with greater attention given to our urban environment, transportation infrastructure, and workplace opportunities for education and exercise. Governments — local, state and federal — should commit to optimising opportunities for exercise in a safe environment. A multidisciplinary, politically driven, coordinated approach in health, finance, education, sports, and agriculture can contribute to reversing the underlying causes of the diabesity epidemic. Our medical leaders must recognise their crucial role, and federal and state politicians must look beyond the next election. Is anyone in Canberra listening? Regulatory measures needed to prevent diabesity in Australia Ban all marketing of food to children, including television advertisements. Establish strict food and physical activity requirements for schools. Remove junk foods and drinks from all publicly funded premises. Require “traffic light” food labelling (based on nutritional profiling) on all foods, drinks and meals, wherever sold. Adjust fiscal policies to progressively change the relative prices of foods and drinks high in fat or sugar in favour of vegetables and fruit. Specify urban environmental requirements favouring pedestrians and cyclists.

Paul Z Zimmet AO, FRACP, FRCP(London), FTSE · W Philip T James MD, DSc

Routine infection control strategies are likely to have the most benefit There is increasing concern regarding the possibility of another influenza pandemic arising from genetic mutation or reassortment of the avian influenza strain H5N1.1-3 Governments have stockpiled billions of dollars worth of antiviral agents, even though efficacy may be limited.4 Vaccines are being developed for a disease that does not yet exist.5 Many birds have been destroyed in the hope of preventing a possible future mutation and spread of disease to humans.6 Meanwhile, since the 1918 influenza pandemic, the seasonal winter flu has killed more people than the number who died in the pandemic.7 The recent SARS epidemic was a wake-up call regarding the risk of major epidemics. While important differences exist between SARS and pandemic influenza, the experience of controlling SARS provides some lessons on how to prepare for major outbreaks. It is possible that the next global infectious disease threat will not be influenza. Improving general infection control procedures and preparedness has the potential to improve routine health care on a daily basis as well as improve our ability to manage the next pandemic (Box). The SARS epidemic was not predicted. It took time to recognise that there was an epidemic and then to identify the virus.8 Cooperation among affected countries led to a coordinated effort to improve infection control procedures and limit spread of the disease. The epidemic was controlled largely with basic epidemiological principles of outbreak management and basic infection-control strategies. Hospital infection controlInfection control in hospitals is likely to have the most benefit in controlling a pandemic. The following points need to be considered. Overcrowding: Several of the hospitals affected in the SARS outbreak were suffering from chronic overcrowding (common to all Western countries). Patients were accommodated in beds less than one metre apart and routine infection-control procedures such as hand washing and changing gowns between patients were not possible. Overcrowding in emergency departments, and hospitals generally, inevitably increases the risk of infectious disease outbreaks.9 A separation of at least one metre should be maintained between patients and staff wherever possible. Separation of patients should be routine for all patients with undifferentiated, potentially infectious, illnesses. The easiest way to enforce separation of patients and encourage hand washing and other basic infection-control behaviour is to physically separate the patients in single rooms. Hand washing: Many studies have shown that hand washing protocols are not followed. This is partly related to ward layout, but also involves training and use of innovative solutions, such as staff having small antiseptic lotion bottles around their neck. It does need concerted effort and a culture change. Masks should be used routinely when dealing with patients who have undifferentiated, potentially infectious, respiratory illnesses or any infection that can be spread by droplets or aerosolisation (eg, measles, SARS). It is unclear whether high-performance masks (eg, N95) are needed or whether fit-testing is required, but it is probably more important to wear some type of mask routinely rather than a high-performance mask intermittently. Experience suggests that known high-risk patients represent a lesser threat than an unrecognised patient presenting with what is thought to be a common condition. Both patients and staff should wear masks. Personal protective equipment should be simple, such as disposable gowns, gloves, masks and eye protection.10 Expensive and complicated equipment, if used at all, should be limited to high-risk procedures (eg, airway procedures), as it is difficult to use properly. Design flaws are present in many hospitals. Examples include turbulent ventilation across patient areas and flow of aerosolised gases between treatment areas. Negative pressure rooms are frequently in short supply, if they exist at all, and would be insufficient in a pandemic. Therefore, other strategies are needed, such as physically separating patients, using curtains as separators, and cohorting infected patients as required. The benefits of good infection control were demonstrated during the SARS epidemic, with reduced staff sickness rates and fewer common infections such as gastroenteritis.11 A recent study has shown that in-hospital infection rates with multiresistant organisms are also reduced by good basic infection control.12 Improving day-to-day infection control will also ensure staff familiarity with basic infectious disease principles and allow rapid implementation in a pandemic. It is prudent to ensure that all first-line staff are fully vaccinated for common diseases, and risk assessment should be undertaken regarding other vaccination for staff. Other lessons from SARSEpidemiological skills: Many of the hospitals and communities affected by the SARS epidemic did not have the ability to rapidly deploy skilled staff for epidemiological study of the epidemic as it unfolded. This led to delays in contact tracing and control of the outbreak. Epidemiological skills need to be readily available, either directly through the hospital, or through a regional or national facility. Agreed isolation procedures: During the SARS outbreak, there was little consensus on how to quarantine and cohort potentially affected people — both in hospitals and in the community. Planning and capability to perform these functions should be researched now. Additionally, planning for surge capacity should be part of routine health care planning.13 Coordination and oversight: A poorly integrated public health system meant policies and protocols could vary even in neighbouring communities. Governments scrambled to set up expert committees composed of individuals with varied backgrounds and no history of working together. The absence of legislation empowering governments to compel health authorities and hospitals to comply with directives led to confusion and often incomplete compliance. An agreed regional approach for an infectious disease outbreak is essential; there are many authoritative guidelines.14,15 Equally, the dangers of a profusion of lengthy guidelines must be avoided. Materials must be made available to front-line staff, and should be concise, applicable and accessible. If a major infectious disease outbreak occurs, antivirals and vaccines are unlikely to be effective initially, as it will be a new disease or mutation (whether avian flu or not). Improving routine infection control procedures within hospitals is likely to have a much greater effect on limiting a new outbreak within hospitals, as well as providing benefits on a daily basis to patients and staff. Strategies to limit an infectious disease outbreak from any likely cause Strictly follow routine precautions in hospitals: Hand washing (alcohol/non-alcohol based lotions preferable to soap and water) Wearing of masks, gowns, gloves, goggles Maintaining one metre distance between patients and staff where possible Placing patients with undifferentiated infectious disease in single rooms. Avoid overuse of complicated or expensive approaches, as they cannot be used routinely (eg, negative pressure rooms, isolation suits). Limit exposure to procedures that produce aerosolisation (eg, intubation, nebulisation). Avoid hospital overcrowding, especially in emergency departments. Have a planned approach for isolation and cohorting of large groups of potentially affected people. Develop epidemiological and disease surveillance skills. Ensure staff are up to date in regular staff vaccination schedule. Ensure health system has a sustained surge capacity.

Peter A Cameron MB BS, FACEM · Michael Schull MD, MSc, FRCPC · Matthew Cooke PhD, FCEM, FRCS(Edin)

Objective: To evaluate the use of cardiovascular medications in patients with and without heart failure after myocardial infarction (MI).Design and setting: Multicentre study of drug therapy for patients with MI in 16 major metropolitan teaching hospitals in Australia over a 1-month period at each hospital in the period November 2004 – March 2005.Participants: 479 patients admitted consecutively to the individual hospitals.Main outcome measures: Proportion of patients with and without heart failure who were prescribed key cardiovascular medications after MI.Results: 116 of the 479 patients admitted for MI (24.2%) had heart failure at some point during their hospitalisation. Patients with heart failure were older (68 v 63 years; P < 0.05), more likely to be women (34% v 24%; P < 0.05) and a higher proportion had diabetes (26% v 21%). There was significantly reduced prescribing of β-blockers, clopidogrel and statins for patients with heart failure compared with those without heart failure. Mineralocorticoid receptor antagonist use was low (< 10%) in the former group.Conclusions: We found reduced prescribing of some prognostically relevant medications for patients with heart failure. For β-blockers, this may be explained by the greater clinical instability in patients with heart failure. Given the absolute benefit of drug therapy in patients with heart failure after MI, our findings suggest suboptimal prescribing in Australian teaching hospital practice.

Henry Krum MB BS, PhD, FRACP · Adam Meehan · John Varigos BSc(Hons) · Philippa R Loane BBiomedSc · Baki Billah PhD

Objective: To assess the feasibility of administering an inexpensive preparation of vitamin D3 100 000 IU orally 3 monthly to aged-care residents.Design: Prospective, controlled open-label implementation trial.Setting: Residential aged care, November 2003 to May 2004 (primary study).Participants: 137 ambulant residents: 107 treated (mean age, 85 years; 79 were women), 30 untreated controls (mean age, 87 years; 22 were women).Interventions: Lactose microencapsulated vitamin D3 100 000 IU orally at baseline, then 3 monthly (three or more doses); untreated subjects were observed contemporaneously.Main outcome measures: Serum levels of 25-hydroxyvitamin D [25(OH)D] at 6 months compared with baseline; acceptability of the program to residents and staff.Results: At baseline, 95% of residents assessed (n = 137) had serum 25(OH)D levels below the desirable range of 60–160 nmol/L. At 6 months, all treated residents (n = 98) achieved desired levels, with the mean (± SD) 25(OH)D level increasing from 36.4 ± 12.6 nmol/L (range, 12–75 nmol/L) at baseline to 124.0 ± 27.9 nmol/L (range, 68–244 nmol/L). In no resident did 25(OH)D approach toxic levels. The mean serum 25(OH)D level remained low in the control group (n = 27): 42.8 ± 18.3 nmol/L (range, 18–98 nmol/L). The difference between the mean 25(OH)D levels of treatment and control groups at 6 months was 81.2 nmol/L (95% CI, 69.7–92.0 nmol/L). The cost of the supplement was $4 per resident per annum. Substudies showed mean trough serum 25(OH)D levels in the desired range at 3 months (n = 31), but below the desired range at 6 months (n = 50). Subjects given 3-monthly doses for up to 2 years maintained serum 25(OH)D levels within the desired range, with no trend toward undesirable accumulation (n = 11).Conclusions: Vitamin D3 100 000 IU given orally 3 monthly is a practical, safe, effective and inexpensive way to meet the vitamin D3 requirements of aged-care residents.

Alison E R Wigg BAppScPhysio, MAppScPhysio, MBA · Caroline Prest RN · Peter Slobodian BPharm, MClinPharm · Allan G Need MD, FRACP, FRCPA · Leslie G Cleland MD, FRACP

Objective: To assess the efficacy of endovenous laser therapy (EVLT) for treating varicose veins with saphenous reflux.Design: A trial of treatment, with results assessed by ultrasound surveillance.Setting: Outpatient clinics with sonographer and nursing support.Main outcome measures: Control of reflux; occlusion or obliteration of the saphenous veins assessed by ultrasound.Results: EVLT was used to treat 404 veins in 308 patients. Univariate life table analysis showed primary success in 80% (95% CI, 69%–87%) and secondary success after further treatment of recurrent saphenous vein reflux by ultrasound-guided sclerotherapy in 88% (95% CI, 78%–95%) at 3 years. On multivariate Cox regression analysis, none of the covariates studied were associated with ultrasound failure.Conclusions: Early results indicate that EVLT effectively controlled saphenous reflux. Its advantages are that it is performed as an outpatient procedure under local anaesthesia with immediate mobilisation, causes minimal disruption of activities, and avoids surgical trauma.

Kenneth Myers MS, FRACS, FACS · Robert Fris FRACS, FACS · Damien Jolley MSc(Epidemiol)

Objectives: (i) To determine the proportion of patients in New Zealand who claim compensation from the national no-fault compensation program after experiencing a compensable injury; and (ii) to identify characteristics of injured patients who are least likely to claim despite having sustained a compensable injury.Design: We estimated the percentage of eligible patients who claim no-fault compensation by linking a national claims database (Accident Compensation Corporation) to records reviewed in the New Zealand Quality of Healthcare Study (NZQHS). Bivariate and multivariate analyses were used to investigate socioeconomic and sociodemographic differences between claimants and injured non-claimants.Participants and setting: Patients who experienced an adverse event associated with care in NZ public hospitals in 1998 and claimed compensation with the ACC, the national no-fault insurer (n = 741). Patients identified by the NZQHS as having sustained an adverse event associated with hospital care in the same year who did not file a compensation claim (n = 839).Main outcome measures: Adverse events, compensable adverse events, and compensation claims.Results: Among patients judged by NZQHS reviewers to be eligible for compensation, 2.9% (6/210) claimed. Odds of claiming after an adverse event were significantly lower for patients who were elderly (odds ratio [OR], 0.20; 95% CI, 0.14–0.28), from the most deprived areas (OR, 0.36; 95% CI, 0.23–0.57), or of Māori; or Pacific ethnicity (OR, 0.47; 95% CI, 0.32–0.69 and OR, 0.26, 95% CI, 0.11–0.58).Conclusions: Despite few apparent institutional or economic barriers, the proportion of injured patients in NZ who seek compensation after sustaining a compensable injury is very low. Hence, substantial underclaiming occurs in both negligence and no-fault systems. The disproportionately low propensity of elderly, poor and minority patients to seek compensation also appears to be pervasive.

Marie M Bismark MB ChB, LLB, MBHL · Troyen A Brennan MD, JD, MPH · Peter B Davis PhD · David M Studdert LLB, ScD, MPH

Objective: To evaluate the outcomes of the research investment of the National Heart Foundation of Australia (NHF).Design and setting: The NHF Research Evaluation Working Group was established in 2002 to oversee evaluation of research funding and outcomes data collected over a 5-year period. The evaluation included a bibliometric analysis conducted by the Research Evaluation and Policy Project at the Australian National University.Outcome measures: Level and leverage of research funding; funding levels across the disciplines of biomedical, clinical, and public health research; and visibility and knowledge impact of NHF-supported research in international cardiovascular journals.Results: The NHF’s investment in research increased by 27% from 2001 to 2005. This increase resulted from leveraged support for fellowships and scholarships of $1.5 million over this period, and $2.2 million from the pharmaceutical industry. There was an increase in fellowship and scholarship funding from 26% in 2001 to 46% in 2005. There was a 75% increase in the funding allocated to public health research from 2002 to 2004. NHF-funded research publications were found in high impact journals at levels above Australian and world averages, but received fewer citations than expected based on citation rates for all similar articles.Conclusions: The NHF has been successful in implementing a policy to allocate 50% of its research funding to people and 50% to projects. This strategy has led to an increase in funding support for public health research. NHF-funded research has performed very well in terms of knowledge impact. The NHF is now well placed to strategically fund relevant research in the future.

Moira A Clay PhD · Claire Donovan PhD · Linda Butler BEcon · Brian F Oldenburg PhD

Contemporary medicine has much to its credit, but has created an insatiable demand for new technologies and more health services, fed by commercial promotion, professional advocacy and sociopolitical pressure. Total health expenditure at the national level is now almost 10% of gross domestic product and is expected to top 16% by 2020. After recent inquiries into the failings of its public health system, the Queensland Government has committed itself to a 25% increase in expenditure on health over the next 5 years. But will it lead to better population health, and is it sustainable? The return-on-investment curve for modern health care may be flattening out, in an environment of growing numbers of older patients with chronic illnesses, maldistribution of services and hospital overcrowding. A change in thinking is required if current medical practice is to avoid imploding when confronted with the next major economic downturn. Health policy, service funding and clinical training must focus on critical appraisal of the effectiveness of health care technologies and the structure and financing of health care systems. Practising clinicians will be obliged to provide leadership in determining value for money in the choice of health care for specific patient populations and how that care is delivered.

Ian A Scott FRACP, MHA, MEd

Australia is one of the few developed countries without routine antenatal HIV screening, despite having the resources to undertake such a screening program and the availability of antiretroviral therapy. National policy recommends that only women with identified risk factors should be offered testing; however, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists recommends that all pregnant women be offered HIV testing as part of their antenatal care. Knowledge of a woman's HIV status during pregnancy allows interventions to improve her health and reduce the risk of transmission of HIV to her child. A universal antenatal HIV screening program meets many of the Wilson and Jungner criteria for population-based screening programs. This should be considered in the current review of Australia's HIV testing policy.

Michelle L Giles MB BS, FRACP · Margaret E Hellard FRACP, PhD · Sharon R Lewin FRACP, PhD · Anne M Mijch MB BS, FRACP

Clinical record A 29-year-old man presented with a history of increasing lethargy and malaise for 3 months. He had lost 3 kg in weight and noticed mild ankle oedema. His previous medical history was unremarkable, and he had no relevant family history. He had been a professional body builder for 10 years, previously competing at high levels. He attended a gymnasium daily for weight-lifting. His dietary protein intake was very high (3.5 g/kg daily) and he took 5 g/day creatine powder supplement. Although he was not taking any regular medication, he admitted to extensive use of anabolic steroids (including testosterone and nandrolone) over a 10-year period. On examination, he weighed 103 kg and was 175 cm tall (body surface area, 2.24 m2) and his blood pressure was 195/110 mmHg. His chest was clear, and cardiovascular examination showed no abnormalities except for mild peripheral oedema. Investigations revealed a serum creatinine level of 1346 μmol/L (reference range [RR], 30–120 μmol/L) and a urea level of 63.5 mmol/L (RR, 2.5–7.5 mmol/L). Values obtained in other investigations included: haemoglobin, 112 g/L (RR, 125–175 g/L); albumin, 35 g/L (RR, 34–50 g/L); potassium, 3.8 mmol/L (RR, 3.5–5.0 mmol/L); corrected calcium 1.98 mmol/L (RR, 2.10–2.55 mmol/L); phosphate, 2.95 mmol/L (RR, 0.81–1.45 mmol/L); and parathyroid hormone, 31.8 pmol/L (RR, 1.3–6.8 pmol/L). Results of a mid-stream urine test were unremarkable except for protein 3+, and a 24-hour urine collection revealed 10.7 g/day proteinuria. An ultrasound examination of the renal tract showed two normal-sized kidneys without hydronephrosis, but with diffusely increased parenchymal echogenicity. A renal biopsy confirmed a diagnosis of focal segmental glomerulosclerosis, with marked tubulointerstitial damage. Counselling was provided, with information about dialysis and kidney transplantation options. The patient was prescribed amlodipine, which gave good blood pressure control, and calcium carbonate as a phosphate binder. He was also given dietary advice. As he had only mild symptoms, and to avoid using a tunnelled dialysis catheter, haemodialysis was not immediately initiated. Calculations of overall renal function gave varying results (Box 1). Calculated from the serum creatinine level at presentation, the estimated glomerular filtration rate (eGFR) (based on the abbreviated MDRD [modification of diet in renal disease]) was 5.18 mL/min/1.73 m2. The full MDRD equation (6-variable) gave a GFR of 4.96 mL/min/1.73 m2. However, the Cockcroft–Gault formula, weight included, gave a GFR of 8.05 mL/min/1.73 m2, and 24-hour urine collection gave results for creatinine clearance of 12.97 mL/min/1.73 m2. A radioisotope nuclear renal scan (DTPA [diethylenetriaminepentaacetate]) to better clarify the degree of renal impairment showed equal function of both kidneys and a GFR of 13.51 mL/min/1.73 m2. Over the following few weeks, with changes in diet and cessation of creatine supplements, serum creatinine and urea levels decreased slightly, and arrangements for an early living-related renal transplant were formulated. However, because of worsening uraemic symptoms, dialysis was eventually commenced and was required for 3 months before successful transplantation with a kidney donated by the patient’s mother. Serum creatinine level, the most commonly used measure of kidney function in clinical practice, varies with factors other than kidney function. These include age, sex, muscle mass, and dietary protein intake. Glomerular filtration rate (GFR) is therefore widely accepted as a better marker. Numerous equations using the serum creatinine level have been developed to calculate estimated GFR (eGFR) (Box 2). Recently, automated reporting of eGFR using the MDRD (modification of diet in renal disease) formula has been introduced, but limitations exist, especially with extremes of body size. Our patient illustrates the difficulties of calculating GFR for a person with a large muscle mass, with different methods giving widely varying results. The recently published CARI (Caring for Australasians with renal impairment) guidelines recommend that serum creatinine level alone should not be used to measure kidney function, because of the multitude of factors other than renal function that can affect this marker.1,2 Serum creatinine is derived from the metabolism of creatine in muscle and the generation of creatinine tends to be proportional to muscle mass. In adults, the abbreviated (4-variable) MDRD, the 6-variable MDRD, and the Cockcroft–Gault equations generally provide reliable eGFRs. The Cockcroft–Gault formula is probably the most widely recognised formula for conversion of serum creatinine level, although with reductions below 60 mL/min it becomes increasingly inaccurate compared with the MDRD formula. Recently, the abbreviated MDRD formula has been used in the automated laboratory reporting of eGFR in Australia, given extensive validation with no correction needed for body surface area. It is important to note that the different units for GFR measurements (mL/min for Cockcroft–Gault versus mL/min/1.73 m2 for MDRD) can create some discrepancy in their comparison (see Box 1). MDRD and Cockcroft–Gault equations are essentially rescaled serum creatinine levels with the same pitfalls as using the serum creatinine level itself. They are based on statistical models predicting averages, and our patient was not average. Therefore, clinical judgement is always required with eGFR, and the clinician has the advantage of being able to consider dietary history and physical examination — factors not considered in these equations. Lessons from practice Estimated glomerular filtration rate (eGFR) may be inaccurate in patients whose body size and muscle mass, or dietary intake (eg, high protein diets and creatine supplements), are at the extremes of the normal range. In such patients, formal measurement of GFR by radioisotope nuclear renal scan should be undertaken. eGFR should not be relied on as the sole determinant in making decisions about the commencement of dialysis; investigations should be interpreted in conjunction with the overall clinical picture. Previously, 24-hour urine collections to assess creatinine clearance were commonly used. These are inconvenient, inaccurate because of inadequate collection techniques, and, with severe renal impairment, creatinine clearance overestimates GFR. With worsening impairment there is an increase in tubular creatinine secretion, ranging from 10% to 50%, and therefore variations may alter the relationship between serum creatinine level and GFR.3 Nuclear medicine scans provide validated direct measures of GFR and are useful in circumstances of extremes of body size or age, high or low dietary intake of creatinine or creatine supplements, and patients with muscle disease or atrophy. They determine renal clearance of exogenous filtration markers, most commonly DTPA (diethylenetriaminepentaacetate), and provide acceptably accurate measurements, although it is recognised that they may overestimate GFR.1,2 The disadvantages of radionucleotide GFR measurement relate to safety with the use of radiolabelled compounds and the cost. In our patient, different methods of GFR measurement provided a range from 4.96 to 13.51 mL/min/1.73 m2, depending on the equation or the investigation used. The CARI guidelines suggest that dialysis should be commenced when GFR falls below 10 mL/min/1.73 m2, if associated with symptomatic uraemia or malnutrition, or below 6 mL/min/1.73 m2, if asymptomatic.4 Initiation of dialysis in our patient, with risks of temporary dialysis access, was weighed against the decision to wait for a renal transplant, given that the patient was initially relatively asymptomatic. The best option for renal replacement therapy is kidney transplantation where appropriate, and the patient’s mother had volunteered as a potential donor. The commencement of dialysis is sometimes a difficult decision and clinicians need to recognise the inaccuracies with eGFR measurement. Symptoms, treatment options and rate of GFR decline are among a multitude of factors that must be taken into account in the decision to initiate dialysis. Having illustrated some of the limitations in determining renal function using eGFR, we strongly advocate routine automated reporting in clinical practice. eGFR is extremely useful for identifying patients at risk of progressive chronic kidney disease and correlates well with complications, including an increased risk of cardiovascular morbidity and mortality. An educational program is underway, involving distributed written material and short courses organised by Kidney Health Australia, to ensure that information is available to help health professionals interpret eGFR values. It should be appreciated that there are specific clinical settings in which eGFR is not appropriate and GFR should be measured directly through other methods. 1 Variations in estimated and measured glomerular filtration rate (GFR) for the same patient (serum creatinine level, 1346 μmol/L; body surface area, 2.24 m2) Method of calculation GFR (mL/min) GFR (mL/min/1.73 m2) MDRD 6.42 4.96 MDRD (abbreviated) 6.71 5.18 Reciprocal serum creatinine 7.33 5.66 Cockcroft–Gault 10.43 8.05 Creatinine clearance (24-h urine) 16.80 12.97 Radioisotope scan (DTPA) 17.50 13.51 MDRD = Modification of diet in renal disease. DTPA = diethylenetriaminepentaacetate. 2 Equations for calculating estimated glomerular filtration rate (eGFR) Body surface area (BSA): BSA (m2) = 0.007184 × (height [cm])0.725 × (weight [kg])0.425 Cockcroft–Gault formula: GFR (mL/min) = (140 − age) × weight × 1.228/SCr × (0.85, if female) Reciprocal serum creatinine: GFR (mL/min) = 100/SCr × 100 MDRD (6-variable): GFR (mL/min/1.73 m2) = 170 × (SCr/88.4)−0.999 × age−0.176 × (SU × 2.78)−0.17 × albumin0.318 × (0.762, if female) × (1.18, if African American) Abbreviated MDRD (4-variable): GFR (mL/min/1.73 m2) = 186 × (SCr/88.4)−1.154 × age−0.203 × (0.742, if female) × (1.210, if African American) GFR = glomerular filtration rate. SCr = serum creatinine level (μmol/L). SU = serum urea level (mmol/L). MDRD = Modification of diet in renal disease.

Nigel D Toussaint MB BS, FRACP · John W M Agar MB BS, FRACP · Vincent D'Intini MB BS, FRACP

A 50-year-old man was transferred to the intensive care unit with high anion gap metabolic acidosis. Investigations suggested a diagnosis of pyroglutamic acidaemia. Factors contributing to the acidosis were medications (paracetamol and flucloxacillin), sepsis and renal failure. The acidosis resolved with supportive therapy and withdrawal of the drugs. It is important to recognise this treatable aetiology of metabolic acidosis. Clinical recordA 50-year-old man with cerebral palsy, intellectual impairment and epilepsy was referred to hospital with a 1-week history of fever, chills, rigors, haematuria and loin pain. His usual medications included phenytoin 300 mg/day, phenobarbitone 30 mg/day and carbamazepine 1200 mg/day. There was no history of prior renal disease. At hospital admission (Day 1), he was conscious, in no obvious distress, and afebrile. He was dehydrated and tachypnoeic (respiratory rate, 22 breaths/minute), but haemodynamically stable. There was no pallor, jaundice or cyanosis. Cardiorespiratory examination was unremarkable. Abdominal examination revealed tenderness in the left renal angle, left loin and right upper quadrant with no features of peritonism. Key initial (and subsequent) screening investigations are summarised in Box 1. Of note was neutrophilia and significant renal impairment (glomerular filtration rate, 28 mL/min by MDRD 4-variable equation). Urinalysis showed sterile pyuria, haematuria (dysmorphic red blood cells on microscopy) and proteinuria (3.46 g following 24-hour collection). A chest x-ray (CXR) showed mild generalised bronchial wall thickening, with no focal parenchymal opacity. Treatment with empirical broad-spectrum intravenous antibiotics (ceftriaxone and gentamicin) was initiated for suspected urinary tract infection following blood and urine cultures. A computed tomography (CT) scan on Day 1 revealed a 2.3 cm simple cyst in the upper pole of the right kidney, multiple nodules in the lung bases and a small left pleural effusion. A vasculitic work-up, including assessment of antinuclear antibody, extractable nuclear antigen, antibodies to double-stranded DNA, antineutrophil cytoplasmic antibodies and complement levels, did not assist in diagnosis. Urine culture was negative, so a renal biopsy was performed to establish the aetiology of the acute nephritic syndrome, consistent with IgA nephropathy with mild activity (segmental crescents/necrotising lesions in two of 14 glomeruli), but without scarring. No treatment was indicated. In view of the persistent fever on Day 3, a repeat CXR was performed. A small left-sided effusion was noted and pleural fluid aspirate was consistent with an exudate (pleural fluid white cell count [WCC], 16.6 × 109/L; 85% neutrophils; total protein, 37 g/L; lactate dehydrogenase [LDH], 420 U/L), which was presumed secondary to an underlying pneumonic process. Intravenous flucloxacillin was commenced at 2 g/day to broaden the gram-positive antibiotic cover and continued for 11 days. Blood, urine and pleural fluid cultures were negative. Despite initial clinical and laboratory improvement, the fever recurred on Day 7 with a radiographically visible increase in the pleural effusion size. Repeat pleural aspirate confirmed an empyema (pleural fluid pH 6.4; LDH, 833 U/L; glucose, 0.2 mmol/L) requiring intercostal catheter insertion. However, there was minimal further drainage, despite intrapleural streptokinase administration. On Day 14, ceftriaxone and gentamicin were changed to empirical timentin and ciprofloxacin because of persistent fever and rising WCC. Flucloxacillin was increased to 4 g/day. Oral paracetamol (1 g every 6 hours as required) and subcutaneous fentanyl were administered for pain relief. On Day 18, deteriorating renal function and conscious state necessitated transfer to the intensive care unit (ICU). Investigations at ICU admission (Box 1) revealed a severe high anion gap (42 mmol/L) metabolic acidosis. Arterial blood gas analysis (on 100% inspired oxygen) showed a pH of 7.31, PaO2 242 mmHg, PaCO2 12 mmHg, and HCO3 5.6 mmol/L. Flucloxacillin and paracetamol were ceased, and intravenous vancomycin was commenced. Intravenous bicarbonate infusion (25 mL/hour), commenced in the ward for the acidosis, was continued. With supportive therapy (fluids, oxygen, antibiotics), the patient improved over the next 36 hours and the metabolic acidosis resolved. Following stabilisation, the patient underwent decortication of the left pleura. Histopathology was consistent with an organising fibrinous pleuritis. No bacteria were seen. Decortication was complicated by significant bleeding, requiring massive transfusion. After surgery, the patient’s renal function, respiratory function and conscious state steadily improved; he was extubated 5 days after decortication. Recovery was complicated by protracted vomiting. Endoscopy confirmed a Barrett’s oesophagus and small hiatus hernia; he improved with a proton-pump inhibitor. In the absence of further respiratory compromise, he was discharged home. DiagnosisThe cause of the high anion gap metabolic acidosis at ICU admission was not immediately apparent. Serial evaluation of biochemical markers showed worsening renal function. However, even with a creatinine level of 0.541 mmol/L, the expected level of unmeasured anions was only 10–19 mmol/L and was insufficient to explain an anion gap of 42 mmol/L and the severity of the metabolic acidosis. Lactate (0.7 mmol/L) and blood glucose levels (6.1 mmol/L) were not elevated, and urinalysis was negative for ketones, suggesting that lactic or keto-acidosis were unlikely causes (blood ketones were not measured). There was no history of salicylate administration or ethylene glycol, ethanol or methyl alcohol consumption. Case-note review indicated that the patient had received a total of 8 g of paracetamol and 16 g of flucloxacillin in the 4 days before ICU admission. Ongoing sepsis and worsening renal failure, in combination with these drugs, suggested a possible diagnosis of pyroglutamic acidaemia (PGA). Urine pyroglutamic acid levels, highly elevated 36 hours after ICU admission (Box 1) remained elevated 10 days later, although the values had decreased significantly. Plasma pyroglutamic acid levels were also markedly elevated 36 hours after ICU admission (Box 1). The very high urine and plasma pyroglutamic acid levels supported our diagnosis of PGA. Red cell glutathione synthetase activity was normal (5.6 μmol/g haemoglobin; reference range, 4.2–9.8 μmol/g haemoglobin), suggesting that it was unlikely that this patient had a hereditary disorder of the γ-glutamyl cycle. DiscussionHigh anion gap metabolic acidosis is frequently encountered in critical care practice. Recently, there have been several reports of high anion gap acidosis resulting from excess production of 5-oxoproline, and termed “pyroglutamic acidaemia”.1-5 This acidaemia is most frequently reported with paracetamol therapy,1 but has also been associated with flucloxacillin2 and vigabatrin,3 particularly in the setting of severe sepsis, renal or hepatic dysfunction.4 The reported inciting dose of paracetamol has been variable: 8 g of paracetamol daily for 3 weeks in one study,6 and a cumulative dose of 20.8 g of paracetamol over 2 weeks in another.7 In a series of 11 patients with transient oxoprolinuria, all patients were taking paracetamol, with most receiving therapeutic dosages.8 A serum paracetamol level of > 200 μmol/L was seen in only one of the eight patients in whom paracetamol levels were checked. Our patient received a cumulative dose of 8 g of paracetamol over 4 days, and it is likely that PGA was precipitated by a combination of factors, including sepsis, renal dysfunction, and co-administration of flucloxacillin. PGA also occurs with genetic deficiency of either glutathione synthetase or 5-oxoprolinase.5 However, not all causes of 5-oxoprolinuria are necessarily associated with acidaemia. The mechanism of non-hereditary PGA is probably multifactorial. Suppression of glutathione levels because of sepsis, as seen in animal models of polymicrobial sepsis,9 may have contributed to the development of PGA in our patient. Flucloxacillin could have further compounded this acidosis by inhibiting the breakdown of pyroglutamic acid by 5-oxoprolinase.2 The role of paracetamol in PGA is more complex. The metabolite of paracetamol, N-acetyl benzoquinoneimine, reacts irreversibly with glutathione. Under normal circumstances, glutathione depletion leads to increased γ-glutamyl cysteine synthetase activity and excessive production of γ-glutamyl cysteine (Box 2). However, under altered conditions, glutathione synthetase activity becomes rate-limiting, leading to the conversion of γ-glutamyl cysteine to 5-oxoproline by γ-glutamyl cyclotransferase.5 Our patient’s antiepileptic medications, which are known hepatic enzyme inducers and metabolised via CYP2E1, may have further compromised glutathione availability by decreasing glutathione stores and competing with paracetamol for metabolism. Renal impairment may also be important. Renal tubular epithelial dysfunction may impair intracellular glutathione re-formation (a high ATP-requiring state), leading to accumulation of 5-oxoproline and prompt excretion (because of its small molecular size) into the urine, peritubular capillaries and systemic circulation. The use of N-acetyl cysteine to treat PGA has been advocated to replenish glutathione stores by supplying cysteine for glutathione synthesis. Another theoretical treatment option is the use of cysteamine, which increases cytosolic cysteine and restores substrate availability for the glutamate pathway, normalising pyroglutamic acid levels. As PGA can be easily missed in a critically ill patient, where several factors may contribute to a metabolic acidosis, a high index of suspicion is required to diagnose this condition. PGA should be considered in the differential diagnosis of high anion gap acidosis, especially when the levels of organic acids do not sufficiently account for the degree of anion gap and when there is co-administration of drugs such as paracetamol and flucloxacillin. Where PGA is suspected, the offending drugs should be withdrawn and treatment with N-acetyl cysteine considered. 1 Investigations* Day 1 Hospital admission Day 18 ICU admission Day 63 On recovery Reference range Haematology Haemoglobin (g/L) 125 115 120 135–175 White cell count (× 109/L) 13.6 24.7 7.82 4–11 Neutrophil count (× 109/L) 11.1 22.75 6.09 1.8–7.5 International normalised ratio 1.2 7.6 1.0 0.8–1.2 APTT (s) 27 65 26 24–37 Fibrinogen level — 5.7 — 1.5–4.0 D-dimer FDP — 2.15 — < 2.0 Biochemistry Sodium (mmol/L) 134 138 137 137–145 Potassium (mmol/L) 3.9 2.8 4.1 3.5–4.9 Chloride (mmol/L) 97 93 99 100–109 Bicarbonate (mmol/L) 23 6 29 22–32 Urea (mmol/L) 9.1 18.6 2.7 2.7–8.0 Creatinine (mmol/L) 0.210 0.541 0.100 0.05–0.12 Gamma GT (U/L) 152 92 116 0–60 Albumin (g/L) 25 17 23 34–48 Lactate dehydrogenase (U/L) 252 293 210 110–230 Serum amylase (U/L) — 119 — 20–100 C-reactive protein (mg/L) 290 160 47 < 10 Anion gap (mmol/L) 18 42 13 7–17 Lactate level (mmol/L) — 0.7 — 0.2–2.0 Serum pyroglutamic acid level† (μmol/L) — 11 010 — 15–215 Urine pyroglutamic acid level† (μmol/mmol creatinine) — 20 495 13 103 < 100 * Platelet count, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and creatinine kinase were normal when measured. † Initial serum and urine pyroglutamic acid levels were measured 36 hours after admission to the intensive care unit, and repeat urine test was performed on Day 10. Serum and urine pyroglutamic acid levels not measured at discharge. — = Not measured. Bold indicates highly abnormal results. APTT = activated partial thromboplastin time. FDP = fibrinogen degradation products. GT = glutamyl transpeptidase. ICU = intensive care unit. 2 The γ-glutamyl cycle: mechanism of oxoprolinuria Sepsis and paracetamol reduce glutathione levels, lifting feedback inhibition of γ-glutamyl cysteine synthetase. Excess γ-glutamyl cysteine is converted by γ-glutamyl cyclotransferase to 5-oxoproline, the build-up of which leads to acidaemia and oxoprolinuria. Flucloxacillin may inhibit further the rate-limiting enzyme 5-oxoprolinase.

John V Peter MD, DNB, FRACP · Natasha Rogers MB BS · Shailesh Murty MB BS, MD · Rosemarie Gerace BSc · Richard Mackay FRACP · Sandra L Peake BM BS, FJFICM, PhD

Australian researchers are at the forefront of allergy prevention and treatment Allergic diseases increased dramatically throughout the 20th century, a change that has been described as an “epidemic”.1,2 To mark the launch of the the MJA Practice Essentials — Allergy series in this issue, we review some aspects of the Australian response. The incidence of allergic disease in Australia is one of the highest in the world. Between 1993 and 2002, the Australian arm of the International Study of Asthma and Allergies in Childhood demonstrated increases in the 12-month prevalence of rhinitis (from 9.7% to 12.7%) and eczema (from 11.1% to 17.2%), but a fall in asthma prevalence (from 27.2% to 20.0%).3 The reasons why asthma prevalence almost doubled between 1984 and 1994,4 but then fell,3 remain unclear. Food allergy and anaphylaxis are also increasing.5,6 The emergence of new food allergy-related disorders, such as the eosinophilic enteropathies (inflammatory disorders of the gastrointestinal tract with significant eosinophilic infiltration),7 and the unabated increase in demand for hypoallergenic formulae in infants8 and injectable adrenaline for people at risk of anaphylaxis indicate that the epidemic has not subsided. One popular explanation for the epidemic is the “hygiene hypothesis”, which postulates that lack of recurrent early exposure to infections and bacterial products (such as endotoxin) may promote an allergic response to environmental allergens.9 Australian researchers have been at the forefront in demonstrating that potentially allergic infants have an imbalance between allergy-promoting (TH2) and non-allergy-promoting (TH1) cytokines.10,11 It has been proposed that this imbalance, combined with early allergen exposure, promotes the development of allergic disease. However, the simplistic TH1/TH2 paradigm that forms the basis for the hygiene hypothesis can be challenged.12 The role of allergen exposure has been explored in Australian studies that have demonstrated an association between asthma incidence and levels of exposure to fungal13 and house dust mite allergens14 and the triggering of acute asthma attacks by submicronic pollen particles released after rain (so-called “thunderstorm asthma”).15 Despite the associations between allergen exposure and disease prevalence and severity, it has been difficult to demonstrate a clinical benefit from a reduction in exposure to inhaled allergens such as house dust mite allergen in the Australian environment.16 As the response to allergen minimisation is often incomplete and pharmacological therapies are not curative, the prospect of permanently modulating the immune response is attractive. Injectable allergen immunotherapy has been shown to reduce the severity of allergic respiratory disease and the onset of new sensitisations,17,18 but is not acceptable to young children and poses a small (but definite) risk of adverse allergic reactions. Immunotherapy substantially reduces the risk of anaphylaxis to stinging insects. For example, the Australian Jack Jumper ant is a major cause of severe allergy in many parts of Australia, and immunotherapy has proved effective in combating serious reactions to its sting.19 The ant is a uniquely Australian problem and the market for such a vaccine is relatively small, so funding is problematic. However, in view of the seriousness of anaphylaxis in susceptible people, making ant venom immunotherapy available to the at-risk population should be a major priority. Future challenges include reducing the risk of adverse reactions to immunotherapy (eg, by using modified or peptide-derived allergens20) and making immunotherapy more acceptable to younger patients (eg, by sublingual or oral administration).21 The ultimate goal is to understand the reasons for the epidemic of allergic disease and develop preventive strategies. While breastfeeding of infants22 and preventing children from being exposed to cigarette smoke have a role in reducing allergic disease, it is unclear whether benefits extend beyond childhood. Modification of atopic eczema by dietary supplementation with probiotics (supplements containing live bacteria given with the aim of altering the gut flora) has shown promising results,23 and research is continuing in this area. Based on the possible role of early dust mite allergen exposure and the proinflammatory impact of arachidonic acid metabolites (derived from ingested fatty acids), a study of asthma prevention by dietary supplementation with omega-3 fatty acids and house dust mite allergen avoidance from birth was commenced in 1999. The study showed that neither intervention achieved a significant reduction in asthma or eczema at 5 years.24 Allergic disease has a negative impact on quality of life.25 Excluding visual conditions and deafness, asthma, hayfever and “allergy” comprised three of the top six most common long-term self-reported illnesses in New South Wales in 1997.26 Food allergy engenders significant anxiety regarding care in schools, risk of death and the potential need for injectable adrenaline.27 In response to these issues, the Australasian Society of Clinical Immunology and Allergy has published guidelines on allergy prevention, anaphylaxis, prescription of EpiPen (CSL Limited, Melbourne, VIC) and the care of food-allergic children in schools and preschools.28 So, what challenges remain for the future? We have some understanding of the immunological mechanisms of the allergic response and of epidemiological associations, but this is yet to be translated into proven preventive measures. We require more reliable testing for the non-IgE mediated immune responses to food observed in some patients with atopic dermatitis and the eosinophilic enteropathies. Current tests for food allergy provide reliable indicators that hypersensitivity exists, but do not necessarily prove that a food is the cause of allergic symptoms or help us predict the severity of reactions. As immunotherapy may alter the natural history of allergic disease, there is a major need for more effective and child-friendly therapy modalities. We also need to educate our doctors and patients on the impact of allergic disease and on evidence-based methods for management. We hope that the current MJA Practice Essentials — Allergy series, which addresses all the topics raised here, will achieve some of these goals.

Andrew S Kemp MB BS, PhD, FRACP · Raymond J Mullins PhD, FRACP, FRCPA · John M Weiner MB BS, FRACP, FRCPA

Allergy is defined as an immune-mediated inflammatory response to common environmental allergens that are otherwise harmless. The diagnosis of allergy is dependent on a history of symptoms on exposure to an allergen together with the detection of allergen-specific IgE. The detection of allergen-specfic IgE may be reliably performed by blood specific testing or skin prick testing. Skin prick testing is not without its attendant risks, and appropriate precautions need to be taken. A doctor should be present for safety and test interpretation. Accurate diagnosis of allergies opens up therapeutic options that are otherwise not appropriate, such as allergen immunotherapy and allergen avoidance. Allergen immunotherapy is an effective treatment for stinging insect allergy, allergic rhinitis and asthma. The most effective methods for primary prevention of allergic disease in children that can currently be recommended are breastfeeding and ceasing smoking. Emerging trends in allergen treatment include sublingual immunotherapy.

Jo A Douglass MD, FRACP · Robyn E O’Hehir FRACP, PhD, FRCPath

Although allergen injection immunotherapy (AII) has been around for nearly a century, many doctors are still not aware of the evidence for its efficacy. About 15 000 patients are treated by AII in Australia each year, with about 300 000 injections administered annually for a wide range of allergens. The 10 most commonly prescribed allergen vaccines in Australia are house dust mite; five-grass pollen mix; 12-grass pollen mix; cat; couch grass, ryegrass and plantain pollens; Alternaria mould; cockroach; and olive/privet pollen. Patients receive regular subcutaneous doses of the allergens to which they are allergic, often for 3–5 years.1 Does the treatment work, and, if so, is it cost-effective and is it safe? Does it work? To date, about 200 completed randomised controlled trials have examined the question of whether AII is an effective treatment for allergic airway disease. Based on National Health and Medical Research Council levels of evidence, AII significantly reduces symptoms and medication usage in both allergic rhinitis (Level I) and asthma (Level I), although the former is the usual indication in Australia for this intervention. Evidence-based practice tip The incidence of mild immediate reactions to allergen injection immunotherapy is reduced by pre-medication with an oral antihistamine before each injection (Level II).* * NHMRC levels of evidence. Improvements with AII are clinically as well as statistically significant. In asthma,2 the number needed to treat (NNT) (ie, number of patients treated to avoid asthma worsening in one subject) is four, the NNT to avoid increasing medication in one patient is five, and there is a significant reduction in both specific and non-specific bronchial hyper-responsiveness. Data are homogenous, and most studies are of medium to high quality. Further, AII may reduce the progression from allergic rhinitis to asthma in some children (Level II),3 and monotherapy for one specific allergen reduces the risk of development of new sensitisation to other allergens (Level II).4 Whether AII is effective for treating food allergy has not been established, but research in this area is continuing. Is it cost-effective? AII is cost-effective for treating atopic airway disease. Two large, rigorous German studies5,6 examining the pharmacoeconomics of AII for treating atopic airway disease found that there are net savings 3–6 years after starting treatment. Other research from Italy and the USA supports these findings. AII treatment is cost-effective because (a) allergen extracts are relatively cheap (about $10–15 a month in Australia); (b) the tolerance induced persists for years after treatment has stopped (Level II);7 and (c) the reduction in new asthma and prevention of additional allergen sensitisation may reduce the incidence of new disease.3,4 Is it safe? Most debate on AII centres on questions of safety and risk. Mild to moderate systemic effects (rhinitis, mild bronchospasm, urticaria) occur in one in 1500 injections, there is one severe (near-fatal) anaphylaxis per million injections, and one death per 2.5 million injections.8 An Australian general practitioner treating 10 patients with AII annually could expect one instance of a mild to moderate systemic reaction every 7 years. AII might cause one death in Australia every 8 years. Notwithstanding the tragedy of any treatment-related death, this statistic has to be compared with the rate of rare deaths associated with other treatments and balanced against the proven reduction in development of asthma in most patients. Most severe adverse events result from giving an incorrect dose, giving the wrong extract, or giving the vaccine to a patient who has unstable asthma or is taking β-blockers. As adverse reactions are not predictable, safety can be enhanced by adhering strictly to the requirement that patients remain in the clinic for a minimum of 30 minutes (ideally, 45 minutes) after each injection (even maintenance doses). This facilitates early access to medical treatment if an adverse reaction occurs. When should patients be referred? There are good reasons for referring a patient to an allergist or clinical immunologist before initiating AII: apart from obtaining a second opinion on contraindications and other safety issues, this allows the consultant to assist with management if problems arise. Medical practitioners administering AII should be aware of the data on safety and compare these with data on the adverse effects of other interventions that they prescribe, and the disease itself, to put the issue into perspective. With proper selection of patients and vaccines, attention to contraindications, provision of a suitable administration milieu, strict adherence to the recommended waiting time after giving the injection, and a team approach with a consultant, AII can be a rewarding treatment for the patient.

John M Weiner MB BS, FRACP, FRCPA

To the Editor: A nationwide colorectal cancer (CRC) screening program will commence in 2006. It has been shown that general practitioners can influence their patients in the decision to have CRC screening.1,2 There are several screening test options in Australia, and the relative geographical isolation of rural centres may influence attitudes and participation. We sought to determine the attitudes of GPs towards CRC screening and test preferences. Between January and September 2005, all GPs in Western Australia (n = 1837; 1298 metropolitan, 539 rural) were sent a questionnaire, which was completed by 801 (43.6%). Overall, 62.8% of respondents believed that asymptomatic average-risk subjects should have CRC screening (67.1% of metropolitan GPs v 54.2% of rural GPs; P = 0.003). The questionnaire revealed major differences between which test GPs would recommend for their patients and which test they preferred for their own personal screening (Box). These differences were related to the factors GPs believed were most likely to influence choice of screening test. For colonoscopy, accuracy and speed of result were considered most important; for faecal occult blood testing, no need for bowel preparation or time off work and no discomfort were considered the strongest determinants. Previous studies that included patients’ views have found that physicians may incorrectly perceive certain factors in screening to be important to their patients.3 There were no significant differences in choice of test between rural and metropolitan GPs. Although the target age group for the Australian pilot study and the national screening program is 55–74 years,4,5 two thirds of GP respondents felt screening should be offered from the age of 50 years, and a quarter believed it should continue beyond 80 years. Many GPs (65%) indicated they would like further education on CRC screening. In summary, there is good support for CRC screening among Western Australian GPs, but the availability of different screening tests and variations in GPs’ opinions are likely to significantly influence clinical practice. Colorectal cancer screening methods and general practitioners’ recommendations and attitudes Test recommended by GP for patients GPs’ perception of patients’ choice of test GPs’ preferred test for their own screening Faecal occult blood testing 430 (53.7%) 396 (49.4%) 236 (29.5%)* Colonoscopy 285 (35.6%) 278 (34.7%) 479 (59.8%)* Flexible sigmoidoscopy 37 (4.6%) 20 (2.5%) 20 (2.5%) Computed tomography colonography 18 (2.2%) 69 (8.6%) 32 (4.0%) Barium enema 0 2 (0.25%) 3 (0.4%) * P = 0.004 (χ2)

Graham B Turner · Marcus W Chin · Noellene M Foster · Jon Emery · Geoff M Forbes

To the Editor: Australia’s imminent bowel cancer screening program will revolve around the general practitioner,1-3 whereas, in the United Kingdom, the GP will have virtually nothing to do with the national screening program now underway.4 It is curious that two programs with the same evidence base regarding effectiveness should be so fundamentally different. One explanation could be the differing health care systems in each nation. However, they are more alike than not, so the true explanation for the Australian methodology could rest with the outcome of the Australian pilot studies. If that is the case, then perhaps one should be both alert and alarmed. Given the inequity in access to GPs in Australia, it is not surprising that the Final Evaluation Report5 of the pilot national screening program stated that: Some GPs interviewed in Woolcott’s Qualitative Research focus groups . . . expressed concern over access to FOBTs [Faecal Occult Blood Tests] for people without a fixed address. It was mentioned that this group, particularly Aboriginal and Torres Strait Islander people and people in low socioeconomic groups, particularly homeless people, did not receive invitations to participate in the Pilot. Some GPs commented that the information packs, in both English and the translated versions, were too complicated for people with low literacy and those from culturally and linguistically diverse backgrounds.5 The same report noted that 38% of people overall (men, 42%; women, 34%) and 52% of non-English speakers did not visit their GP after a positive FOBT. Nevertheless, the report favours the continued central role of the GP.5 This is not the case in the UK screening program, which has a more direct approach, with program hubs and associated screening centres — all with defined accountabilities. The Australian approach is to simply add to the workload of GPs — a more pragmatic approach in the short term, but less imaginative. Our program will undoubtedly be a step forward in colorectal cancer prevention. The question is how large that step will be. Reliance on the existing system threatens to reinforce existing health care inequities.

Allan D Spigelman

To the Editor: The recent report by the Multicentre Australian Colorectal-neoplasia Screening (MACS) Group1 offered some intriguing findings. Participation in bowel cancer screening was lower than expected, despite a range of tests being offered. In addition, people offered a choice of different faecal occult blood tests (FOBTs) were less likely to participate than those not offered this choice. The accompanying editorial by Salkeld and colleagues concluded that “Informed consumers making smart choices about screening . . . would be a public health success”.2 We believe the available evidence indicates otherwise. As the MACS Group study showed, participation in FOBTs was lower than in the Australian Government FOBT pilot program,3 and participation in screening by colonoscopy was lower than for other studies, including our recent Australian study.4 They suggested this may be because local general practitioners were not engaged in the project. Our study was designed to address this issue, and concluded that involvement of GPs had a small, non-significant effect on participation rates and no effect on response to invitation.4 This is not to say that involvement of GPs is undesirable. The MACS Group study found participation in FOBTs of 27.4% when only an FOBT kit was provided and a significantly lower participation when a choice of four screening modalities was offered, with an FOBT kit provided (18.6%, P = 0.03). These data confirm the findings of a large multicentre study from the SCORE2 Working Group.5 In that study, participation in FOBT was 30.1%, while participation in either FOBT or flexible sigmoidoscopy, when a choice of the two was offered, was 27.1%. The authors did not offer this analysis, but the difference was again significant (P = 0.015, two-tailed Fisher’s exact test). The editorial by Salkeld et al suggested that the Australian bowel cancer screening program should incorporate decision-support systems to allow informed choice of screening options. The “choice paradox” reported by the MACS and SCORE2 studies argues against this. Further, there is no evidence that decision support improves rates of participation in screening, and some explicit evidence that it has no effect.6 This should not be troubling. At this time, most colon cancer screening is still performed after consultation between patient and doctor, and in this setting informed choice is possible and desirable. Decisionmakers such as the Australian Government Department of Health and Ageing use a different process, which is explicit and quantitative,7 in determining screening policy. With the evidence available, the Australian mass-screening program should offer and evaluate a single test modality.

Douglas R Taupin · Mike Corbett

In reply: Taupin and Corbett contend that the “choice paradox” reported by the MACS Group study argues against decision-support systems to allow informed choice of screening options. That would be true if the purpose of informed choice was simply to increase participation in screening.1 Our point is that the purpose of informed choice is to support an ethical basis for individuals’ decisions about screening.2,3 This can occur within the single-test modality (faecal occult blood tests) of the national screening program. It would be desirable to have decision-support systems embedded in a doctor–patient consultation. But this may not be feasible in terms of screenee access to a general practitioner, nor affordable for the Australian Government — hence our call for a self-directed decision-support system as an adjunct to a doctor-guided system. This is one way of applying the principle that patients should be given unbiased information on the benefits and harms of screening that enables them to make an informed choice about their own participation in screening.4

Glenn P Salkeld · Jane M Young · Michael J Solomon

To the Editor: We read with alarm the skin cancer clinic profile published recently in the Journal.1 This article publicly states what has been privately suggested for some time — that doctors in skin cancer clinics provide a service no better than the average Australian general practitioner. Surely, if these doctors are calling themselves skin cancer “experts”, the aim of their practice should be to reduce the skin biopsy rate. This is obviously not the case. They report a consultation to biopsy ratio of 1.79. Thus, 56% of all their consultations result in a skin biopsy. The biopsy to treatment ratio of 3.1 is also very high. In addition, they report that only 32% of all biopsies yield a non-melanoma skin cancer. This figure indicates either no additional diagnostic ability on the part of the skin cancer clinic doctors compared with the average Australian GP (who, according to a recent retrospective study, can clinically diagnose a basal cell carcinoma 34% of the time2) or an effort to maximise income. Similarly, the article describes a number needed to treat (NNT) of 28.6. This means that for every 29 benign lesions excised and sent for histological examination to exclude melanoma, only one melanoma is detected. The authors concede that this figure is equivalent to that observed in mainstream general practice. We therefore question the motives of doctors at these clinics in presenting themselves as skin cancer “experts”. However, perhaps the greatest indicator of their seeming intent to maximise financial gain can be demonstrated by an analysis of skin flap item numbers. The article indicates that the total number of excisions was 8055, of which 116 were melanomas and 4709 were non-melanoma skin cancers (ie, 4825 cancers were excised). If one assumes that a suspicious or benign mole biopsy is never closed with a skin flap repair (standard clinical practice), then, of the 4825 skin cancers excised, 2651 (55%) were closed with a flap procedure, and of these, 55% were either “complicated” or “site-specific” flap repairs. There were only 111 skin grafts performed out of the 4825 cancers excised (2.3%). Thus, more than half of the skin cancers excised were closed with a flap repair! Moreover, more than half of the flaps used were “complicated” or “site-specific” flaps, with 24 flaps performed for every skin graft! Surely, no one can argue that these figures are reasonable or consistent with good clinical practice. In comparison, current Australian Medicare data indicate that dermatologists and specialist surgeons close large skin cancer excisions (lesions > 2 cm on the trunk [item number 31290]) with skin flaps at rates of 15% and 17%, respectively (Andrew Miller, Australian Medical Association Skin Representative Group, personal communication). Large lesions normally require a higher skin flap closure rate than smaller lesions. Hence, a flap repair rate of 55% — for lesions of all sizes and sites — reported by the skin cancer clinic doctors is all the more extraordinary. We believe that the above suggests that many skin cancer clinic practitioners are more concerned with maximising income than improving patient care.

Alvin L K Chia · Stephen Shumack

In reply: Our previous publications1,2 should calm Chia and Shumack’s “alarm”. We have urged for the development of education, standards, accreditation, research and audit for skin cancer clinics.1 Over the past 12 months, the Skin Cancer Society of Australia has been formed (http://www.skincancersociety.com.au), standards have been developed, a process of skin cancer practice accreditation has been established, and a masters-level degree in primary care skin cancer medicine has been created (http://www.som.uq.edu.au/skincancer/masters.htm). Our results described activities of a single network of skin cancer clinics.2 They should not be viewed as a benchmark, and caution must be exercised in making any generalisations from them. They are simply the first such data to be presented for public scrutiny. It will be important to see results from other skin cancer clinics. Regarding flap repairs, we were unable to confirm the findings alluded to by Chia and Shumack based on a personal communication. However, we are currently undertaking a detailed analysis of relevant Medicare Benefits Schedule data for general practitioners and specialists and we look forward to presenting this for rigorous peer review and publication shortly. Skin cancer medicine is an established component of primary care. Whether this occurs in mainstream general practice, “special interest services” or skin cancer clinics, the same standards apply to all.

David Wilkinson · Deborah A Askew

Bacteria on film Chronic otitis media may be due to recurrence of infection rather than re-infection, say US and German researchers. They detected bacterial biofilms — adherent clusters of bacteria enclosed in a matrix — on most middle ear mucosa biopsy specimens taken from children with chronic otitis with effusion or recurrent otitis media; however, they found none on similar specimens from uninfected control patients who were to have cochlear implantation. Further, the bacterial species involved in the mucosal biofilms were the same pathogens commonly associated with otitis media. Biofilm bacteria provide a physical barrier to host defences; also, they are more antibiotic resistant than single cells in suspension. JAMA 2006; 296: 202-211 No magic bullet Raloxifene, a non-steroidal selective oestrogen-receptor modulator (SERM), led to an increased risk of death from stroke in women taking it in the Raloxifene Use for The Heart (RUTH) study, warns a health and drug alert in the Canadian Medical Association Journal (CMAJ).1 The RUTH study was designed to determine whether raloxifene reduced the risk of coronary heart disease in postmenopausal women.2 More than 10 000 such women at risk of, or with established, coronary heart disease, enrolled from 177 sites in 26 countries, were randomly assigned to receive either 60 mg raloxifene or placebo daily on a long-term basis. At follow-up more than 5 years later, those in the raloxifene group had a reduced risk of invasive breast cancer and vertebral fracture but an increased risk of venous thromboembolism and, as reported in CMAJ, fatal stroke. An editorialist said that, for now, there is no magic bullet that can reduce the risk of major health problems related to oestrogens and ageing without introducing other potentially serious health concerns.3 1. CMAJ 2006; 175: 147-148 2. N Engl J Med 2006; 355: 125-137 3. N Engl J Med 2006; 355: 190-192 A web of herbal nephropathy A 30-year-old Chinese man in the UK has end-stage renal failure and is preparing for renal replacement therapy after taking the Chinese herb Longdan xieganwan for at least 5 years to “enhance” his liver. The herb contains aristolochic acid, which is well recognised as being nephrotoxic, leading to a non-inflammatory interstitial fibrosis which can progress to renal failure. It is also a potential urological carcinogen linked with transitional-cell carcinoma, which also occurred in this patient. Aristolochic acid is banned in many countries, including the UK and Australia; however, as the report’s authors point out, aristolochic acid continues to be available over the Internet. Lancet 2006; 368: 338 Gender gap closing now . . . In 1970, only 5.9% of first authors and 3.7% of senior (last listed) authors of original US research papers published in six prominent medical journals were women.1 By 2004, this proportion had risen to 29.3% of first authors and 19.3% of senior authors. Two journals, one focused on paediatrics and the other on obstetrics and gynaecology, had the highest proportions. According to an accompanying editorial (co-authored by four women), women compose a larger proportion of faculty members overall in these two fields.2 The editorialists say the authorship gender gap is only likely to narrow substantially when more women reach senior faculty positions. 1. N Engl J Med 2006; 355: 281-287 2. N Engl J Med 2006; 355: 310-312 Fat adolescent Sibutramine therapy may have a role in managing the severely overweight adolescent who cannot otherwise lose weight, suggests a US expert.1 Dietz was commenting on a multicentre US study conducted over 1 year in about 500 overweight adolescents aged 12 to 16 years whose body mass index (BMI) was above the 95th percentile.2 The study found that, when added to a behavioural therapy program, sibutramine reduced BMI and body weight more so than placebo. For example, the average change in BMI was just over −3 kg/m2 in the sibutramine group compared with −0.3 kg/m2 in the placebo group. Sibutramine also improved several metabolic risk factors. However, the long-term risks (or benefits) of drug therapy in children or adolescents remain unknown. 1. Ann Intern Med 2006; 145: 145-146 2. Ann Intern Med 2006; 145: 81-90 Rickets returns Major paediatrics centres in Sydney have seen a dramatic increase in the presentation of young children with vitamin D deficiency rickets, according to Australian authors. Robinson and colleagues reported a case series of 126 cases of vitamin D deficiency and/or rickets seen in these centres from 1993 to 2003. A steady increase in numbers of cases had occurred each year, with a doubling between 2002 and 2003. Patients presented most commonly with hypocalcaemic seizures and bowed legs. Almost all cases occurred in children in families who had recently immigrated to Australia or first generation offspring of immigrant parents, especially from the Indian subcontinent, Africa and the Middle East. Among suggested measures to reverse the trend, the authors specified screening as well as education of at-risk immigrant groups about the need for some sun exposure. Arch Dis Child 2006; 91: 564-568

Ann Gregory

Med J Aust 2006; 185 (4 Suppl).