Pulmonary embolism (PE) affects 0.5–1 per 1000 people in the general population each year, and is one of the most common preventable causes of death among hospitalised patients. The clinical diagnosis of PE is unreliable and must be confirmed objectively with ventilation perfusion scanning or computed tomography pulmonary angiography. The diagnosis of PE can be reliably excluded, without the need for diagnostic imaging, if the clinical pretest probability for PE is low and the D-dimer assay result is negative. The initial treatment of PE is low-molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target international normalised ratio [INR], 2.0–3.0) for at least 3–6 months. Patients with a high clinical pretest probability of PE should commence treatment immediately while awaiting the results of the diagnostic work-up. Thrombolysis is indicated for patients with objectively confirmed PE who are haemodynamically unstable. Percutaneous transcatheter or surgical embolectomy may be life-saving in patients ineligible for, or unresponsive to, thrombolytic therapy. Unresolved issues in the management of venous thromboembolism include the roles of thrombophilia testing, thrombolysis for the treatment of stable PE patients who present with right ventricular dysfunction, and new anticoagulants; and the duration of anticoagulation for first unprovoked venous thromboembolism.

Cindy H Lee MB BS · Graeme J Hankey MD, FRACP, FRCP · Wai Khoon Ho MB ChB, FRACP, FRCPA · John W Eikelboom MB BS, FRACP, FRCPA

We report on an elderly couple who presented with a syndrome that included severe generalised tremor and incoordination after eating soup from a damaged can. Black mould contaminating the can was subcultured and the fungus Penicillium crustosum was identified. This fungus usually produces a potent neurotoxin called penitrem A. The couple displayed symptoms consistent with penitrem A ingestion, all of which resolved fully. Penitrem A intoxication has been well documented in animals, but not in humans. Clinical recordsAn elderly couple was admitted to hospital after sudden onset of severe muscle tremors. The husband (aged 89) and wife (aged 84) described an uneventful morning. At about 12:00, they had shared a can of soup and toast, followed by chocolate cake, before catching a bus to the local shopping centre. They noticed the soup had a bitter taste, but dismissed the finding because it was a new brand and type to them. There had been no recent changes to their medications, and no recent exposure to garden sprays, insecticides or pesticides. Patient 1The man was first to develop symptoms. He reported feeling slightly shaky as the bus arrived at the shops at about 13:00. He had difficulty getting off the bus, his legs felt “wobbly” and he had to sit down. He developed uncontrollable shaking throughout the body, and felt sticky and sweaty. Initial assessment by ambulance officers at about 13:10 was that he had severe muscle tremors and was unable to walk, and that it was difficult to understand his speech. He had no nausea or vomiting, and his abdomen was soft. He was diaphoretic, with blood pressure 160/76 mmHg, pulse rate 80 beats/min, respiratory rate 32 breaths/min, and Glasgow Coma Score 15 out of 15. His oxygen saturation level was 85%, improving to 97% with high-flow oxygen. Subsequent assessment in hospital at 13:40 revealed that the patient’s Glasgow Coma Score had fallen to 11. Although his speech was incomprehensible, he was able to obey commands; he also displayed generalised weakness and intention tremor. He remained hypertensive and diaphoretic, but was afebrile. He later recounted (to P R L) that he had thought he was going to die. All symptoms, apart from the intention tremor, had subsided by 16:30. The patient’s medical history included chronic airway limitation, asthma, hypertension, episodic atrial fibrillation, osteoarthritis, a left total hip replacement, and an essential tremor. He had no known allergies. His medications included verapamil, digoxin, aspirin, salbutamol, tiotropium bromide, salmeterol xinafoate, quinine bisulfate prn, paracetamol and rofecoxib prn. His essential tremor remained untreated because of the contraindicated use of β-blockers in asthma. A chest x-ray was unremarkable, but electrocardiography revealed a right bundle branch block. A computed tomography brain scan showed generalised volume loss with no intracranial haemorrhage or early changes of infarction; a small low-density focus present in the right basal ganglia region was consistent with chronic lacunar infarction. The results of haematological and biochemical tests were within normal limits, except for urea (8.7 mmol/L; reference range [RR], 2.5–6.4 mmol/L), white cell count (11.2 × 109/L; RR, 4.0–11.0 × 109/L), and haemoglobin (128 g/L; RR, 130–165 g/L) (red cells were normocytic and normochromic). The patient’s blood glucose level (measured by glucometer) was 7.3 mmol/L (RR, 3.5–8.0 mmol/L). Pseudocholinesterase (13.5 U/mL; RR, 7.0–19.0 U/mL) and serum digoxin (1.5 nmol/L; RR, 1.3–2.6 nmol/L) levels were within normal limits. No urine screen for drugs was carried out. The patient was admitted for observation and investigation. The following day he was lethargic, exhausted, and displayed minimal tremor. He was eventually able to mobilise with the aid of a walking stick, as usual. Patient 2The woman had a similar presentation. She complained of feeling dizzy and shaky, but had no nausea or vomiting. Ambulance officers described her as being anxious, diaphoretic, and with uncontrollable shaking. Her blood pressure was not palpable because of severe shaking, but she was well perfused. She was tachycardic (pulse rate, 110 beats/min, taken from electrocardiographic monitoring), with a respiration rate of 20 breaths/min, temperature 36.5ºC, Glasgow Coma Score of 15, and blood glucose level (measured by glucometer) 7.0 mmol/L (RR, 3.5–8.0 mmol/L). Although she was no longer tachycardic on admission to hospital, she remained anxious and diaphoretic, with a generalised tremor that increased with stimuli (eg, being questioned). Her oxygen saturation level on room air remained above 95%. All symptoms, apart from the intention tremor, subsided by 16:30. The patient’s medical history included a left nephrectomy for calculi, right renal calculi and lithotripsy, chronic airway limitation, asthma, hypertension, and a left-eye cataract. Her medications included hydrochlorothiazide, frusemide, nitrofurantoin, aspirin, trimethoprim, salbutamol prn, beclomethasone dipropionate, quinine bisulfate prn, paracetamol prn, and Macu-Vision tablets (containing ascorbic acid, vitamin E, zinc oxide and cupric oxide). A chest x-ray and electrocardiogram were normal. A computed tomography brain scan showed no abnormality apart from a polypoid density in the inferior maxillary sinus. The results of haematological and biochemical tests were normal, except for urea (9.1 mmol/L; RR, 2.5–6.4 mmol/L) and creatinine (0.13 mmol/L; RR, 0.06–0.12 mmol/L). The level of pseudocholinesterase was within normal limits (18.7 U/mL; RR, 7.0–19.0 U/mL). A urine screen conducted for drugs of abuse (including amphetamines, methamphetamines, benzodiazepines, cocaine, opiates and cannabis) was negative. The patient was admitted for observation, and gradually improved the following day. Follow-upBoth patients were discharged 2 days after admission with a very slight residual intention tremor. When assessed by their general practitioner 2 weeks later, the man had only a mild increase in his usual essential tremor and the woman’s tremor had completely resolved. Identification of mouldThe damaged soup can was retrieved from the couple’s residence on the day of onset of their illness and sent to Food Science Australia for analysis. Examination of the can revealed a dent in the top adjacent to the ring-pull on the lid. There was black mould inside the can at the top near the damaged area, and a small amount on the underside of the lid (Box 1). The mould was subcultured onto three different media suitable for growth of common food spoilage moulds.2 The plates were incubated at 25ºC for 4 days. All plates grew a pure culture of a Penicillium species. The mould was then cultured onto identification media, incubated at 5ºC, 25ºC and 37ºC for 7 days and examined again.2 Both microscopic and colony morphology characteristics identified the mould as Penicillium crustosum. It had typical sporing structures for this species (Box 2), and its colonies on malt extract agar shed spore masses in a manner typical of the species. No mycotoxin analyses were attempted. DiscussionPenicillium crustosum is a common foodborne fungus that causes spoilage in a wide variety of foods, including meat, cereals, nuts, cheese, eggs, fruit, and processed and refrigerated foods. Almost all P. crustosum isolates produce the mycotoxin penitrem A.1-3 Its potent neurotoxic effects have been demonstrated in various laboratory animals,4,5 and naturally acquired intoxication has been reported in sheep, cattle, horses and domestic dogs.4,6-9 In animals, symptoms include ataxia, tremors and severe muscle fasciculations.4-9 Larger doses may cause seizures, massive liver necrosis and death.5 To our knowledge, there has been only one case documented in humans of a tremorgenic syndrome following ingestion of P. crustosum.10 A man who had ingested about 30 mL of beer from a can contaminated with a fungus later identified as P. crustosum developed tremorgenic syndrome. About 4 hours later, he developed headache, vomiting, diplopia, weakness and bloody diarrhoea. After 12 hours he developed a tremor. All symptoms resolved within 30 hours. In this case, the fungus isolated was found to produce the mycotoxin roquefortine, but penitrem A was not reported. The authors acknowledged that the isolate lacked a feature typical of P. crustosum. As isolates of P. crustosum almost always produce penitrem A, it is quite possible that the mould involved in this mycotoxicosis was not actually P. crustosum, but some other closely related species such as P. roqueforti.11,12 Inhalation of mouldy silage was implicated in a similar tremorgenic illness in a 16-year-old male.13 Malaise, fatigue, headache, pyrexia and vomiting occurred within hours, progressing to coarse fasciculations and tremors. Symptoms had resolved by the 7th day. A variety of fungi were isolated from the silage, including Aspergillus and Penicillium, both of which produce tremorgenic mycotoxins. Aspergillus fumigatus, which is particularly common in silage, can produce tremorgenic toxins known as fumitremorgens, but not penitrem A.14 There are strong similarities between the cases we report here and numerous documented cases of penitrem A intoxication in animals. Domestic dogs are at particular risk when they have access to household waste.6-9 P. crustosum also produces the mycotoxin roquefortine,15 whose neurotoxic effects have been implicated concurrently with those of penitrem A in some cases.7-9 However, roquefortine has been found experimentally to be far less toxic than penitrem A.15 The elderly couple experienced a comparatively rapid onset of symptoms, but had no nausea or vomiting. The differential diagnosis included a reaction [from exposure] to either a food toxin or an environmental pollutant such as a pesticide or insecticide. The canned soup was a common source of exposure, and its unusual taste further implicated the can as the toxin source. Although we did not attempt to identify the mycotoxin in the cases reported here, isolates of P. crustosum usually produce penitrem A (in one study, of 308 isolates tested, all produced penitrem A12). The highest levels of penitrem A production by P. crustosum isolates occur in liquid media,11 so the soup can in this case would have provided optimal conditions for mycotoxin synthesis. Unfortunately, none of the implicated soup remained for analysis. Most mycotoxins are heat-resistant and comparatively stable,3 so would have survived the mild cooking process. Visual impairment may have contributed to this illness occurring, in that the elderly couple were not aware that the soup can was damaged and discoloured. Experimentally, penitrem A inoculation has been found to produce a tremorgenic syndrome that leads to convulsions and death when larger doses are given.4,5 Administration of pentobarbitone has been found to be effective in controlling muscle tremors and seizures in animals.7,8 This case study highlights the need to avoid ingesting food from damaged cans. Medical and food-authority personnel should be aware of the possibility of P. crustosum ingestion and its potent neurotoxic effects. Limited reporting of this syndrome in humans suggests that it is either rare or under-reported. 1 Damaged can, showing black mould around lid 2 Sporing structures of Penicillium crustosum* * Scale bar is 10 m in length.

Peter R Lewis MB BS, DipObs, FAFPHM · Michael B Donoghue MB BS, FACEM · Lucy Cook BA(SocSc), RN · Linda V Granger BHSc, MPH · Ailsa D Hocking PhD, FAIFST, FASM

Trial registration, transparency and less reliance on industry trials are essential Over the past 20 years, politicians, hospital administrators and university deans have encouraged academic researchers to increase their participation in projects sponsored by the pharmaceutical industry, and the industry’s share of biomedical research has increased dramatically in that time (from 32% to 62% in the United States).1 Increasingly, the wisdom of this development has been challenged. It would be even better if testing drugs in patients was a public enterprise . . . The research agenda predominantly serves the interests of industry rather than those of patients. Surveys have shown that manipulation of clinical trials — whereby, if the results are published at all, the control treatment is disadvantaged by design, analysis, or interpretation2-5 — is common. Even when the results for the active and control therapies are no different, industry-sponsored trials come to a positive conclusion in favour of the sponsor’s drug five times more often than do not-for-profit-sponsored trials.4 This sponsor bias can have serious consequences. A meta-analysis supported by Merck concluded that there was no increased risk of arterial thrombosis with the company’s cyclo-oxygenase-2 (COX-2) inhibitor, rofecoxib.6 However, another meta-analysis, not sponsored by industry, showed an increased risk, which was apparent in publications available to the authors of the industry-sponsored meta-analysis 4 years before the drug was withdrawn because of thromboses.7 Such down-playing of harms in published papers has often required the collaboration, or acquiescence, of academic clinical researchers. It is likely that the widespread use of COX-2 inhibitors has caused thousands of premature deaths. An article by Henry and colleagues in this issue of the journal (page 557) reports important breaches in research integrity in industry-sponsored research, based on the experience of medical specialists in Australia.8 There are several reasons why the prevalence of the problems probably represents only the tip of the iceberg. Firstly, the authors note that their findings are limited by reliance on self-report, and only 39% responded. Secondly, while only about 9% of respondents reported one or more episodes of potentially serious research misconduct, the authors note that this is equivalent to 21% of those who had an active research relationship with industry. Thirdly, the authors did not consider protocol changes to be serious research misdemeanours. They need not be, but we found that at least one primary outcome was changed, introduced, or omitted while research was under way in 51 of 82 trials (62%).5 We think this is a serious problem as, with a median of 27 outcomes per trial,5 one would expect one outcome to become statistically significant by chance, even if the compared treatments were identical. Finally, 2% of respondents in the paper by Henry et al reported changes to study protocols while trials were under way.8 Our study comparing protocols with corresponding publications showed that formal changes submitted to scientific ethics committees are not common, but that informal changes are. We found that 86% of the respondents in a survey of triallists denied the existence of unreported outcomes, despite clear evidence to the contrary — we did not reveal to them until later that we had access to their trial protocols through the scientific ethics committees.5 Research misconduct and bias in intervention research could be markedly reduced if ongoing initiatives to register all trials at their inception, and ensure public access to trial protocols and all data generated by a trial, become successful. The International Committee of Medical Journal Editors have made a very positive and strong move towards this goal. They have agreed that after 1 July, 2005, its member journals, as a condition of considering a trial for publication, will require that it be registered in a public trials registry before patients enter the trial.9 Ethics committees would also have to play a central role to make this happen, and to ensure that commercial considerations will not be allowed to block access to the collected data, whether or not they are formally published. It would be even better, of course, if testing drugs in patients was a public enterprise (whether or not financed by industry) with blinding during data analysis and writing of manuscripts, till everyone involved had approved them.10 This would ensure that commercial influences on trial design, analysis, manuscript preparation and publication would no longer distort our views of the value of drugs and other treatments. It would also ensure that the comparison treatment was relevant, that the outcomes were directly relevant for patients, and that the patient population was relevant (eg, elderly patients in the case of COX-2 inhibitors, who are also those most likely to develop thromboses). A case in point is the publicly sponsored ALLHAT trial, the biggest trial ever performed on hypertension, which showed that the cheapest drug available was also the best.11 It is clear that governments could save money and treat patients better by investing much more in trials and academic trial centres than by relying on industry’s own trials and conclusions. Who would buy a washing machine that is five or 10 times more expensive than other machines just because its manufacturer has compared it with other machines and claims that it is the best? Unfortunately, such absurdities are often seen in health care, and are allowed to happen even in the absence of any direct head-to-head comparisons.

Peter C Gøtzsche MD, DrMedSci

Timothy C Crowe,* David Cameron-Smith† * Lecturer, † Senior Lecturer, School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC 3125. tcroweATdeakin.edu.au To the Editor: Low-carbohydrate diets have re-emerged into the public spotlight and are enjoying widespread popularity. However, current evidence indicates that low-carbohydrate diets have no significant advantage over more traditional energy-restricted diets for long-term weight loss and maintenance.1-3 While these diets have shown short-term efficacy in modifying some lipid parameters and measures of insulin sensitivity, questions remain about the risk of adverse effects with long-term carbohydrate restriction.4 The scientific literature has not addressed the questions of how the general public perceive these diets, and what dieting approaches they adopt. Dieting perceptions and practices within the community may be far removed from the strictly controlled situation of published research. A national telephone survey of 1200 adults aged 18 years and over was conducted by the private market research company Newspoll from 6 to 8 August 2004. The survey asked about knowledge of and attitudes to carbohydrates and dieting. Telephone numbers were randomly selected, with a quota for capital city and non-capital city areas. Selection of an individual in each household was based on the last birthday. Response rate to the survey was 11%. Sex, age, marital status and working status demographics were representative of the Australian adult population. The main findings are summarised in the Box. Most of those surveyed correctly identified foods such as pasta and bread as “carbohydrate foods”. Only a third of people identified soft drinks and lollies as carbohydrate foods, and 20% incorrectly identified cheese and eggs as carbohydrate foods. Almost 17% of people had either tried, or intended to try, a low-carbohydrate diet, with women more likely to have tried this diet. Half of those surveyed believed that carbohydrate foods should make up a quarter or less of the daily diet (current health recommendations are that about half the diet should comprise carbohydrates). Almost 70% of those surveyed believed they needed to cut back on carbohydrates to lose weight. Based on this survey, low-carbohydrate dieting practices are as widespread in Australia as in the United States.5 Interestingly, the US study noted a greater propensity to use carbohydrate-reduced diets among those who were obese, had diabetes, hypertension or high cholesterol. Our data demonstrated widespread misunderstanding of what constitutes a high-carbohydrate food, which may leave many individuals at risk of choosing a diet that selectively excludes wholegrain foods, fruits and some dairy products. Health professionals should be aware that low-carbohydrate diets remain popular, that the people who are following these diets may represent a more “at risk” population, and that the food choices made by those following this dietary pattern may have adverse long-term health effects. Respondents’ knowledge of and attitudes to carbohydrate foods and low-carbohydrate dieting Question Total (n = 1200) Men (n = 600) Women (n = 600) Which of the following foods, if any, do you regard as carbohydrate foods? Bread 89% 85% 93% Pasta 90% 88% 93% Rice 80% 76% 83% Breakfast cereal 79% 77% 80% Lollies 35% 36% 35% Soft drink 34% 31% 36% Cheese 20% 22% 19% Eggs 18% 20% 16% Have you tried or do you intend to try the Atkins diet, or some other low-carbohydrate diet? 17% 11% 22% Based on official recommended guidelines for a healthy diet, about how much of a person’s diet should be made up of foods such as bread, breakfast cereal, pasta and rice? Less than a quarter 7% 7% 7% About a quarter 43% 34% 51% About half 29% 31% 26% About three quarters 6% 8% 4%

Timothy C Crowe · David Cameron-Smith

Objective: To compare rates of percutaneous coronary interventions (PCI) and bypass surgery after acute myocardial infarction (AMI) in Indigenous and non-Indigenous patients.Design: Cohort study of public-sector patients who were followed up for 1 year using administrative hospital data.Participants and setting: We followed up 14 683 public-sector patients admitted to Queensland hospitals for AMI between 1998 and 2002. Of these, 558 (3.8%) identified as Indigenous.Outcome measures: Rates of PCI and bypass surgery, adjusted for differences between the Indigenous and non-Indigenous cohorts according to age, sex, socioeconomic status, remote residence, hospital characteristics, and comorbidities.Results: The adjusted rate for PCI during the index admission was significantly lower by 39% (rate ratio [RR], 0.61; 95% CI, 0.38–0.98) among Indigenous versus non-Indigenous patients with AMI; the adjusted rate for subsequent PCI was significantly lower by 28% (RR, 0.72; 95% CI, 0.54–0.96). Adjusted rates for bypass surgery were similar in the two cohorts. For any coronary procedure (ie, PCI or bypass surgery), the adjusted rate was significantly lower by 22% (RR, 0.78; 95% CI, 0.64–0.94) among Indigenous patients with AMI. Diabetes, chronic renal failure, pneumonia, and chronic rheumatic fever were at least twice as common among Indigenous patients with AMI as in the rest of the cohort, and chronic bronchitis and emphysema and heart failure were at least 60% more common. If a patient had at least one comorbidity, then their probability of having a coronary procedure was reduced by 40%.Conclusions: There are likely to be several reasons for the lower rates of coronary procedures among Indigenous patients, but their high rates of comorbidities and the association of comorbidities with lower procedure rates was an important finding. As investment in primary care can reduce the prevalence and severity of comorbidities, we suggest that adequate primary health care is a prerequisite for effective specialist care.

Michael D Coory PhD, FAFPHM · Warren F Walsh FRACP, FACC

Thirty per cent of the Northern Territory’s population are Indigenous Australians. Their cultural diversity and complexity is illustrated by the more than 50 different language groups that make up this population.1 Because of their high burden of disease, Indigenous Australians can at times occupy up to 60% of inpatient beds at Royal Darwin Hospital (RDH).2 This is particularly so in RDH’s Division of Maternal and Child Health, where the health status of Indigenous women and children is arguably the worst in the developed world. The conditions associated with Indigenous pregnancy include social issues such as high rates of smoking, alcohol ingestion, domestic violence and teenage pregnancy. Compounding these are medical problems, including hypertension, gestational diabetes and rheumatic heart disease.3 As to the outcomes of pregnancy, Indigenous neonates at RDH have not only high rates of prematurity, but also intrauterine growth retardation and a mortality rate three times that of the rest of Australia.4 The high burden of disease continues throughout childhood. For example, over the past 25 years, between 400 and 500 Indigenous children from remote communities have been admitted each year to RDH, most commonly with gastroenteritis. Associated comorbidities include malnutrition, iron deficiency, pneumonia, urinary tract infection, chronic suppurative otitis media and scabies (often secondarily infected).5 Although Indigenous people comprise 30% of the Territory’s population, less than 3% of the 1300 people employed by RDH are Indigenous Australians. There are four Indigenous people among some 700 nurses and two among 190 doctors. In 2003, the NT Health Minister, Peter Toyne, in announcing a new framework for the NT Department of Health and Community Services, laid down a challenge: “By the end of the decade, I want the world’s best practice health care for Indigenous communities in the Northern Territory. I want to see a time when we don’t have to keep talking about how bad the situation is.”6 Some 12 months later, a proposal was put to the NT Department of Health and Community Services by RDH clinicians for a Centre of Excellence for Clinical Training in Aboriginal Health (Box). The proposed centre would deliver initiatives for the professional development of Indigenous health professionals — doctors, nurses, Aboriginal health workers and other health professionals — through the centre’s proposed Aboriginal Health Professionals’ Development Unit. If established, the centre would be the first of its kind in Australia. A Centre of Clinical Research Excellence in Aboriginal and Torres Strait Islander Health had recently been funded by the Federal Government at Flinders University.7 The proposal for a centre of excellence at RDH argued that, in providing the best clinical training in Indigenous health in Australia for postgraduate staff and medical and allied health students training at RDH, the centre would provide the impetus for creating key performance measures to benchmark RDH against the world’s best, and thereby identify gaps and areas for improvement. The centre would strengthen existing professional relationships with the Northern Territory Clinical School (which accepts students from Flinders University and James Cook University), the Bachelor of Nursing course at Charles Darwin University and the Menzies School of Health Research — institutions that all are located on the RDH campus. Furthermore, the proposal fits well with other exciting local initiatives, including the proposed Flinders University Inaugural Chair in Indigenous Women’s Health, to be located at RDH, and the Postgraduate Diploma in Indigenous and Tropical Child Health currently being considered by the Royal Australasian College of Physicians. One year on, the proposal is still a dream. Barriers to its implementation have come from several sources. Firstly, some public health physicians feel that the centre would distract focus from the primary care arena, in which the major challenges to Indigenous wellbeing are to be found. However, RDH is unique in having many senior clinicians across all specialities, who have provided specialist outreach to remote communities over many years. They have accumulated an enormous depth of experience in primary through to tertiary care of Indigenous people — experience that could be better utilised for clinical training through such a centre. Furthermore, by bringing on stream such a centre, RDH would be better placed to link with cross-sectoral initiatives such as the NT preventable chronic diseases strategy. Secondly, administrators, like their counterparts in most major Australian public hospitals, are so focused on the crisis management of access block, elective surgery and budget matters that future planning is often of low priority. Thirdly, health bureaucrats newly arrived in the Northern Territory are convinced that the objective of the proposal is not unique and should have been already embedded in RDH’s core business plans. They are not inclined to commit even the modest resources necessary to make the proposal a reality. This inertia should come as no surprise. It is par for the course in initiatives involving Aboriginal and Torres Strait Islander health. Strong leadership is required to overcome the bureaucratic and financial obstacles as well as the professional rivalries that are inevitably fuelled by change. The implementation of the proposal for a centre of excellence at RDH by NT doctors and other health professionals is seen as integral to realising the NT Health Minister’s vision for dramatic improvement in Indigenous health. It remains to be seen whether there is the leadership to achieve this vision. Key components of the proposal for a centre of excellence in Indigenous health at Royal Darwin Hospital (RDH) The development of a Centre of Excellence for Clinical Training in Aboriginal Health, including an Aboriginal Health Professionals’ Development Unit An employment strategy for RDH that incorporates responsibilities to the local population and Aboriginal staff into its core functions An increase in recruitment and retention of both Indigenous and non-Indigenous RDH staff Participation of a majority of RDH’s clinical staff in initiatives designed to improve understanding of Indigenous social and cultural issues A more acceptable hospital environment for Aboriginal patients Improved communication between RDH and Indigenous communities Acknowledgement and incorporation of traditional Indigenous practices into hospital protocols (eg, maternal health and birthing, men’s health) Improved Indigenous health outcomes in the Top End within 10 years Correspondence: Dr Paul A Bauert, PO Box 42531, Casuarina, NT 0811. paulbauertATozemail.com.au AntiSpam note: To avoid spam, authors' email addresses are written with AT in place of the usual symbol, and we have removed "mail to" links. Replace AT with the correct symbol to get a valid address. ©The Medical Journal of Australia 2005 www.mja.com.au PRINT ISSN: 0025-729X ONLINE ISSN: 1326-5377

Paul A Bauert

Venous thromboembolism (VTE) affects 1–2 per 1000 people in the general population each year. Clinical diagnosis of deep venous thrombosis (DVT) is unreliable, and must be confirmed by compression ultrasonography or venography. A low clinical pretest probability of DVT and negative D-dimer result reliably exclude the diagnosis, with no need for diagnostic imaging. Initial treatment of DVT is with low-molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target INR, 2.0–3.0) for at least 3 months. A vena cava filter is indicated in patients who are ineligible for anticoagulant therapy or who experience embolism despite therapeutic anticoagulation. Thrombolysis or surgical embolectomy may be used as a limb-saving measure in patients with extensive proximal DVT and circulatory compromise that threatens the viability of the leg. Decisions regarding the optimal duration of anticoagulation to prevent recurrent VTE should be individualised and balance the risk of recurrence if warfarin is stopped against the risk of major bleeding and inconvenience of continuing treatment. The risk of recurrence is highest in people with recurrent unprovoked DVT or chronic predisposing factors (eg, cancer) who require indefinite anticoagulant treatment.

Wai Khoon Ho MB ChB, FRACP, FRCPA · Graeme J Hankey MD, FRACP, FRCP · Cindy H Lee MB BS · John W Eikelboom MB BS, FRACP, FRCPA

Allergic bronchopulmonary aspergillosis (ABPA) is an uncommon condition which may complicate asthma and cystic fibrosis; it is seldom considered life-threatening. We report a well 8-year-old boy with cystic fibrosis and normal lung function who progressed to respiratory failure over several days, attributable to ABPA. He recovered with non-invasive ventilation and oral corticosteroid and antifungal medications, regaining normal lung function within 2 months. To our knowledge, such an acute severe presentation of ABPA in a previously well child has not been reported before. Clinical record An 8-year-old boy with pancreatic insufficient, homozygous ΔF508 cystic fibrosis (CF) was transferred from a district hospital with a 7-day history of progressive cough, wheeze and tachypnoea, despite 4 days of broad-spectrum antibacterial therapy (intravenous flucloxacillin and cefotaxime with oral roxithromycin), frequent nebulised salbutamol, oral prednisone (2 mg/kg/day) and chest physiotherapy. There were no other systemic symptoms such as rash, myalgia, arthralgia, diarrhoea or headaches. Initial sputum cultures isolated only normal respiratory flora. The provisional diagnosis was an atypical lower respiratory tract infection, attributed to a viral infection or Mycoplasma pneumoniae. Cystic fibrosis had been diagnosed at newborn screening. His height and weight had tracked along the 10th percentile. Lung function had been normal. Previous sputum cultures had grown Staphylococcus aureus but never Pseudomonas aeruginosa or Burkholderia cepacia. He had not previously wheezed. On arrival, he was mildly dyspnoeic on supplemental mask oxygen at 6 L/minute with a blood oxygen saturation (Spo2) of 94%. He was tachypnoeic (44 breaths per minute), tachycardic (112 beats per minute), afebrile and normotensive. He had bilateral expiratory wheeze with basal crackles. Within 24 hours of transfer, our patient’s condition deteriorated, and he required more frequent nebulised salbutamol and developed signs of respiratory fatigue. At this point an arterial blood gas analysis in 12 L of mask oxygen showed: pH, 7.3; partial pressure of oxygen (Po2), 58 mmHg; partial pressure of carbon dioxide (Pco2), 62.7 mmHg; bicarbonate (Hco3) level, 30 mmol/L; and base excess, 2.7. He was transferred to the paediatric intensive care unit (PICU) for respiratory support with mask continuous positive airway pressure (CPAP). Subcutaneous emphysema developed over the chest wall and neck during the first 48 hours of his PICU admission. A full blood count showed leukocytosis (19.6 × 109/L), and his initial mycoplasma complement fixation test titre was low (< 4). The mycoplasma IgM test result was subsequently negative. Immunofluorescence and culture of nasopharyngeal secretions to isolate a viral pathogen were negative. Total serum IgE titre was 1664 IU (normal range, 0–180 IU) and the skin prick test was positive for Aspergillus fumigatus. The provisional diagnosis was changed to allergic bronchopulmonary aspergillosis (ABPA). Prednisone therapy was continued, and antifungal treatment with oral itraconazole (100 mg twice daily) was added to his therapy. His respiratory status gradually improved and he was weaned off the nasal mask CPAP after 5 days, avoiding endotracheal intubation. He had clinically apparent subcutaneous emphysema, a small pneumomediastinum, but no pneumothoraces during his PICU stay. The chest radiograph before discharge from PICU (Box 1) showed increased perihilar opacities and left lower lobe infiltrates with resolution of the pneumomediastinum and subcutaneous emphysema. His improving spirometry measurements with treatment are shown in Box 2. He was discharged on Day 13 of admission with marked improvement in symptoms and an FEV1 (forced expiratory volume in 1 second) 66% of predicted. A provisional diagnosis of ABPA was confirmed by the significantly elevated serum IgE titre, positive skinprick tests for aspergillus, positive IgG aspergillus precipitins (× 4) and clinical findings consistent with the diagnostic criteria outlined in Box 3.1-5 He received decreasing doses of oral corticosteroids over 3.5 months, as well as oral itraconazole. Within 2 months, his spirometry results had returned to normal. Predictably, he became transiently cushingoid, developed mild untreated hypertension (maximum recorded blood pressure, 116/84 mmHg), and gained 4 kg in weight, but had no glycosuria. He was weaned from corticosteroids and itraconazole, and the side effects resolved within 3 months of discontinuing corticosteroids. Ten months later, he remains well, with normal lung function. DiscussionAlllergic bronchopulmonary aspergillosis (ABPA) is an uncommon condition that can complicate asthma and cystic fibrosis (CF),6,7 and is seldom considered life-threatening.7 The rapid deterioration in the condition of our previously well patient highlights the spectrum of disease severity that can occur in ABPA, and is a reminder that not all deteriorations in respiratory function in patients with CF are attributable to Pseudomonas aeruginosa or Burkholderia cepacia.7,8 Furthermore, this patient’s prompt clinical response to systemic corticosteroids with a return to normal lung function within 2 months suggests that his prognosis will not be adversely affected.9 The presence of Aspergillus species in the sputum cultures of patients with CF has been reported in up to 57% of patients,9 yet the prevalence of ABPA is reported to be between 2% and 14%.1,6 The diagnostic criteria are listed in Box 3. ABPA is a hypersensitivity reaction to the inhalation of aspergillus spores manifesting as chronic wheeze, pulmonary infiltrates and systemic immune activation.5 This results in elevated IgE, IgG and IgA titres.9 Interestingly, although aspergillus grows in the bronchial mucus, this is not an invasive disease.3-5,9 The exact mechanism by which bronchial wall damage evolves and how this gives rise to bronchiectasis and fibrosis is poorly understood.10 Aspergillus fumigatus infection often occurs months before a clinical diagnosis of ABPA is considered. Moreover, as about 40%–50% of school-aged patients with CF have aspergillus in their sputum, comparatively few develop ABPA.3 The reasons for this are not clear, but presumably relate to genetic predisposition, host defences and environmental exposure to aspergillus. Most children with CF who develop ABPA have relatively mild symptoms, respond to treatment over weeks and can often avoid hospital admission altogether.7 Patients with ABPA complicating CF more commonly follow a course of gradually worsening lung function (because of progression of their CF related bronchiectasis) with recurring relapses of ABPA, particularly in summer and autumn, when spore levels in the environment are at their highest.9,10 Treatment of ABPA has centred on the use of systemic corticosteroids for periods of 2–6 months, reducing from doses of 1.0 mg/kg/day of prednisone.4 The adjunctive use of oral antifungals has been advocated for the treatment of ABPA complicating CF11,12 and asthma.6 The response can be dramatic, as in our patient (Box 2). Itraconazole in combination with inhaled corticosteroids was recently shown to be useful for reducing eosinophilic airway inflammation, reducing systemic immune activation and reducing severe exacerbations over a period of 16 weeks in adults with ABPA complicating asthma.13 The use of itraconazole in children is less well studied. However, a recent case series of patients aged 9 to 33 years with CF and ABPA, treated with inhaled budesonide (800–1600 μg/day) and itraconazole (400–600 mg/day), showed a high prevalence of biochemical adrenal insufficiency on adrenocorticotropin testing. This was attributed to an increased systemic budesonide concentration through a reduced or inhibited metabolism (potentially caused by itraconazole), leading to inhibited steroidogenesis.14 This reminds us to use caution when treating patients who take inhaled steroids with courses of itraconazole for exacerbations of ABPA. In conclusion, we are unable to find another case report in which a previously well child with ABPA presented with severe acute respiratory failure. This case highlights the importance of considering a diagnosis of ABPA in highly unusual presentations which may complicate cystic fibrosis. 1 Chest x-ray 3 days after admission to intensive care Shows hyperinflated lung fields, perihilar inflammatory changes, emergence of an interstitial infiltrate in the left lower lobe and a small right-sided pleural effusion. 2 Relationship between IgE levels and FEV1 (forced expiratory volume in one second) before, during and after admission Inverse relationship between IgE levels and FEV1 over time (non-linear scale), showing the drop in lung function at the peak of the disease. 3 Classic case criteria for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis1-5 Clinical deterioration (increased cough, wheezing, exercise intolerance, increased sputum, decrease in pulmonary function) Immediate cutaneous reactivity to aspergillus or presence of serum IgE from A. fumigatus Total serum IgE concentration >1000 IU/L Precipitating antibodies to A. fumigatus or serum IgG from A. fumigatus Abnormal chest x-ray (infiltrates, mucus plugging, or a change from earlier films) Adapted from the ABPA Consensus Conference of the Cystic Fibrosis Foundation4

Emma Skowronski BMedSci · Dominic A Fitzgerald PhD, FRACP

Peter A Frith Head of Southern Respiratory Services, Respiratory Unit, Flinders Medical Centre, Bedford Drive, Bedford Park, SA 5042. Peter.frithATrgh.sa.gov.au To the Editor: The informative study by Simons and colleagues1 has highlighted a major concern. Chronic obstructive pulmonary disease (COPD) is one of Australia’s top four causes of death and burden of illness,2 yet the authors have made no mention of COPD. Failure to recognise the importance of this disease is an endemic attitude in Australia and globally3-5 that results in under-representation of COPD in epidemiological surveys and in inadequate funding for effective treatments and research. The study found that peak expiratory flow (PEF) provides the highest hazard ratios for predicting time to death in women (and the second highest in men). There is even a “dose–response” effect. Using the term “impaired PEF” is a bit like saying “impaired ECG” without attributing a diagnosis. PEF is a measure of airway calibre, and impairment of PEF indicates airway disease — largely COPD in this population. Smoking accounts for about 85% of the risk of COPD, and about 50% of smokers develop airflow limitation,4-6 so it is not surprising that the interaction between PEF and smoking was the most important predictor of reduced survival in this large cohort. It’s time to stop hiding our heads in the ashtray! Smoking combined with low PEF is COPD. We must demand that our medical and epidemiological professions uncover people with undiagnosed COPD. Early diagnosis is simple.5 It’s not normal to be unable to keep up with friends at work or during recreation because of breathlessness, and a daily cough is really an airway disease. If symptoms are acknowledged, spirometry will confirm the diagnosis. We should help our patients to enunciate these hidden symptoms so their condition can be diagnosed accurately, and effective management begun, as highlighted in the “COPDX management guidelines”.5 Primary and secondary prevention must focus on reducing smoking among young people. Smoking cessation, the use of effective drugs, and pulmonary rehabilitation are the cornerstones of COPD therapy that lead to better quality survival. COPD is common and under-diagnosed. Simons et al have partly exposed this deadly condition. Their data, added to other Australian data,7 should trigger actions that facilitate earlier diagnosis throughout Australia and support delivery of effective treatment to the thousands “dying a slow death” from COPD. Australia’s illness burden from COPD is high. Its prevalence and burden in Australia are rising, especially in women. Globally, the World Health Organization expects COPD to rise from 12th to 5th as a cause of illness burden by 2020. We must acknowledge that PEF impairment is not simply a mysterious risk factor for early “all-cause mortality”, but is indicative of COPD being a major contributor to death in this population.

Peter A Frith

Leon A Simons,* Judith Simons† * Director, Dubbo Study of the elderly, † Data Manager, Lipid Department, St Vincent’s Hospital, Darlinghurst, NSW 2010. L. SimonsATnotes.med.unsw.edu.au In reply: The prospective Dubbo Study of the elderly has produced a series of publications in which reduced peak expiratory flow (PEF) has been shown to be associated with increased risk of death,1,2 as well as increased risk of heart attack,3 ischaemic stroke4 and admission to a nursing home. 5 We have employed a purely statistical definition of impaired PEF, namely the lowest third of our sex-specific population distribution. We agree that many subjects so defined with impaired PEF, and who are smokers, will have underlying and potentially undiagnosed chronic obstructive pulmonary disease (COPD). Epidemiological studies have highlighted the importance of impaired PEF. It is now time for health professionals to implement the COPDX management guidelines referred to by Frith6 in a still more effective manner and to devise better prevention programs.

Leon A Simons · Judith Simons