Volume 186 Issue 4

The current whole-cell vaccine and protocol for Q fever prophylaxis are effective At the end of 2006, the Australian Ministers for Health and Agriculture announced funding for an upgraded facility to allow CSL Limited to recommence production of the Q fever vaccine (Q-Vax) and comply with changed biocontainment regulations.1 Production of the vaccine had ceased at the end of 2005 because of inability to meet these new regulations and other production pressures. Federal government support is a welcome step forward in the control of a major infective disease in Australia, and comes as a substantial relief to the rural community and meat processors. In addition, it keeps faith with the considerable efforts by state health department immunisation teams and medical practitioners to extend the use of the vaccine from abattoirs to the at-risk rural community during the government-subsidised National Q Fever Management Program, 2001–2003/2004 (http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/q-fever-man). Attempts to control Q fever by vaccination have a long history.2 After the discovery of clinical Q fever and isolation of the causative organism by Edward Derrick in Queensland in the 1930s, and the subsequent identification of the isolates (an obligate intracellular bacterium) by Macfarlane Burnet, the disease emerged as an important “campaign” infection (Balkan grippe) for armies in the Mediterranean arena during World War II. At the time, various vaccine formulations were prepared from the coxiella grown abundantly in chick embryo yolk sacs, as devised by H R Cox at the National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratory, Montana, USA. Suspensions of infected yolk sac were inactivated with formalin and ether (eg, by Smadel and colleagues).2 These were protective in animals and in human volunteer and challenge trials. But use in humans produced unpredictable, severe local reactions. Derrick expressed a common view of these early Q fever vaccines in his 1964 Elkington Oration: “What of the future; there is an effective vaccine but it produces unacceptable reactions”.3 His assessment is still repeated uncritically in the medical literature. The experience in Australia from 1980 to 2005 with the present generation of whole-cell vaccines (eg, Q-Vax [CSL Limited]) and a different vaccination protocol has been quite the reverse. The contemporary whole-cell, formalin-inactivated Q fever vaccine has also sometimes been dismissed as “old-fashioned”— ignoring a protective efficacy of over 95%. In fact, the formulation is appropriate for the complex immunopathology of acute Q fever. Insight into the critical components for an improved whole-cell vaccine started in Cambridge in the 1950s with Stoker and Fiset’s4 discovery of the antigenic phase variation of Coxiella burnetii. Concurrent studies, also in Cambridge, by Abinanti and Marmion5 showed that antibody to the Phase I antigen (ie, the lipopolysaccharide of coxiella cells with a complete set of sugar residues in its O-chains) was protective in a mouse spleen model of Q fever infection. On the other hand, protection was not conferred by antibody to Phase II antigens (ie, from coxiella with a full complement of proteins, but with genetically driven or other variations in the level of synthesis of complete lipopolysaccharide O-chains — recent research reports6,7 give a more detailed explanation of the chemistry of phase variation). Subsequently, Ormsbee et al8 at Rocky Mountain Laboratory extended these observations to show that a formalin-inactivated vaccine made from coxiella predominantly in the Phase I antigenic state was significantly more protective in a guinea pig model of Q fever on a weight-for-weight basis than one made from cells predominantly in Phase II. The latter preparation, and indeed the earlier vaccines developed by Smadel, probably owed their partial protective properties to residual Phase I cells in a population of Phase II variants. The importance of Phase 1 lipopolysaccharide as a protective immunogen is supported by the finding that a Phase I Q fever vaccine loses its protective efficacy in mice when treated with potassium periodate to ablate the sugar residues in the lipopolysaccharide (unpublished data). The major host cells for C. burnetii in animals and humans are in the monocyte–macrophage lineage. The interactions of coxiella with this key regulatory cell series for the cellular immune system underlie both the immunopathogenesis of Q fever and the prophylaxis afforded by the vaccine. The coxiella proteins (as peptides) stimulate T-lymphocyte immunity and memory, with the generation of interferon-γ and other cytokines that control intracellular replication of coxiella.2 On the other hand, interactions of coxiella and monocyte–macrophage cells produce mediators that down-regulate the cellular immune system and the formation of interferon-γ by T lymphocytes.9,10 A possible explanation for the central requirement of the Phase I determinant in a vaccine is that antibody to it blocks interaction of coxiella and the monocyte–macrophage cells. Consequently, down-regulation of the cellular immune system does not occur and coxiella growth is restricted. A contributory component for vaccine efficacy may be the slow biodegradability of the small-cell variant of coxiella. This displays both Phase I lipopolysaccharide and protein antigens, thus providing continuing antigenic stimulation and protection. An important step in the development of the current protocol for vaccination was the finding by Lackman and colleagues2 at Rocky Mountain Laboratory that adverse reactions to whole-cell vaccine could be minimised by intradermal skin testing of potential vaccinees with a dilute vaccine to detect prior cellular immune sensitisation. In the early 1980s, 50 years after Derrick’s discovery — and probably after some 40 000 overt cases of Q fever — Dick Ormsbee and I asked CSL Limited to make Ormsbee’s highly purified version2 of Q fever vaccine with its negligible residual yolk protein. At the time we knew that Hornick, Fiset and colleagues,2 under the auspices of the Commission on Rickettsial Diseases (US Armed Forces), had vaccinated volunteers with whole-cell vaccine and challenged them with aerosols of living C. burnetii. Even small doses (1–10 μg) of vaccine were protective. Open clinical trials of the Ormsbee-type vaccine (Q-Vax) (produced by CSL) at a dose of 30 μg as a subcutaneous injection were performed in workers at four abattoirs in South Australia in the 1980s.2 These established the vaccine’s safety in an industrial environment in which prior clinical or subclinical infection and immune sensitisation were common. As in the US volunteer trials, the vaccine was protective. A formal “blind” comparison of Q-Vax and influenza virus vaccine performed at three Queensland abattoirs also showed complete protection.2 Box 1 shows the practical value of vaccine prophylaxis in a large abattoir group in Queensland, 1992–2005. Occupationally acquired, laboratory-proven Q fever is compensable. Compensation claims — a significant expense for the industry — declined steadily after the vaccination program started. Box 2 shows the number of Q fever cases notified to the National Notifiable Diseases Surveillance System across Australia, 1991–2006. The yearly totals include Q fever cases both in and outside abattoirs. Abattoirs across the country gradually took up vaccination from 1993–1994, greatly aided by CSL’s vaccine consultants. During the period 1994–2000, although the number of Q fever notifications stabilised at around 500–600 per year, probably reflecting fewer cases in abattoirs, an unambiguous downward trend in Q fever notifications for the country as a whole did not occur. This is not surprising, as it has been apparent since the 1930s that only a variable proportion of Q fever cases occurs in abattoirs (eg, 68% of Derrick’s series of 273 cases11). During the National Q Fever Management Program, state immunisation teams worked intensely to vaccinate abattoir workers, and rural and other at-risk groups in the population. Evaluation continues, but Box 2 shows an encouraging and significant decline in case numbers from 2003 to 2006. What of the future? Further refinement of existing vaccine protocols is needed as problems surface from wider use. Efforts to produce less reactogenic vaccines for use without pretesting are summarised in Box 3.2 Balanced against the continuing and substantial Q fever problem in Australia, the current whole-cell vaccine and protocol are effective, they have been tested in over 150 000 subjects, and prophylaxis for this disease is available now. 1 Control of abattoir-associated Q fever in a major Queensland abattoir complex Claims per annum for compensation for clinically and laboratory-proven, occupationally acquired Q fever. (Data supplied by and reproduced with permission of Australian Meat Holdings, Queensland.) 2 Vaccination and changing trends in the numbers of notified cases of Q fever across Australia, 1991–2006 Means (SEs) for 1991–2002 and 2003–2006; P = 0.01 for comparison of means. (Yearly totals for Q fever notifications and the basic curve are from the National Notifiable Diseases Surveillance System.) 3 Efforts to produce less reactogenic, alternative vaccines without the need for pretesting Extracts of coxiella containing lipopolysaccharides and protein (eg, chemovaccine)2 or delipidated coxiella cell residues2 are protective in animals. Chemovaccine has been used in Eastern Europe in laboratory workers and some industrial groups. It is protective, but about as reactogenic as whole-cell vaccine. To establish efficacy, duration of protection and reactogenicity (severe adverse incidents are rare and idiosyncratic), comparative trials are needed of these vaccines versus whole-cell vaccine in larger numbers of subjects. There is also active research into simpler vaccines of coxiella proteins prepared by recombinant DNA methods.12 So far, coxiella proteins alone appear not to be protective,13 although a recombinant fusion protein given with Freund’s complete adjuvant (a potent macrophage activator) protected in a mouse model.14 The quest for a simpler vaccine should continue; whether successful or not, it is yielding valuable insights into the immunobiology of Q fever. But the three-component nature of the existing vaccine and the roles in protection of lipopolysaccharides, macrophages and antibody need to be taken into account.

Barrie Marmion AO, MD, FRCPA, DSc

Testing for Helicobacter pylori, and acid-suppression therapy are nearly always better strategies Most patients with upper gastrointestinal symptoms can be effectively managed without investigation. Recent long-term follow-up of patients with upper gastrointestinal symptoms shows that most have a benign course.1,2 A recent follow-up of 300 patients 9 years after investigations showed that 40% were asymptomatic; 70% of these without medication.2 Such a good outcome is the result of the decline of Helicobacter pylori3 (making peptic ulcer uncommon and gastric cancer rare in the absence of genetic or ethnic predisposition) and the easy availability of effective acid-suppression therapy (making gastro-oesophageal reflux disease easily treatable). For the vast majority of patients, upper gastrointestinal symptoms are now a dis-ease, not a disease. These changes in epidemiology and treatment simplify the management approach to upper gastrointestinal symptoms (Box). Gastroscopy now has a low diagnostic yield. A review of 22 studies investigating dyspepsia found that, overall, findings in 50% of gastroscopies were normal, 12% revealed reflux oesophagitis, 33% gastroduodenal ulceration, and 1.2% malignancy.5 International management guidelines recommend two alternatives to gastroscopy: empiric acid-suppression therapy; or H. pylori testing and treatment.4 Acid-suppression therapy is effective treatment for gastro-oesophageal reflux disease (GORD), and the “omeprazole test” (a simple trial of omeprazole [40 mg twice daily for a week]) diagnoses GORD more accurately than endoscopy, and with a sensitivity of around 80%.6 For population groups with a high prevalence of H. pylori infection, such as the elderly and some ethnic groups, H. pylori testing and treatment has advantages. For younger patients, H. pylori infection is unlikely, as childhood domestic hygiene has improved. If a test for H. pylori is positive, treatment provides: definitive treatment of peptic ulcer disease; no adverse outcome for non-ulcer disease; risk reduction for ulcer disease associated with non-steroidal anti-inflammatory drug (NSAID) treatment; and possible risk reduction for future H. pylori-associated gastric cancer. For those who test negative for H. pylori, the test provides reassurance. Population studies have shown that people who do and those who don’t consult general practitioners for their upper gastrointestinal symptoms have similar symptom severity, suggesting that reasons for consultation may include anxiety about the significance of symptoms.7 Patients should be asked why they present. For those who want information, data show that lifestyle contributes to GORD and adenocarcinoma development, in particular, obesity, smoking, poor fruit and vegetable intake and a sedentary lifestyle.8,9 This information is a useful tool in encouraging patients with GORD to modify their risk and improve their overall health. Overly rapid prescription of acid-suppression therapy may waste opportunities for lifestyle modification. H. pylori testing should be offered to those likely to be infected because of advanced age, ethnic background, or a past or family history of ulcer disease, and to those who take NSAIDs. After advice, and serological or urea breath testing and treatment of patients with a positive result, symptomatic patients can be offered empiric therapy. Whether this should be a step-up approach with initial antacids followed by H2-receptor antagonists, or a step-down approach with proton-pump inhibitors followed by H2-receptor antagonists remains controversial, as does on-demand versus ongoing treatment. Population data show that, after initial consultation, a substantial proportion of patients cease therapy or continue on an intermittent basis.2 There are no data to indicate that for most patients this is harmful. Non-responders often have non-ulcer or functional dyspepsia and treatment is unrewarding. Prescribed and complementary medications, a frequent cause, should be reviewed. Delayed gastric emptying affects up to 40% of non-ulcer dyspepsia patients and is particularly frequent in patients with long-standing diabetes. Previous gastroenteritis is a recently identified cause of non-ulcer dyspepsia. Prokinetic therapy (with drugs that increase the contactility of the smooth muscle of the upper gut, such as motilium) may benefit both groups. Endoscopy should be reserved for those with a familial or ethnic risk of upper gastrointestinal cancer, older patients with alarm symptoms such as dysphagia, haematemesis or weight loss10 and cancer-phobic patients, as its role in patient reassurance is small and not cost-effective compared with other strategies.11 Concern about missing a cancer diagnosis should be tempered by awareness of its low incidence and the limited value of “alarm symptoms”.5,10 In 2001, there were 10 gastric cancers and fewer than six oesophageal cancers per 100 000 population reported in Australia.12 A recent meta-analysis found alarm symptoms had sensitivity of 0–83% and specificity of 40%–98%, and a study of patients with newly diagnosed gastric cancer found poor correlation between symptoms and resectability with: 41% having symptoms; 81% of these having alarm symptoms; 12% of patients with early gastric cancer having prior symptoms; and no correlation between symptom duration and disease stage.10,13 In clinical practice, a third of people with upper gastrointestinal symptoms consult their GP within 6 months of symptom onset.2,6 As oesophageal adenocarcinoma is associated with severe, long-standing upper-gastrointestinal symptoms, “one-off” endoscopy is unlikely to improve early diagnosis.10,13 Today, most patients, particularly those aged under 55 years, can be reassured that: their symptoms are benign; organic disease, if present, is likely to be responsive to H. pylori eradication or acid-suppression therapy; and their lifetime risk of upper gastrointestinal cancer is exceedingly small and may best be reduced by primary prevention with lifestyle modification. If the temptation to refer a patient for endoscopy persists, then the question is, is this to meet an unmet need or is an un-need being met? Algorithm for the management of uninvestigated dyspepsia* * Adapted from Talley.4 OGD = Oesophago-gastro-duodenoscopy. PPI = Proton-pump inhibitor.

Anne E Duggan MHP, FRACP, PhD

Objective: To compare the location and accessibility of current Australian chronic heart failure (CHF) management programs and general practice services with the probable distribution of the population with CHF.Design and setting: Data on the prevalence and distribution of the CHF population throughout Australia, and the locations of CHF management programs and general practice services from 1 January 2004 to 31 December 2005 were analysed using geographic information systems (GIS) technology.Outcome measures: Distance of populations with CHF to CHF management programs and general practice services.Results: The highest prevalence of CHF (20.3–79.8 per 1000 population) occurred in areas with high concentrations of people over 65 years of age and in areas with higher proportions of Indigenous people. Five thousand CHF patients (8%) discharged from hospital in 2004–2005 were managed in one of the 62 identified CHF management programs. There were no CHF management programs in the Northern Territory or Tasmania. Only four CHF management programs were located outside major cities, with a total case load of 80 patients (0.7%). The mean distance from any Australian population centre to the nearest CHF management program was 332 km (median, 163 km; range, 0.15–3246 km). In rural areas, where the burden of CHF management falls upon general practitioners, the mean distance to general practice services was 37 km (median, 20 km; range, 0–656 km).Conclusion: There is an inequity in the provision of CHF management programs to rural Australians.

Robyn A Clark BN, MEd, FRCNA · Andrea Driscoll BN, MN, MEd · Justin Nottage BEnv, GradDipSpISc · Skye McLennan MPsych · David M Coombe BApplSci(BioEnv · Errol J Bamford BEcon · David Wilkinson PhD, DSc · Simon Stewart PhD, FCSANZ

Objective: To identify the views of health professionals, patients and their carers on strategies to improve the use and management of warfarin in older patients with atrial fibrillation.Design: Qualitative study based on analysis of group interviews.Setting: A major metropolitan teaching hospital, from 1 March to 30 April 2003.Participants: 14 patients (≥ 65 years) with established atrial fibrillation and taking warfarin, three carers, 12 specialists, eight general practitioners, six community pharmacists, nine hospital pharmacists, and 11 nurses volunteered in response to flyers promoting the study.Results: Suggested strategies to improve warfarin management targeted support services for GPs and patients. Hospital-based clinicians felt that dissemination of trial evidence to GPs to support treatment recommendations is required, and that GPs need to enlist allied health professionals in the management of patients taking warfarin. GPs preferred access to practical advice from expert colleagues on the day-to-day management. Patients requested more information about warfarin therapy, as access to information is inadequate, particularly from primary sources (GPs, community pharmacists). Verbal and written information are equally important, but a single counselling session or supply of a booklet was viewed as inadequate. Participants identified various interventions for all levels of warfarin management; from the collective input, a framework for management strategies was developed.Conclusions: Health professionals and patients require more customised information to support warfarin use and management.

Beata V Bajorek PhD, BPharm · Susan J Ogle MB BS, FRACP · Margaret J Duguid BPharm · Gillian M Shenfield DM, FRCP, FRACP · Ines Krass PhD, BPharm

Objective: To identify the prevalence of mental health problems, rates of suicidal ideation and behaviour, and use of professional mental health services among children and adolescents residing in home-based foster care, and to compare these rates with those reported for children and adolescents in the general Australian community.Design: Cross-sectional survey.Participants and setting: 326 children and adolescents (aged 6–17 years) residing in home-based foster care in the Adelaide metropolitan region between August 2004 and January 2006.Main outcome measures: Prevalence of emotional and behavioural problems, suicidal ideation and behaviour, and use of professional services to obtain help for emotional and behavioural problems.Results: 61.0% of children and adolescents living in home-based foster care scored above the recommended cut-off for behaviour problems on the Child Behavior Checklist and 35.2% of adolescents scored above the cut-off on the Youth Self Report. 6.7% of 13–17- year olds in home-based foster care reported a suicide attempt that required medical treatment during the previous year. Caregivers reported that 53.4% of children needed professional help for their mental health problems but only 26.9% had obtained help during the previous 6 months.Conclusion: Children in home-based foster care experience high rates of mental health problems but only a minority receive professional help for their problems.

Michael G Sawyer PhD, FRCPC, FRANZCP · Josephine A Carbone BA(Hons) · Amelia K Searle BPsych(Hons) · Philip Robinson PSM, DipAppPsych, MPsych

Objective: To assess influenza vaccine uptake among health care workers in Victorian public hospitals in 2005.Design, setting and participants: Infection control staff in all Victorian public hospitals were asked to collect standardised data on numbers of non-casual staff and vaccinations administered to these staff during the 2005 vaccination period.Main outcome measures: Proportion of total non-casual staff vaccinated; proportion of non-casual staff vaccinated in various staff categories.Results: Seventy-four of 122 hospitals or health services (85 individual campuses) submitted data for 63 330 non-casual staff. The overall proportion vaccinated in 2005 was 38%, ranging from 34% for non-clinical staff to 42% for laboratory staff.Conclusion: Vaccine uptake among staff in Victorian hospitals is low, and increased uptake is desirable to improve staff health and reduce the occurrence of hospital-acquired influenza and the risk to patients.

Ann L Bull BSc(Hons), MAppEpid, PhD · Noleen Bennett MPH · Helen C Pitcher RN · Philip L Russo MClinEpid · Michael J Richards FRACP, MD

Nanomaterials — a wide variety of materials with a diameter of less than 100 nm — have unique properties. Nanotechnology is being promoted as the technology that will drive the next industrial revolution. Nanomaterials may have unique biological activities, but little research has been undertaken to investigate their potential effects on human health and the environment. Many seminal reports have identified gaps in our knowledge, and a large multidisciplinary effort will be required to undertake the necessary research to assist the framing of regulatory models to deal with any novel risks.

Brian G Priestly MPharm, PhD · Andrew J Harford BAppSc, PhD · Malcolm R Sim PhD, FFOM

Nanotechnology is a revolutionary field of micro-manufacturing involving manipulation, by chemical or physical processes, of individual atoms and molecules. Pharmaceutical and medical device manufacturers, both in Australia and internationally, have significant investments in nanotechnology research and development. It is important that safety regulation of nanotherapeutics keep pace with this growing level of industry interest. A recent senate inquiry recommended the establishment of a working party, including representatives of the Therapeutic Goods Administration, to consider whether bulk materials classified as safe should be routinely reassessed for use at the nanoscale level by a permanent, distinct nanotechnology regulator. Safety regulation of nanotherapeutics may present unique risk assessment challenges, given the novelty and variety of products, high mobility and reactivity of engineered nanoparticles, and blurring of the diagnostic and therapeutic classifications of “medicines” and “medical devices”. Nanotherapeutics is likely to make increasing claims on a particular area of Australian health care regulatory strength: scientific cost-effectiveness assessment of innovation in medical products. Any review of Australian regulation of nanotechnology should include a critical analysis of both safety issues and cost-effectiveness assessment systems for nanotherapeutics.

Thomas A Faunce BA/LLB, BMed, PhD

From July 2007, the Health Professions Registration Act 2005 (Vic) will significantly alter the medical disciplinary process in Victoria. For practitioners: Formal hearings for allegations of serious unprofessional conduct will be heard by the Victorian Civil and Administrative Tribunal (VCAT); There will be no right of appeal from a VCAT decision other than on a point of law; The maximum fine for serious unprofessional conduct will increase from $2000 to $50 000; Performance standards panels (PSPs) will be established to conduct informal hearings, with a power to impose conditions on registration; and Costs of the new system will cause an increase in annual registration fees. For complainants: There are new avenues for conciliation; There is a right to seek a review of certain Medical Practitioners Board of Victoria decisions; and Reasons for a PSP decision will be provided. Despite government argument that these changes will make the health complaints handling system fairer, the new Act has the potential to diminish the rights and interests of doctors.

Sarah L Middleton BA, LLB(Hons), PhD · Thomas D Pearce · Michael D Buist MB ChB, FRACP, FJFICM

The incidence and prevalence of atrial fibrillation are increasing because of both population ageing and an age-adjusted increase in incidence of atrial fibrillation. Deciding between a rate control or rhythm control approach depends on patient age and comorbidities, symptoms and haemodynamic consequences of the arrhythmia, but either approach is acceptable. Digoxin is no longer a first-line drug for rate control: β-blockers and verapamil and diltiazem control heart rate better during exercise. Anti-arrhythmic drugs have only a 40%–60% success rate of maintaining sinus rhythm at 1 year, and have significant side effects. The selection of optimal antithrombotic prophylaxis depends on the patient’s risk of ischaemic stroke and the benefits and risks of long-term warfarin versus aspirin, but is independent of rate or rhythm control strategy. Ischaemic stroke risk is best estimated with the CHADS2 score (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, 1 point each; prior Stroke or transient ischaemic attack, 2 points). For patients with valvular atrial fibrillation or a CHADS2 score ≥ 2, anticoagulation with warfarin is recommended (INR 2–3, higher for mechanical valves) unless contraindicated or annual major bleeding risk > 3%. Aspirin or warfarin may be used when the CHADS2 score = 1. Aspirin, 81–325 mg daily, is recommended in patients with a CHADS2 score of 0 or if warfarin is contraindicated. Stroke rate is similar for paroxysmal, persistent, and permanent atrial fibrillation, and probably for atrial flutter.

Caroline Medi BMed · Graeme J Hankey MD, FRCP, FRACP · Saul B Freedman FRACP, FACC, FESC

Despite the emergence of multidrug-resistant strains of hepatitis B virus (HBV) and previous success with combination therapy for other chronic viral infections, we are still using sequential monotherapy for chronic HBV infection. Antiviral-resistant HBV can result in major life-threatening complications. We now have complementary drugs, such as lamivudine and adefovir dipivoxil, with fundamentally different structures and associated with different signature resistance mutations, with adefovir dipivoxil showing antiviral activity against most lamivudine-resistant strains. Studies of combination therapy to date have used traditional endpoints — short-term reduction of HBV DNA levels and HBeAg seroconversion — rather than evolution of resistance. There is now an emerging body of data suggesting that combination therapy can decrease antiviral resistance in HBV infection, the endpoint likely to be of greatest long-term importance, and, rather than adding or replacing an antiviral agent after resistance develops, it is likely to be more effective in treatment-naïve patients.

Joseph J Sasadeusz FRCPC, FRACP, PhD · Stephen L Locarnini PhD, FRC(Path) · Graeme Macdonald FRACP, PhD

An elderly woman presented with her third episode of back pain, fever and neurological deficits. She subsequently developed pseudogout of the knee, and a diagnosis was made of systemic calcium pyrophosphate deposition disease (CPPD) involving the spine and causing intermittent cauda equina syndrome. This case illustrates the difficulty of differentiating infection from CPPD. Clinical recordIn December 2005, a 78-year-old woman presented to the emergency department with acute onset of severe lumbar back pain radiating down both posterior thighs, bilateral leg weakness, and paraesthesiae of the feet on getting out of bed that morning. On examination, lower limb tone was normal, but power was reduced in all movements of the knee and ankle. Reflex testing showed reduced knee jerks, absent ankle jerks and downgoing plantar reflexes. Although anal tone was reduced, sacral sensation was intact. In keeping with cauda equina syndrome, she was unable to pass urine and required a urinary catheter for 2 days. Two similar episodes had occurred previously. In 2003, she had been diagnosed with lumbar discitis, after presenting with severe lumbar back pain and subsequently developing urinary retention and lower limb weakness. A magnetic resonance image (MRI) scan showed 50% spinal canal compromise, at multiple levels, due to marked osteophytosis of the facet joints, ligamentum flavum hypertrophy and spondylolisthesis; the spinal cord was normal, but an abnormal signal was detected in the L3/L4 disc. Cerebrospinal fluid (CSF) aspirated under computed tomography (CT) guidance was sterile, but calcium pyrophosphate crystals were present (these were deemed to be not significant). A bone scan showed patchy increased uptake of a radioactive tracer in the lumbar spine, thought to be consistent with discitis. The level of the inflammatory marker C-reactive protein (CRP) was raised (282 mg/L; reference range, < 20 mg/L), the erythrocyte sedimentation rate (ESR) was 79 mm/h (reference range, < 45 mm/h), and the patient was febrile. She was treated with intravenous and then oral flucloxacillin for 6 weeks. Levels of inflammatory markers returned to normal after 2 months. In 2004, the patient had presented with severe neck pain radiating to both shoulders and fever up to 39°C, with a CRP level of 332 mg/L, ESR of 108 mm/h and white cell count of 18.0×109/L (reference range, 4–11 × 109/L). A neurological examination was normal. An MRI scan showed diffuse enhancement around the cervical spinal canal, suggesting inflammation or infection, and prominence of the ligamentum flavum. CSF microscopy was normal, and culture of CSF for tuberculosis was negative. The patient was diagnosed with cervical spine osteomyelitis, based on the MRI findings, fevers, and raised levels of inflammatory markers, and was commenced on intravenous flucloxacillin. Over 6 weeks of hospitalisation, she gradually improved, and levels of inflammatory markers fell to normal. She continued to take oral antibiotics for 6 months. Her previous history had included longstanding osteoporosis, hypertension, osteoarthritis of the hands, a gastric ulcer (in 1999), and diverticulosis. However, before this second admission she had been well. The most recent admission followed a similar pattern to the earlier admissions. Initial investigations included an MRI scan of the lumbar spine (Box), which was essentially unchanged from 2003. A bone scan showed increased uptake at several sites, including L1, the patellae, the right foot, and the cervical spine, which was thought to reflect degenerative changes only. She began to spike fevers up to 39°C, the CRP level rose to 393 mg/L, and she developed a normocytic anaemia (haemoglobin level, 88 g/L; mean cell volume, 86 fL). Blood and urine cultures were repeatedly negative. A CT scan of the abdomen showed no focus of infection, and a chest x-ray was normal. On the basis of the pain, fevers, and raised inflammatory marker levels, she was treated with antibiotics for presumed recurrence of lumbar osteomyelitis/discitis. After 10 days, she developed painful bilateral knee effusions. X-rays of the knees revealed chondrocalcinosis, and aspirated fluid contained calcium pyrophosphate crystals. We made a diagnosis of systemic calcium pyrophosphate deposition disease (CPPD), involving the spine and causing intermittent cauda equina claudication. The patient was started on colchicine 0.5 mg twice daily and prednisone 40 mg, and the pain settled within 36 hours. A later attempt to withdraw these medications precipitated a flare in pain and a rise in the level of inflammatory markers; she responded promptly to their re-introduction. The woman was discharged home after a month of rehabilitation, and remains well on a small dose of colchicine. Subsequent review of her extensive previous laboratory data revealed that the disc aspirate from 2003 contained numerous calcium pyrophosphate crystals, and, in retrospect, the two previous diagnoses of lumbar and cervical spine osteomyelitis/discitis were probably episodes of CPPD. DiscussionOur case is notable because of its rare combination of factors: systemic CPPD, and CPPD involving the intervertebral disc and ligamentum flavum, which, with spondylolisthesis and facet joint hypertrophy, caused intermittent cauda equina syndrome, in a patient who had not previously had peripheral involvement. This made the diagnosis challenging, despite the fact that calcium pyrophosphate crystals had previously been identified in her lumbar disc. We found no such cases reported in the Medline, EMBASE, CINAHL or Google Scholar databases. CPPD was first described in the early 1960s by McCarty et al1 and Zitnan and Sit’aj.2 Both reports noted inflammatory joint involvement accompanied by fever, anorexia, weight loss and raised ESR. CPPD is characterised by the clinical features of arthritis (pseudogout), radiographic chondrocalcinosis in both hyaline and fibrocartilage, and identification of calcium pyrophosphate crystals in either synovial fluid or excised tissue.3 There are several distinctive clinical patterns, the most common being acute monoarthritis of the larger joints such as the knee, elbow, shoulder and hip (seen in 35%–60% of patients). The onset of severe pain, swelling, stiffness and erythema typically occurs over a few hours, reaching maximal intensity after 6–24 hours.3 The incidence of calcium pyrophosphate deposits in the intervertebral disc varies from 3.1%4,5 to 14%6 in postmortem and surgical series, respectively. In the surgical series,6 17% of samples had crystals in the ligamentum flavum and disc. In the same study, the incidence of crystal deposition in the ligamentum flavum was 24.5% in patients undergoing laminectomy (contributing to their lumbar spinal stenosis) and 5% in control cadavers. There have been case reports of calcium pyrophosphate deposits in the ligamentum flavum causing chronic myelopathy.7,8 In a case series from Japan, five patients had intermittent cauda equina claudication and sciatica as a result of anterior spondylolistheses and hypertrophy of the medial facet joint and ligamentum flavum. All patients had calcium pyrophosphate deposition in the ligamentum flavum.9 A case of CPPD mimicking infection in the lumbar spine10 was reported in an elderly woman with progressive lumbar pain, fevers, and elevated levels of inflammatory markers. She underwent surgery before a diagnosis of CPPD was made. The authors comment on the difficulty of differentiating infection from CPPD because of the similar clinical signs. Like spinal CPPD, systemic CPPD is an uncommon diagnosis. Several case series have described patients who presented with fever and raised inflammatory markers and underwent expensive and invasive investigations and lengthy delays in diagnosis until they developed peripheral arthritis, with CPPD being subsequently diagnosed.11-13 Bong and Bennett11 comment that fever is not a well recognised sign of CPPD, causing diagnostic confusion, over-investigation, and delay in appropriate therapy. By the time of correct diagnosis, our patient had had 32 plain x-rays, six MRI scans, two bone scans, three CT scans (including two CT-guided biopsies under general anaesthesia), two lumbar punctures and six blood culture sets, and had spent 4 months in hospital. This emphasises the need to consider CPPD in the differential diagnosis of any case of back pain or pyrexia of unknown origin, even if there has been no previous peripheral involvement. Magnetic resonance image of the L4/L5 disc, showing 50% canal stenosis due to facet joint hypertrophy, spondylolisthesis and ligamentum flavum hypertrophy Anterolisthesis of L4 on L5 (white arrow). Facet joint hypertrophy (grey arrow). Ligamentum flavum hypertrophy (black arrow).

Christina R Cameron MB ChB · Carl D Burgess FRACP, MD

To the Editor: Humans may serve as intermediate hosts in hydatid disease, a parasitic infection caused by the tapeworm Echinococcus granulosus. They are infected through contact with infected dogs or by ingestion of tapeworm eggs in contaminated food, water, or soil.1 The larvae form cysts in body organs. Although the liver is the most common site, lung cysts are seen in up to 30% of cases of hydatid disease. Lung cysts are generally asymptomatic, but symptoms occur if the cysts rupture.2 Here, we describe an adolescent girl with a lung cyst that ruptured across the thoracic cage into the subcutaneous fascia, presenting as a breast swelling. A 14-year-old girl had had left-sided pleuritic chest pain, a high-grade fever, and marked swelling of the left breast for 10 days, which did not respond to antibiotics (oral amoxycillin and parenteral amikacin). Clinical examination revealed a slender, febrile and tachy-pnoeic patient with a tender swelling of the left mammary region. The swelling had a tense cystic feel, and transmitted impulses were felt when she coughed. A diffuse pleural rub was heard anteriorly, with reduced air entry. Investigations revealed a neutrophilic leukocytosis of 12.7 × 109/L. Chest x-ray showed diffuse opacification of the left hemithorax, and a computed tomography scan revealed a cystic, low-attenuation lesion in the left hemithorax extending into the submammary region (Figure A). On anterolateral thoracotomy, an infected ruptured cyst was seen in the left upper lobe of the lung, with degenerated membranes and pus extending across the chest wall into the submammary space. The cyst was removed, capitonnage of the residual cavity was performed, and pus and laminated membranes were removed from the submammary space. Small communications seen between the pus cavity and the bronchi were closed. After the operation, parenteral anti-biotics (vancomycin and amikacin) were administered for 10 days and albendazole for 4 weeks. Casoni’s skin test was positive and antihydatid antibodies were detected in serum. Surgically obtained pus revealed non-viable scolices of E. granulosus (many degenerated), and the histopathology of the surgical specimen was consistent with hydatid membrane (Figure B). Pulmonary hydatid cysts can rupture; however, rupture into the pleural cavity is rare.1-3 Although spontaneous rupture of a cyst into the pleural cavity, or rupture after trauma, has been reported,4,5 a rupture across the pleural cavity into the submammary fascial tissues has, to our knowledge, not been reported previously. A. Computed tomography scan showing a cystic lesion in the left hemithorax, extending into the submammary region (arrow). B. Degenerated hydatid cyst membrane (original magnification × 200).

Parvaiz A Koul · Abdul Wahid · Ghulam N Lone · Tariq A Bhat

To the Editor: St John’s wort (SJW) (Hypericum perforatum) is a natural medicine commonly used for treating depression. We recently encountered a case of an overdose of SJW leading to serious manifestations in the patient. A 16-year-old girl presented to the emergency department with seizures and confusion. She was intubated and admitted to the intensive care unit. The only relevant history was of febrile convulsions at the age of 4 years. There had been no head trauma. Results of a computed tomography brain scan and cerebrospinal fluid examination were unremarkable. Electrolyte levels were normal, and standard drug toxicological screens were negative. An electroencephalogram (EEG) confirmed diffuse spike wave activity consistent with generalised epileptic activity. On further questioning, it was found that she had taken large quantities of SJW — up to fifteen 300 μg tablets a day in the 2 weeks leading up to admission and an additional 50 tablets just before presentation — for a recent “depressive episode”. Depression had not been formally diagnosed, and the tablets had been obtained “over the counter” from a local pharmacy. A provisional diagnosis of seizures due to an overdose of SJW was made. High performance liquid chromatography was not performed to quantify hypericum extract in serum and urine, as these tests are not available in our hospital. A repeat EEG at discharge on Day 6 was normal, and there were no further seizures in the following 6 months. Psychiatric assessment during the patient’s hospital stay revealed a likely suicide attempt following recent social stresses. There is some evidence for the efficacy of SJW in treating depression.1 In the United States and Australia it is available without prescription, but in Germany, where it is prescribed more frequently than fluoxetine for depression, it is available by prescription only. The reported incidence of adverse drug reactions to SJW is 0–5.7%.2 Although these are usually minor and transient, more serious adverse reactions (such as serotonin syndrome) have been reported.3 SJW was implicated as a likely, but unproven, cause of seizure-related events in a recent review,4 but our case appears to be the most severe reported so far. Adverse reactions are thought to be more common if SJW is taken in conjunction with selective serotonin reuptake inhibitors, but have also been described when SJW is taken alone.5

Dharshi C Karalapillai · Rinaldo Bellomo

To the Editor: Sanderson et al provide an interesting viewpoint about how the community, including medical practitioners, have embraced complementary and alternative medicine (CAM).1 However, if we were reviewing this article for publication, we would ask the authors to: make a valid distinction between those complementary and alternative therapies promoted as curative versus those considered palliative; define how they decided which therapies belong to one or other side of the arbitrary CAM boundary; review and justify the boundaries for the “therapeutic footprint” in a more evidence-based and rigorous way; locate specific therapies inside the footprint; locate where chemotherapy lies within the footprint, in light of the recent review showing, for the vast majority of adult malignancies, its marginal survival benefits considering its high costs, both monetary and healthwise;2 emphasise that there are relatively few recorded adverse events for CAM compared with conventional cancer care (Therapeutic Goods Administration Medicine Summary reports 2003, 2004, 2005 — Dr K Mackay, Acting Director, Adverse Drug Reactions Unit, TGA, personal communication); and vigorously question the marketing of conventional medicines, such as trastuzumab (Herceptin, Roche), to vulnerable patients and an uncritical public when the evidence suggests huge expense and little, if any, survival benefit.3 Perhaps a distinction also needs to be made between CAM therapies, many of which provide proven symptomatic relief, and those lifestyle interventions, such as exercise,4 dietary change,5 and social support, which provide symptomatic relief and may also confer a survival benefit. It does not serve the profession well when many cancer patients and their carers have to go outside the medical system to access information, advice and therapies which they should have easy access to within the system. In fact, we might even question how helpful these arbitrary boundaries are when all that patients and doctors want is to use what works and what is safe.

Craig S Hassed · Vicki Kotsirilos · Marie Pirotta · Avni Sali

In reply: We would like to thank Hassed and colleagues for their comments on the “therapeutic footprint” and their questions about locating specific therapies within the model. While it was outside the scope of our article to critically analyse different treatments using the model (as benefits and risks will vary from patient to patient), we would like to direct Hassed et al to a more detailed consideration of the risks and benefits of chemotherapy.1 We do not see our model as a tool to categorise or economically appraise specific treatments, but rather as one to help conceptualise the key issues to be considered when proposing treatment — the evidence for benefits and risks, contextualised according to treatment goals. The model provides a basis for comparison, taking us beyond arbitrary and unhelpful arguments about the distinctions between complementary and alternative therapies and their boundaries. We hope that the model will encourage evaluation of evidence for all therapies and support critical evaluation not only of drugs, but also lifestyle interventions that may benefit patients. The primary or essential purpose of the model is to encourage the posing of questions like those articulated by Hassed and colleagues to any therapist — whether they identify as medical, complementary or alternative.

Christine R Sanderson · Bogda Koczwara · David C Currow

To the Editor: In From the Editor’s Desk in the 20 November 2006 issue of the Journal, Van Der Weyden acknowledged the 100th anniversary of the first performance of George Bernard Shaw’s play The doctor’s dilemma, and the fact that both society and medical practice have since changed dramatically in the ensuing century. He then asked: “. . . what is the modern doctor’s dilemma?”1 Contemporary Australian medical practice faces challenges posed by changes in community and government expectations, free market policies, workforce shortages and infrastructure changes, so this question should not be regarded as rhetorical. Answers to it will depend to some degree on the type of medical practice under consideration and where it is situated geographically, but to get the ball rolling, I suggest that in respect of general practice anywhere in Australia, a significant set of dilemmas surround notions of responsibility. Traditionally, general practitioners have held responsibilities primarily to individual patients. With increasing emphasis being placed, appropriately, on preventive and screening activities, to what extent should GPs’ responsibilities be extended to the community as a whole, and how should any such extension be resourced? Given that the interests of individuals and communities will not always be in accord, how might the resulting conflicts of interests best be managed? And, to increase the complexity of such considerations, to what extent ought responsibility to patients extend to responsibility for patients? Another dilemma for doctors in respect of responsibility relates to identifying the boundaries between altruism and martyrdom. To what extent should health care professionals be expected to put the interests of their patients or of the community before those of themselves and their families? To extend the notion of responsibility further, and with the GP’s role as patient advocate particularly in mind, to what degree should health care professionals be active against social injustices which impinge on their patients’ health? I know that in responding to the Editor’s question I have posed another set of questions, none of which are easily answered — if they could be, they would not be dilemmas. However, acknowledging and clarifying these questions is the first step towards answering them, and also towards preventing much community misunderstanding.

David E Smith

To the Editor: I am one of the septuagenarians described by Arnold in his cri de coeur over the demise of professional courtesies.1 In my medical student days, my teachers extended the courtesy of free medical treatment to my parents. I have continued this tradition, in the certain knowledge that this will be the only situation in which medical students save their parents money. Such professional courtesies are still the norm in Western Australia. But, with the exception of medical colleagues, I have only once, in the 30 years of operation of Medibank/Medicare, had a bulk-billed patient realise that he has received a discount. I recently asked a picture framer/patient for a 40% discount and he laughed. When I explained that by bulk-billing I was effectively giving him a 40% discount, he was incredulous, but he did reciprocate. In the 1970s, Australian Medical Association spokesmen and medical educators often confused etiquette (a code of desirable behaviour between doctors) with ethics (a more important set of moral principles underlying a person’s general behaviour). This is no longer the case, and etiquette has disappeared from undergraduate and postgraduate medical curricula. I think it is time to reintroduce the topic into the education of both our future doctors and our patients.

Max Kamien

To the Editor: There would be few medical students who have not had drummed into them the tautological aphorism, “Common things occur commonly!” And few practising clinicians who have not come across or read about a serious adverse event arising from the actions of a colleague or nurse who thought, “It was only X, which is so common at this time of the year/around these parts/among these people. I didn’t think it was anything serious.” The patient might have been a child with meningitis sent home with a diagnosis of a winter upper respiratory tract infection or a very anxious young woman with an intracranial haemorrhage discharged with a diagnosis of tension headache. Guided by this aphorism, we doctors will almost always make the correct diagnosis, and nurses an accurate assessment of a patient’s complaints, and we will glow with professional satisfaction. But how does this boost to our professional confidence measure up against what should be our paramount concern — the safety of each patient in our care? When assessing junior colleagues, we must, above all else, be seeking reassurance that patients will be safe in their hands. We do not want to hear a junior doctor brushing aside a commonly occurring symptom or clinical sign as of little importance merely because it is common. But we do want to know that he or she has considered, “What is the most serious condition that this could be?”, followed by relevant enquiries into the patient’s history, appropriate clinical examination and warranted laboratory or other investigations. Knowing that the doctor has checked that there is no suggestion of a serious illness, we can be reasonably assured that the patient will be safe. An excellent candidate would make the correct diagnosis sooner and perhaps with less pain, discomfort and inconvenience for the patient, and at less cost to the health care system, than a less able colleague. But the patient will be safe with either doctor, as a dangerous, perhaps life-threatening, illness has been excluded. All that remains is for the correct diagnosis to be made and appropriate treatment administered — a burden for the patient perhaps, but not a disaster. I suggest that readers of the Journal, in their role as teachers, advise their students to abandon that inane and dangerous “commonness” tautology, and replace it with: “Exclude the worst possibility and then assist Nature in its healing processes”.

Peter C Arnold

Growing old gracefully Growth hormone (GH) is unlikely to be useful as an anti-ageing therapy in the healthy elderly, according to a US-based systematic review. Use of GH as an anti-ageing agent is widespread, due to reports in the mainstream and medical literature, but after conducting a systematic analysis, researchers concluded that the practice is not supported by the evidence base. Although people using GH show changes in body composition, such as increased lean body mass and decreased fat mass, those treated with GH experience adverse events such as soft tissue oedema, carpal tunnel syndrome, and gynaecomastia at significantly higher rates. The researchers acknowledged the limitations in the review, including the lack of robust, large, randomised controlled trials studying the effects of GH in this population, but concluded that “GH cannot be recommended for use among the healthy elderly”. Ann Intern Med 2007; 146: 104-115 Mammographic density and risk of breast cancer Extensive mammographic density (ie, dense tissue in 75% or more of the breast) is strongly associated with an increased risk of breast cancer, regardless of the mode of detection, a Canadian study reveals. Researchers conducted three case-control studies with over 1000 matched pairs of women in a screened population and found the greater risk to be independent of other risk factors for breast cancer. This increased risk is apparently greater in younger women. Moreover, women with extensive mammographic density are more likely to be diagnosed with breast cancer over the 12 months following a negative baseline mammogram. The researchers concluded that alternative screening methods such as digital mammography, ultrasonography, and magnetic resonance imaging should be evaluated and developed for women with extensive mammographic density. N Engl J Med 2007; 356: 227-236 Sex school A specially designed, theoretically based sex education program delivered in schools has had no effect on the number of conceptions or terminations, UK researchers have shown.1 The SHARE (sexual health and relationships) program is delivered in the third and fourth years of high school. It comprises lessons, group exercises, and written information aimed at reducing unwanted pregnancies, reducing unsafe sex, and improving the quality of sexual relationships. The effect of this program on reducing the incidence of conceptions and terminations was compared to that of routine sex education classes (the control group) in a Scottish district. Data were collected from the National Health Service on all births, stillbirths, terminations and miscarriages that linked to the population of schoolchildren who underwent the program and those who did not. All the girls in the sample were followed until the age of 20. There were no significant differences between the two groups in levels of conceptions and terminations, whereas conception rate was strongly linked to socioeconomic factors. An accompanying editorial calls for further evaluation and recognition of alternative “saved sex” programs, commenting that delayed first sex has been shown to be the most significant factor in reducing the teenage abortion rate in the United States and Europe.2 1. BMJ 2007; 334: 133-137 2. BMJ 2007; 334: 103-104 Falling for you Dramatically decreasing benzodiazepine use among the elderly does not appear to decrease hip fracture rates, despite previous evidence to the contrary. Researchers observed benzodiazepine prescribing and hip fracture rates in New York State after the adoption of legislation to control prescription of these drugs. Prescription rates decreased by 60% but hip fracture rates remained the same. In New Jersey, where no changes have been made to prescribing, fracture rates also remained unchanged. While acknowledging the possible existence of unknown confounders and selection bias, the authors conclude that the association between use of benzodiazepines and the risk of hip fracture must be small, if present at all. Ann Intern Med 2007: 146: 96-103 Too late for folate? Folate supplementation may improve cognitive function in older adults, according to Dutch researchers. A randomised, double-blind, placebo-controlled study with over 800 participants conducted in The Netherlands has shown promising results for the benefits of daily folic acid supplements in adults aged between 50 and 70 years. The authors allocated people to one of two groups: a treatment group receiving 800 µg per day of folic acid and a placebo group. After 3 years, cognitive function was assessed using tests for memory, sensorimotor speed, complex speed, information processing speed, and word fluency. The change in global cognitive function (the average of all the measured domains) after 3 years was significantly better in the folic acid group compared with the placebo group. The researchers commented that although folate improved performance on memory tests, more work is required to determine whether folic acid supplementation can reduce the risk of Alzheimer’s disease. Lancet 2007; 369: 208-216 Dr Tanya Grassi, MJA

Tanya Grassi