Letters

To the Editor: A 26-year-old woman presented with 24 hours of severe constant epigastric pain and vomiting. She had no history of similar pains, alcohol consumption or gallstones. Four days before presentation she had received her first dose of human papillomavirus (HPV) vaccine. Two days after vaccination she developed a fever and self-limiting rash of 3 days’ duration. Examination revealed marked epigastric tenderness and temperature of 40°C. Other physical parameters were within normal limits. Biochemical investigations showed normal liver function, moderate leukocytosis, a serum amylase level of 1900 U/L (reference range [RR], 23–85 U/L) and lipase level of 3400 U/L (RR, 0–160 U/L). An upper abdominal ultrasonography showed a non-dilated biliary tree and no evidence of gallstones. Computed tomography showed an oedematous pancreas with peripancreatic fat stranding and arterial enhancement of the pancreatic parenchyma, consistent with pancreatitis without necrosis (Box). Other investigations showed normal serum levels of calcium, triglycerides and parathyroid hormone. Serological tests were negative for acute infection with coxsackie A9, coxsackie B1–6, echo, mumps, herpes simplex, hepatitis and varicella zoster viruses. The patient was diagnosed with pancreatitis and treated conservatively with intravenous fluids and analgesia. Pain, symptoms and biochemical abnormalities settled after 10 days. She was discharged and remains well. Magnetic resonance cholangiopancreatography performed after discharge showed no pancreatic parenchymal or ductal abnormality. Acute pancreatitis is common, with an incidence of 5.4–80 per 100 000.1 Gallstones and alcohol use account for 70%–85% of cases; other causes include drugs, viral infections, tumours, hyperlipidaemia, hypercalcaemia, trauma, iatrogenic injury and pancreatic ductal anomalies. The cause is unidentified in up to 10% of cases.1,2 Viral pancreatitis is well recognised, with cytomegalovirus and mumps, coxsackie, hepatitis, herpes simplex, and varicella viruses all known causes.3 Vaccines have been implicated, with pancreatitis associated with measles–mumps–rubella and hepatitis A and B vaccines.4,5 To date, there has been no report linking HPV vaccination with pancreatitis. The pathophysiology linking vaccination with pancreatitis is unclear. It has been postulated that viral replication in immunodeficient hosts receiving live attenuated viral vaccines can cause pancreatitis. Alternatively, “molecular mimicry” could stimulate production of auto-antibodies, which react with host antigens and cause autoimmunity.5 The HPV vaccine is a quadrivalent, recombinant, non-infectious formulation, eliminating viral replication as a mechanism of pancreatitis. Therefore, an autoimmune mechanism is possible. Extensive clinical testing has demonstrated the safety of HPV vaccine in the general population. In our patient, intensive history taking and investigation failed to identify another cause for pancreatitis, and the close temporal relation of the HPV vaccination, the development of a prodromal illness, and fever without evidence of sepsis led us to postulate that pancreatitis was secondary to vaccination. A coincidental illness causing pancreatitis cannot be ruled out, but neither can HPV vaccination be excluded as a potential cause. We therefore suggest that pancreatitis be considered in cases of abdominal pain following HPV vaccination and if proven, notified to the Adverse Drug Reactions Advisory Committee. Computed tomography scan of the abdomen in a patient with pancreatitis Portal venous computed tomography images showing oedematous enlargement of the pancreas, with surrounding fat stranding and ascites. The pancreas (arrows) appears fully enhanced with contrast, suggesting there was no necrosis. A: Pancreatic head. B: Pancreatic body and tail.

Amitabha Das · David Chang · Andrew V Biankin · Neil D Merrett

To the Editor: Australian consensus guidelines for selecting formulas for infants with cows milk protein allergy (CMPA) have recently been published.1 We reviewed formula choices and outcomes for 51 children with immediate allergic reactions to cows milk protein who were referred to one of us (S S M) in a tertiary specialist clinic over a 2-year period before the guidelines were published. The formula was selected by the referring specialist medical practitioner in 44 cases (and by S S M in the other seven). Of the 51 children (mean age at initial reaction to cows milk protein, 7.8 months), 42 had skin and/or gastrointestinal features, and nine had an anaphylactic reaction with respiratory and/or cardiac features. Forty-six children had a positive skin prick test to cows milk protein, and one had a positive radioallergosorbent test. Four children with immediate (< 30 min) reactions of generalised erythema and/or angioedema (3) or vomiting (1), but a negative skin prick test, were also included. Soy was the most common formula used, followed by extensively hydrolysed formula (EHF) (Box). Three of eight children commenced on EHF had allergic reactions, with urticaria and angioedema, and one child also had a transient (60 s) cough. Three children were given partially hydrolysed formula (PHF), with one experiencing an immediate cutaneous reaction. These observations suggest that, in clinical practice, soy is frequently a satisfactory first choice for children with CMPA, as suggested in the guidelines.1 Some children with CMPA will also react to EHF, providing a rationale for choosing amino acid-based formula as a first-line treatment prior to allergy evaluation in children with anaphylaxis to cows milk protein. As about 5% of infants with CMPA also react to EHF,2 some allergists advocate the introduction of EHF under medical supervision in either all children with immediate CMPA3 or only those who have had severe life-threatening reactions.4 Although PHF is tolerated by a significant proportion of children (70%) with immediate CMPA,3 it is not recommended for the treatment of CMPA1 due to its high content of potentially allergenic cows milk protein. The fact that three children with CMPA were given PHF suggests there is confusion in the prescribing community, and that the availability of the new guidelines may help in achieving a more appropriate choice of formula. Feeding choice for 51 children referred with cows milk protein allergy Type of feeding selected No. of children Mean age at initial reaction to cows milk (months) No. who reacted to selected feeding Soy 29 9.5* 0 Extensively hydrolysed formula (EHF) 8 5.3 3 Amino acid-based formula (AAF) 6 4.2 0 Partially hydrolysed formula (PHF) 3 6.0 1 Breastfeeding 5 6.0 0 * P < 0.05 for soy versus PHF, EHF, AAF or continuing to breastfeed (t test).

Sam S Mehr · Andrew S Kemp

To the Editor: A 37-year-old man was referred to our emergency department with an acute 7 cm abscess of the buttock. The abscess was incised, and the patient was prescribed oral β-lactam antibiotics and discharged. After 48 hours, culture of samples from the abscess showed methicillin-resistant Staphylococcus aureus with a community-acquired antibiotic resistance pattern (CA-MRSA). The isolate was resistant to β-lactam antibiotics, but sensitive to trimethoprim, gentamicin, and tetracycline. Unusually for an Australian CA-MRSA strain,1 the isolate was also resistant to erythromycin and ciprofloxacin. On reviewing the patient’s history, it was noted that he was a previously well United States resident who had visited Australia and New Zealand as part of the support team for an international rock band. Further testing was undertaken, and the isolate tested positive for genes coding for the Panton–Valentine leukocidin toxin, associated with staphylococcal virulence (eg, recurrent furunculosis, abscess formation, and necrotising pneumonia).2 Pulsed-field gel electrophoresis (performed by the Gram-Positive Bacteria Typing and Research Unit, Department of Microbiology and Infectious Diseases, Royal Perth Hospital, WA) confirmed the isolate as the ST8-MRSA-IV strain, also known as USA300. Most CA-MRSA strains remain susceptible to a majority of non-β-lactam antibiotics, including clindamycin, trimethoprim–sulfamethoxazole, tetracyclines and fluoroquinolones. This helps distinguish CA-MRSA isolates from the typically multiresistant hospital strains, and facilitates oral outpatient therapy. USA300 is the dominant strain causing CA-MRSA infections in the US.3 Among 422 patients with soft-tissue infections presenting to 11 US emergency departments in 2004, 59% of cases were caused by CA-MRSA, of which 99% were USA300. Recent reports indicate that multiresistance is emerging within this strain, with acquisition of resistance to erythromycin, clindamycin, mupirocin and fluoroquinolones. An increasing association of USA300 infections with buttock and perineal infections is also reported, as well as potential sexual transmission, particularly among men who have sex with men. Our case highlights the ease of international spread of microorganisms. Arguably, a “one-night stand” tour could be an ideal vehicle for microbial dissemination. CA-MRSA was not considered in the patient’s initial assessment, and the patient was discharged with oral β-lactam antibiotics and no planned follow-up. Moreover, the isolate may not have been identified as the “epidemic” USA300 strain without more involved tests. A recent study documented a rising incidence of USA300 isolates in Western Australia between 2003 and 2007. Of 61 patient isolates, 35 were diagnosed in 2007 (Pearson J, Coombs G, Christiansen K, et al. USA300 MRSA identified in the Australian community [abstract PP3.2]. Abstract presented at the Australian Society for Antimicrobials 9th Annual Scientific Meeting; 2008; Feb 21–23; Sydney). Our case suggests we should be more alert to CA-MRSA infection presenting with furunculosis and soft tissue infections, not only in Indigenous communities and young people, but also in international travellers and patients whose infections fail to respond to usual therapy. It also reinforces the value of incision and drainage. As β-lactam susceptibility is no longer assured, such specimens should routinely undergo culture and susceptibility testing.

Thomas Gottlieb · Wei-Yuen Su · John Merlino · Elaine Y-L Cheong

To the Editor: We report significant sinus bradycardia in a patient presenting with an acute coronary syndrome shortly after beginning bupropion therapy to assist with smoking cessation. A 53-year-old man was attended by paramedics for typical ischaemic chest pain. He had sinus bradycardia (45 beats/min) and hypotension (blood pressure, 85/60 mmHg), and was found to have a serum troponin I concentration of 1.2 μg/L, but no diagnostic electrocardiographic changes. He was admitted to our hospital with an acute coronary syndrome. He reported his medications at the time of admission as including metoprolol 50 mg twice daily (for hypertension) and paroxetine 20 mg daily (for depression). The patient was given multiple doses of intravenous atropine (total, 1.2 mg) and adrenalin (total, 2 mg). After an adrenalin infusion was begun, he developed ventricular tachycardia (170 beats/min), but his cardiac rhythm spontaneously returned to sinus bradycardia. Two days after admission, two coronary stents were successfully deployed in a critically stenosed right coronary artery. Bradycardia (45–50 beats/min) persisted. The following day, it was discovered that 3 weeks previously, the patient’s general practitioner had prescribed bupropion 150 mg twice daily to assist with smoking cessation, which he had been taking up until the day of admission. Bradycardia continued until hospital discharge. One month after discharge, he was in sinus rhythm (60 beats/min) and was clinically well. Bupropion is a selective noradrenalin, dopamine and serotonin reuptake inhibitor. The mechanism by which it enhances the ability of patients to abstain from smoking is unknown.1 Bupropion inhibits the activity of the cytochrome P450 2D6 isoenzyme, which metabolises metoprolol.2 Concurrent use of bupropion and metoprolol can increase serum metoprolol levels, and clinically significant bradycardia has been reported.3 Further, paroxetine, a selective serotonin reuptake inhibitor (SSRI), is a potent cytochrome P450 2D6 inhibitor, which would have further increased serum metoprolol levels. Bradycardia associated with metoprolol and paroxetine dual therapy has been described.5 Additionally, there is the potential for serotonin syndrome to develop in a patient administered multiple SSRIs. In our patient, the administration of bupropion and paroxetine could have potentially led to serotonin syndrome.6 Our patient’s pharmacological profile was complex, with potential adverse pharmacodynamic effects. The most likely precipitant of the patient’s bradycardia was his acute coronary syndrome, although bupropion may have contributed. The case highlights the potential for significant drug interactions when new drug therapies are initiated. Bupropion and metoprolol (and other drugs metabolised by the cytochrome P450 2D6 isoenzyme pathway) should be co-administered with caution. The importance of common pathways of drug metabolism should be recognised to avoid potential adverse events, particularly when multiple medications are used.

Jacqueline Landau · Andrew E Ajani

To the Editor: I challenge the assertion made by Donohoo (Managing Editor of MIMS [the Monthly Index of Medical Specialities]) that “MIMS is held . . . in high regard” and that the “vast majority of MIMS subscribers recognise that the quality information provided by MIMS is essential in their daily encounters with their patients”.1 In fact, the most common MIMS annual to be seen around hospitals, in nursing homes and in doctors’ surgeries is an out-of-date one. Furthermore, as a general practitioner, when I do use MIMS, it is because it is packaged with our desktop software, rather than by choice or active decision. I have online access to the Australian medicines handbook (http://www.amh.net.au/), and various other references. I have no need to refer to MIMS, and I tire of the understandable bias MIMS has always had for proprietary prescribing.

Lilon G Bandler

To the Editor: Walters recently suggested that Australia should implement population control strategies as part of an approach to reduce global warming.1 As a father of four, I found his assertion that my decision to father more than two children is “arrogant” to be offensive. Walters’ arguments are, at best, poorly reasoned. As a “citizen of this world”, he clearly rejects the rights of other citizens to live on an equal footing and follow their religious, cultural or social beliefs if those beliefs oppose contraception. I would argue this is contrary to law.2,3 His mathematical calculations ignore all costs required to achieve his objective, such as those associated with “contraceptives, intrauterine devices, diaphragms, condoms and sterilisation procedures”. Further, he fails to consider costs associated with the supporting bureaucracies required to effect his policy, including material amendments to the Australian taxation system. Rather, and in my opinion strangely, he advocates issuing carbon credits for the additional consumption of contraceptive products. According to Walters, people should be judged by their anticipated rather than actual emissions. A logical extension would be to punish those who exceed a predetermined mean acceptable level of emissions. No doubt, meeting the medical and ancillary needs of many sick, older and disabled people often generates excess emissions. Perhaps we should adopt some of the practices used in China and India, including abandonment and neglect of disabled children and older people.4,5 How would we deter and punish those who cannot pay? Walters addresses the issue of overpopulation by comparing Australia to India and China. This is notwithstanding that Australia has one of the lowest population growth rates in the world6 and, with its ageing population and labour shortages,7,8 has significantly different population and social concerns to these countries. There are no grounds to support the comparison made. Environmental issues are among the greatest challenges facing society. As a father, I am deeply concerned for the world my children will inherit. We must deploy our limited resources efficiently and effectively to maximise their impact. To demand social controls in the manner Walters suggests, within a society heavily burdened with laws and struggling to meet labour and health system demands, would defeat this objective. Reading Walters’ views, which I consider fundamentally flawed, in a publication such as the Journal imparts to them a validity I believe is unjustified. I do not consider that Walters’ social engineering policies could benefit anyone in Australia, while his “moral” concerns are ill conceived.

Cathal A Smith

In reply: I thank Smith for the opportunity to clarify some scientific points. The science behind climate change is undeniable and was reviewed in February this year. Moreover, “there is a greater than 90 per cent probability that the warming observed since the 1950s is due to human activities”. Therefore, attempts to prevent environmental calamity will not succeed with boundless population growth. In this sense, the more people there are, the worse it is for our earth. In particular, no nation should encourage population growth. I do not argue for compulsory sterilisation. I do argue that we recognise the cost of every extra human being to our overburdened earth. Smith labelled my note of caution about limitless procreation as “offensive”. I believe such disparagement is founded on personal and cultural beliefs, not on science, which informs and guides medicine. There is only one atmosphere. Australians occupy this planet with no more rights than others do. Racism is anathema to us. If others must observe population restraint, then so must we. Contrary to Smith’s assertion, I plead that all should be able to “live on an equal footing”. Is this not the laudable basis of law? I share his concern for the world that his “children will inherit”; my concern embraces the children of others as well.

Barry N J Walters

To the Editor: We read Pham and colleagues’ recent article1 with interest, as evidence mounts against the use of probiotics in critically ill patients. Although a plausible and attractive theory, probiotics in the patient with acute illness now appear ineffective, if not positively harmful. A recent randomised trial of probiotics in 298 patients with severe acute pancreatitis showed a non-significant rise in infective complications,2 in keeping with results of previous studies of critically ill patients.3,4 Disturbingly, mortality in the probiotic group was more than double that in the placebo group (P < 0.01). Bowel ischaemia was a prominent feature of deaths in the probiotic group (eight patients), but was not associated with any deaths in the placebo group (P < 0.004). It may be that non-occlusive mesenteric ischaemia in critical illness is exacerbated by the added bacterial load itself, or through a pro-inflammatory response by gut epithelial cells. While probiotics may be a benign and beneficial adjunct to enteral feeding in certain clinical situations, there is persuasive evidence that probiotic therapy is associated with increased infective complications in critically ill patients and significant mortality in patients with severe acute pancreatitis. Until there is evidence to the contrary, we believe probiotics should not be administered to patients with severe acute illness.

Shimonti Chatterjee · John Fraser

To the Editor: Pham and colleagues commented on the effects of probiotics; however, not much is known about the impact of probiotics on weight gain and obesity. It is known that a predominance of certain bacteria, such as Lactobacillus, in the bowel can promote weight gain. Many of these bacteria are found in probiotic products. The human intestinal microbiota is predominantly colonised by the Firmicutes and Bacteroidetes phyla of bacteria. Lactobacillus and Bifidobacterium, found in a number of probiotic products, belong to the Firmicutes phylum. A study has shown that obese people carry a higher proportion of bacteria from the Firmicutes phylum and that there is a statistically significant decrease in the proportion of Firmicutes bacteria as they lose weight.3 A similar pattern of Firmicutes predominance has been found in obese mice. Furthermore, the microbiota of the obese mice were more likely than those of lean mice to break down otherwise indigestible polysaccharides from the diet.4 In other words, a higher proportion of Firmicutes bacteria was associated with increased and more efficient caloric uptake from food. These data did not necessarily imply causation, so the investigators performed another experiment. They transferred intestinal microbiota from obese and lean donor mice to germ-free mice, and found that the mice who received microbiota from the obese donors had a significant increase in body fat after 2 weeks compared with the recipients from the lean donors.4 It is therefore likely that the bacteria often found in probiotics can cause weight gain. Obesity in children and adults is a major health problem in developed nations. Given the increasing use of probiotic products in such countries, large studies should be performed to characterise the association between probiotics and obesity. Such studies may not find any association or may find that there is only a dose-related risk. If there is an association, probiotics may still prove useful in certain circumstances (eg, for weight gain in children failing to thrive).

Sanjaya N Senanayake

In reply: The comments by Chatterjee and Fraser regarding the danger of administering probiotics to patients with acute severe illnesses are important additions to the debate on the risks and benefits of probiotic administration. We also thank Senanayake for his interesting comments on the possible role of probiotics in weight gain. The recently published multicentre trial1 describing unexpected adverse events associated with probiotics in acutely unwell patients with severe pancreatitis is one example of an adverse outcome following probiotic administration. The use of probiotics in patients with severe comorbidities and in those who are immunocompromised is also contraindicated. There are reported cases of Lactobacillus GG sepsis in premature babies with short gut syndrome,2 and Saccharomyces boulardii fungaemia has been described in immunocompromised patients.3 It is interesting to note that two systematic reviews have assessed the efficacy of probiotics in prevention of necrotising enterocolitis in premature (< 33 weeks’ gestation) and very low birthweight (< 1500 g) infants.4,5 Both reviews concluded that probiotics may decrease the incidence of necrotising enterocolitis in preterm infants, and that severe adverse events were not associated with probiotics in these unwell and immunodeficient patients. However, there were insufficient data to comment definitively on the short-term or long-term safety of probiotics in these infants; this will require assessment in future large trials. The increased scrutiny of probiotics resulting from the publication of the adverse outcomes in adults with severe acute pancreatitis1 may, by necessity, slow the commencement and progression of these larger trials in infants in the neonatal intensive care setting.

Mimi Pham · Daniel A Lemberg · Andrew S Day

To the Editor: On 25 January 2008, the Australian Transport Council approved the National Transport Commission’s seventh amendment to the Australian Road Rules. This amendment provides for the mandatory use of forward-facing child restraints for children aged 6 months to 4 years, and the use of Australian Standards-approved booster seats for children aged 4–7 years and weighing up to 26 kg. It also recommends that children aged less than 7 years should not travel in the front passenger seat. These changes are welcome. They bring Australian rules on child restraints and seating position closer to (but still not on par with) restraint laws already implemented in the United Kingdom and other countries in the European Union, where booster seats are mandatory for all children aged under 12 years or less than 145 cm tall. Implementation of the amendment poses several challenges. A small proportion of children will exceed the 26 kg weight limit for booster seats by their seventh birthday; however, there is no evidence that these seats are not safe for slightly heavier children. In addition, the Australian Standard (AS 1754) is currently being revised and is likely to move towards recommending restraint selection based on seated height rather than weight, as well as developing new standards for booster seats for older children. Height is the most important determinant of adequate seatbelt fit, and children need to be about 145 cm tall before the lap portion of an adult seatbelt sits correctly over the iliac crests rather than on the soft abdomen. Community education campaigns will be pivotal in successfully implementing these new road rules. As misuse of restraints is high, education campaigns must emphasise correct use of recommended restraints.-4 Furthermore, the new recommendations may contribute to financial hardship, particularly for low-income families with several children under the age of 7 years. Subsidies or loan schemes may be required to assist such families. Fitting three restraints across the rear seat of small cars may also be difficult. Adequate enforcement will be required to maximise compliance. Research studies and injury surveillance will play an important part in maximising the effectiveness of these rule changes. Finally, the seventh amendment to the Australian Road Rules does not constitute law, and legislative changes will need to be enacted by each state and territory before these changes become law. We hope that the state and territory governments will take swift action to enact these laws, to prevent injuries and deaths in Australian children due to motor vehicle crashes.

Yvonne A Zurynski · Lynne Bilston · Elizabeth J Elliott

To the Editor: Court, Bergh and Södersten raise the issue of why and how some therapies with prima facie evidence for their efficacy have a significant take-up by medical practitioners, while others are allowed to languish, sometimes for decades.1 It is 6 years since Bergh and colleagues conducted their Swedish trial on eating disorders, with significant encouraging results.2 Again they report — albeit this time with a non-randomised but local sample — above-average outcomes.1 Again, the fact that their patients had had previous treatments that failed renders the results compelling. We have to ask why no one has found the time, money or inclination to attempt to reproduce their findings or examine which elements of their intervention are successful. It would be ironic if the answer is that medical researchers are afraid of the unusual. While Australian medical research and public health ignore this mandometer treatment, some private health funds have been prepared to contribute up to $60 000 per patient for it, suggesting that they view it as better value for money than alternative therapies.

Phillip Gray

To the Editor: More than 2000 graduates of South African medical schools have migrated to Australia since 1948. Unlike many immigrants from Europe before and after World War II, all were fluent in English and most were able to start practising almost immediately. In chronicling this unique migration and its contribution to Australian health care, I am trying to contact, by email, as many as possible of the 1800 South African doctors now practising here, as well as surviving spouses or children of the 100 or so who have died since arrival. As a 1961 graduate of the University of the Witwatersrand in Johannesburg, I have a particular personal interest in this migration. Assisted by a sociologist and a statistician, I have prepared an email questionnaire. Responses will be de-identified before analysis. I would be grateful if graduates of South African medical schools would contact me by email.

Peter C Arnold

To the Editor: Although there are data on the population needs for residential aged-care facilities (RACFs)1 and models of engagement by general practitioners once someone is resident in a facility,2-4 there are ongoing administrative barriers for people trying to secure a place in an RACF. The aim of requesting data before admission is to provide continuity and quality of care, but the burden of paperwork currently falling on family members and GPs is of concern. We initiated an audit when it became apparent that local acute public and private hospital inpatient units had a policy of insisting that once an inpatient was eligible for RACF residency, he or she was required to be placed on waiting lists for 8–10 different RACFs. As part of a broader project to coordinate better care at times of transition, all RACFs in southern Adelaide (feeder population 400 000) were approached to provide us with the forms that need to be completed before someone can be placed on their waiting list. All 22 facilities in southern Adelaide provided a copy of the application pack that they normally give to a family member. A median of 4.5 forms had to be completed before a person could be placed on a waiting list (range, 0–13). The most frequently requested forms were an Aged Care Assessment Team form (17 facilities), an application form (15 facilities), a medical history form (12 facilities), and an assets declaration (9 facilities). One RACF required direct debit payment forms to be filled out before considering an application, and another required documentary evidence of funeral arrangements. By contrast, four RACFs required no forms at all. GPs were responsible for the medical history form. This form was unique to each RACF, with the result that similar data had to be provided multiple times in different formats. GPs were also potentially required to witness several other forms for each different application. There is an inherent challenge in balancing the need to run a financially viable RACF and provide best care from the moment a resident arrives with minimising the paperwork that frail spouses or busy family members are often expected to generate or replicate for many facilities simultaneously. These forms, most of which will never be used, create a burden on family members at an already stressful time. An agreed national industry standard for an Aged Care Assessment Team form, an assets form and a medical history form (to be filled out once by a GP) would ease stress at arguably one of the more difficult transitions any person and his or her family can face.

Aine G Greene · Bernadette Kenny · David C Currow

To the Editor: In the January issue of the Journal, Harvey et al raised some serious concerns about the listing system for complementary medicines.1 In particular, they suggest scrapping the listing system (AUST L) and requiring complementary medicine (CM) products to be evaluated by the Therapeutic Goods Administration (TGA) for efficacy. Scrapping the system would be a significant setback for natural medicines, which have an important role to play in the health system. Such a move would be likely to remove products from the market, while the problem outlined by Harvey et al is more about the claims made for products rather than the products themselves. Certain CM products play a valuable role in many chronic diseases, in situations where existing synthetic products are often lacking. The regulatory system should encourage evidence-based CM products, and appropriate sanctions and enforcement should downgrade the claims made on products that don’t have a specific evidence base. CMs, especially herbal medicines, are complex products with numerous biologically active components. This means that the evidence is specific to the product and cannot be extrapolated. This fact has two important consequences for practitioners and the health system as a whole: the “generic” concept of synthetic pharmaceuticals (eg, interchangeability of paracetamol-containing products) is invalid for CM, meaning that a prescription for “St John’s wort” for example is not reliable, as St John’s wort is not one substance; and meta-analyses and systematic reviews of a “substance” (eg, a herb, or glucosamine) are easily misinterpreted because the products made from that “substance” are so different, any conclusions drawn can only be applied to the particular products that have been trialled.2 While the health system fails to discriminate between products that have specific trial evidence and those that do not, practising evidence-based complementary medicine will remain difficult. Encouraging evidence-based use of CM products, including supporting specifically clinically proven products, will lead to further research and better integration of CM into our health system for the benefit of the Australian public.

Nigel A Pollard

To the Editor: I am writing in response to the recent article by Harvey and colleagues about complementary medicines in Australia.1 Rottapharm is the developer and manufacturer of DONA glucosamine, a patented form of glucosamine. DONA is a registered medicine in 54 countries, in many on the equivalent of the Pharmaceutical Benefits Scheme. DONA is the leading glucosamine product in the world measured by specific trial evidence, sales and registration approvals. The fundamental issue is that different products that contain glucosamine and other complementary medicine (CM) products should be considered to be distinct products. Standards of active ingredients and methods of manufacture of finished products are substantially different between companies. Specific clinical trial evidence for glucosamine is essential because of: formulation differences (DONA glucosamine is a patented formulation of crystalline glucosamine sulfate, which is not comparable with glucosamine hydrochloride or other glucosamine sulfate formulations); bioavailability of glucosamine sulfate (unlike all other formulations on the Australian market, DONA has proven plasma concentrations and synovial fluid levels consistent with a clinical effect at a dosage of 1500 mg once a day, and is the only glucosamine product available with proven human bioavailability and pharmacokinetics);2 and results of specific clinical trials (studies of non-DONA glucosamine products [unknown formulations] have had mixed results while DONA has shown consistent efficacy across all trials, and has been assigned level 1A evidence by the European League Against Rheumatism).2-6 Not requiring sponsors to have evidence to support claims made about their products encourages low quality. For example, the market-leading glucosamine products in Australia have not been subject to independent peer review to establish whether they are effective. As the claims allowed on such products are identical to the claims allowed on DONA, there is no incentive for the industry to source the “real thing” or conduct their own clinical trials. In the interests of their patients, we believe that health professionals have a right to be able to identify specific products that have been clinically proven. Use of CMs that is not evidence-based is likely to lead to failure to realise significant health benefits of CM for the Australian public.

Antonino Santoro

To the Editor: The article by Harvey et al raises important concerns about the complementary medicine (CM) industry, particularly with respect to inappropriate marketing and advertising by some sponsors.1 The role of the Therapeutic Goods Administration (TGA) in setting standards and regulation of CMs should not be taken lightly. Australia has one of the highest quality standards for CMs internationally. Many CM products in Australia are assessed by expert authorities within the Office of Complementary Medicines and the Complementary Medicines Evaluation Committee of the TGA for safety and (where appropriate) efficacy relating to claims made for products.2 This is not fully appreciated by the authors. While many CMs may lack high-quality research to validate efficacy, this does not necessarily mean they are not clinically effective. Many clinicians and consumers find CMs to be of clinical value in improving health status. By suggesting that “the listing system should be scrapped, and CAMs [complementary and alternative medicines] . . . be assessed for efficacy and delisted if evidence is lacking” would be to deny consumers choice of treatment and potential health benefits, and lead to a “black market” or buying products from overseas which may not compare in quality. The authors fail to acknowledge that much of the drive for CM sales is actually coming from consumers through their choice of health care treatment.3 Consumers have the right to trial CMs. It is our role to ascertain safety issues and encourage clinical trials where they are lacking. For thousands of years, populations have relied on some CMs for health benefits, not having the advantage of any trials, but relying solely on traditional use. If the risk of harm to human health from the use of a CM outweighs any proven or unproven efficacy, consideration should be given to delisting the product or restricting its use. More research is required to assess safety data and efficacy for CMs. Australia has come a long way in regulating CMs. To say the “listing system should be scrapped” does not appreciate the tremendous efforts and gains made by the TGA compared with international efforts to enforce good manufacturing practice and various methods to better safeguard consumers. The authors do raise a valid point in saying that sponsors should provide “key evidence supporting each indication of the ARTG [Australian Register of Therapeutic Goods] . . . [which] should be publicly available on the Internet”. This may be useful for consumers and health practitioners, but requires appropriate funding to be viable. Furthermore, codes of conduct and complaints procedures for CMs, such as through the Complaints Resolution Panel, need to be strengthened, particularly with respect to breaches in the advertising code.4 To date, the Parliamentary Secretary has asked the TGA for advice on the proposals put forward by Harvey and colleagues.1,5 The government will consider its response to these proposals in the context of taking forward legislative changes that were deferred in anticipation of the establishment of an Australian New Zealand Therapeutic Products Agency (TGA advice, 28 May 2008).

Vicki Kotsirilos

To the Editor: Harvey et al1 have a right to be concerned about the parlous state of regulation in the billion-dollar complementary medicine (CM) industry. They are not alone, with various leaders from CM doctor groups and other leaders also expressing concern.2,3 Predictably, those in the CM industry itself are denying any problems exist, and just repeat their mantra that their products are safe and effective.3 As business people, the leaders of the CM industry must be pleased with the unchallenged run they have had over the past 20 years (except for one challenge with the Pan Pharmaceuticals debacle4). Consider one company (Mannatech) whose multilevel marketed products are promoted by their associates (natural drug representatives) as useful for arthritis, diabetes, dementia, attention deficit hyperactivity disorder, Parkinson’s disease, asthma, cancer and various other chronic diseases. The associates promoted claims that a product, Ambrotose, would assist with the above conditions using literature that did not carry the company logo, and used the company literature for non-specific claims and testimonials, thus absolving the company of responsibility. The Therapeutic Goods Administration is helpless in such a situation, and it was only when a medical practitioner started selling Mannatech products, including Ambrotose, from his surgery that the state medical board took an interest.5 However, the medical board has no jurisdiction over the company, and when the doctor was deregistered, he would have been able to keep marketing the product for the company. Mannatech launched Ambrotose in Australia, quoting the benefits of their product from a trial conducted and published in the Journal of the American Nutraceutical Association by American immunologist Dr See and colleagues.6 Eighteen months later, the published trial was the subject of much controversy.7 There was little if any effect on the company from this, in stark contrast with what one would expect in the pharmaceutical industry. Yes, Harvey and colleagues are just starting to scratch the surface of controversies that are decades old in this unregulated industry. For the good of the public and for the good of the CM industry, there needs to be a watchdog, similar to Medicines Australia, to regulate CM.

C Scott Masters

In reply: We agree with Kotsirilos that the current listing process of the Therapeutic Goods Administration (TGA) provides some protection for consumers by ensuring that complementary medicines (CMs) are manufactured in accordance with good manufacturing practice. The TGA claims that about 25% of new listings are assessed in detail each year for compliance with requirements, including that sponsors must hold evidence to support promotional claims made.1 However, we understand that the TGA does not assess this evidence for quality, and that literature searches are not performed to see if more recent evidence2 contradicts that submitted by the sponsor.3 In addition, sponsors can make a conservative claim at the time of listing but then make very different claims in promotional campaigns. An under-resourced, laboriously slow and largely impotent complaint system provides little disincentive to such unethical (but profitable) behaviour. While the Medicines Australia code of conduct (for prescription medicines) still has room for improvement, we agree with Masters that it currently provides more effective sanctions for breaches (eg, fines up to $200 000) than the options currently available to the TGA. Medicines Australia also proactively monitors compliance with the code of conduct and provides useful annual reports.4 Regardless, claims for CM that cannot be substantiated by appropriate evidence are better dealt with at the time of a marketing application rather than many months after advertisements have been published and when consumers have long been misled. We also recommended that therapeutic equivalence of the product in question should also be assessed at this time; a point reiterated by Santoro and Pollard. We support the right of consumers to choose from a variety of therapeutic modalities offered in the market place. However, good decision making requires evidence-based information about risks and benefits, regardless of whether the medicine in question requires a prescription, can be obtained over the counter or is a CM. Even if the risks of CMs are relatively low, the financial and opportunity cost for consumers can be significant. A pragmatic compromise to delisting CMs that lack evidence of effectiveness would be an opt-in system, funded by an additional fee, that would independently evaluate the effectiveness of specific CM products. A product with reasonable evidence of effectiveness could be awarded a symbol similar to the the National Heart Foundation “red tick”. Implementing this measure, together with the disclaimer and other recommendations we made in our article,5 would assist consumer choice and provide a market advantage for the sponsors of evidence-based, ethically promoted CMs. These proposals have received support from health professional and consumer organisations as well as sections of the CM industry. They have been put to the Parliamentary Secretary who assists the Minister for Health and Ageing.3

Ken J Harvey · Viola S Korczak · Loretta J Marron · David B Newgreen

To the Editor: The recent article by de Crespigny and Savulescu1 is nominally about the medical care of pregnant women, but its ramifications extend more widely into power relations, law and ethics, and matters of life and death. The article is entirely adult-centred: its authors never hint that a doctor who is treating a pregnant woman has not one but two patients. There is never the faintest suggestion that the fetus is a separate human being with his or her own medical interests. The “research” reported is a survey of 20 obstetricians, who all agree with the authors on abortion for fetal abnormality. Unsurprisingly, most said they would prefer fewer constraints on such abortions. Which abnormalities are grounds for termination? The authors never say, although terminations are performed in Victoria for conditions as readily treatable as cleft lip.2 The authors cite an estimate that where Down syndrome is identified in Victoria, 95% of pregnancies are terminated. Yet people with Down syndrome do not appear to find their lives intolerable: is the misery we want to put Down syndrome children out of their misery, or their parents’? The authors insist that in Victoria, “uncertain laws compromise good prenatal care”. The prenatal care they seem to have in mind can hardly be called care of the child: can it be called care of the mother? In one of the cases cited, a woman at Melbourne’s Royal Women’s Hospital was threatening suicide unless her pregnancy was terminated after a diagnosis of dwarfism at 31 weeks.1 Instead of providing her with urgent psychiatric care (had they never encountered a suicidal patient before?), the doctors terminated her pregnancy. If she had demanded the amputation of her left arm, would they have called in the surgeons? The surgical mutilation of an adult patient would not have been considered for a moment, but the surgical killing of a fetal patient was an available and practised routine. This woman was already not well, and the “prenatal care” she received put her further at risk. This case illustrates how true prenatal care is compromised, not by the few remaining legal limits on child destruction and abortion, but by their ready availability. Readers of the literature on post-abortion syndrome will have encountered many other illustrations of what should be obvious: that you are not likely to help a woman by destroying her child. Experienced and attentive general practitioners and psychiatrists will be able to give their own examples. Doctors need to pay close attention to the short paragraph on conscientious objection.1 The authors declare that “a doctor’s conscience should not be allowed to interfere with medical care” and that if “some individuals or institutions have moral objections ... those objections cannot compromise patient care”. If that does not mean that the authors want to exclude anyone who disagrees with them about what constitutes “medical care” from medical practice, what does it mean? There could hardly be a plainer threat to doctors’ personal professional judgement.

Edward D Watt

To the Editor: Superficially, de Crespigny and Savulescu make a compelling case for clarifying late-term abortion law.1 However, at a deeper level, it is disappointing that alternative points of view were not discussed in their article. The only solution offered in the case of a potentially imperfect child is to abort the pregnancy and try again. Unfortunately, this ignores several important issues. First, the consequences of abortion for the mother, both physical and psychological, are neglected.2 Our experience, as general practitioners, is that late-term abortions only lead to heartache and regret, even depression and anxiety, as the mother tries to deal with what has happened to her. Every time she sees either a “normal” or an “abnormal” child, her loss is re-lived. A patient of one of us (S B G) has developed Asherman syndrome as a result of a late-term abortion; she is now infertile. Second, without a definition of “child”, any discussion regarding abortion law is, at best, futile; at worst, it is emotionally charged and reliant on anecdotes. If a fetus is defined as a child, then that child has a right to live, whatever the disability. If not, then any disability up to the defined age could potentially justify “abortion” (ie, destruction). Third, the references given to support the assertion that women might “refuse to consider motherhood” without genetic testing described women who carry germline monogenic abnormalities (eg, thalassaemias, Huntington genotypes). These women would be eligible for earlier antenatal screening, such as pre-implantation genetic diagnosis, amniocentesis and chorionic villus sampling — all of which are available well before the current legal time frames in question. Fourth, de Crespigny and Savulescu’s premise for allowing late-term abortion is that there is a life-threatening fetal abnormality and the mother wishes to have children. However, a consequence of liberalising the law for the benefit of these women would be that women with non-life-threatening fetal abnormalities, and also those who simply did not want a child, could also access late-term abortion more easily. This is obviously a major concern. Finally, use of the term “child destruction” in the law is important when considering these situations. A helpful definition of the purpose of the law is to prevent injustice.3 As seen by the ability for women to access “legal” abortion before 20 weeks’ gestation, any law that protects children needs to stand. The pregnant woman clearly has a voice; unfortunately, the unborn child does not have the same ability to state his or her case before an ethics committee.

Simon B Gerber · John T Wenham

In reply: Watt seems to wish to return to the days of no prenatal testing; we believe today’s women reject this paternalistic view. However, Watt is correct in saying our article is “adult-centred” — it is not self-evident that the fetus is a patient, nor is this view consistent with those of most liberal legal jurisdictions. It has been found that 81% of Australians,1 including a majority in all major Australian religious groups,2 agree with a woman’s right to choose an abortion. Only 4% of Australians consider abortion wrong.3 We echo Amnesty International’s call for abortion to be decriminalised globally.4 Abortion laws should no longer discriminate against pregnant women with fetal abnormalities. Contrary to Watt’s claims, it is well documented that an experienced psychiatrist was central in managing the pregnant woman who had an abortion at 32 weeks at the Royal Women’s Hospital. In addition, we do not believe abortion has been demonstrated to cause psychiatric “post-abortion syndrome”,5,6 nor that abortion is analogous to amputating a healthy limb. We do not challenge doctors’ personal judgements. All individuals must be free to make their own value judgements for their own lives, including doctors. However, doctors have a duty to inform patients of all appropriate treatments. When a patient requests abortion and the doctor has a moral objection to providing it, the doctor must refer the patient to another practitioner.5 Contrary to Gerber and Wenham’s claims, we did not suggest that “to abort the pregnancy and try again” is the only option for fetal abnormality. Abortion — or continuing the pregnancy — must be the woman’s decision. One of us (L J d C) has 30 years’ experience of prenatal testing, including treating many women after terminations for fetal abnormality. Such women are sad about the diagnosis and outcome, extremely worried during subsequent pregnancies, and regret having had to make an awful decision. However, none have said that they made the wrong decision. Regarding Gerber and Wenham’s comments about the definition of “child”, our position is that (before birth) the fetus does not have the rights of a child.7 The data we cited show that prenatal testing for Huntington disease “allows” at-risk women, who might otherwise choose not to conceive, to have children. Personal experience (of L J d C) shows that women with a past history of other serious fetal disorders are no different. We did not suggest that late abortion should be available only in cases of life-threatening fetal abnormality. Indeed, our article clearly related to “pregnant women with fetal abnormalities” (not necessarily life-threatening). The claim that women would request late abortion simply because they don’t want a child demeans women’s integrity. We need clear abortion laws so that pregnant women and their doctors can know when abortion is lawful. Developing clear laws necessitates removing the crime of child destruction.8

Lachlan J de Crespigny · Julian Savulescu

To the Editor: We believe that Tang and Nordin1 misunderstood the findings of our recent study of calcium supplementation.2 We disagree with their claim that the increase in the number of women with self- or family-reported myocardial infarction, stroke or sudden death became non-significant after adjustment for covariables. They correctly noted that the increased number of women experiencing the composite endpoint of cardiovascular events (after adjudication of events and inclusion of unreported events from hospital records) was not statistically significant. However, the increased event rate for this composite endpoint with calcium was statistically significant (rate ratio, 1.43; 95% CI, 1.01–2.04; P = 0.043). Thus, in our study, the number of women needed to treat with calcium for 5 years to cause one cardiovascular event was 29, and the corresponding number to prevent one fracture was 50.2 Tang and Nordin then meta-analysed data from five studies of calcium and vitamin D supplementation to conclude that calcium supplementation does not increase mortality.1 We disagree. For one of the studies, they classified a subgroup of participants who received annual vitamin D but no calcium supplements as having received “calcium supplementation”.3 Further, for the RECORD (Randomised Evaluation of Calcium Or vitamin D) study, they compared the number of deaths between people receiving and not receiving vitamin D (16.5% v 17.4%) rather than between those receiving and not receiving calcium (17.7% v 16.2%).4 The trend for increased deaths with calcium supplementation in RECORD was greater when analysis was restricted to those treated with calcium monotherapy (18.5%) and placebo (16.3%). As our study was of calcium monotherapy, the results of Tang and Nordin’s meta-analysis are of questionable relevance to our findings. In addition, ours was a 5-year study, and the differences in vascular events between the groups only emerged after 2 years.2 Only one study in Tang and Nordin’s meta-analysis had an average follow-up duration of more than 25 months.4 Further, there is evidence from other studies of trends towards vascular events occurring more frequently in people who take calcium monotherapy.2,5,6 In three out of four studies that reported mortality, there were trends towards increased death rates in people receiving calcium.2,4-6 As we concluded,2 these data are not definitive, but flag cardiac health as an area of concern in relation to calcium use. Finally, we did not suggest that calcium supplementation should not be given to older women. However, in view of the evidence that any fracture risk reduction with calcium is small (< 10%),7,8 and the suggestions that calcium supplementation might increase the risk of hip fractures9-11 and vascular events, it seems reasonable and timely to reassess the role of calcium supplementation.

Mark J Bolland · Andrew B Grey · Ian R Reid

In reply: In Table 5 of Bolland and colleagues’ study, the P value after allowing for covariables was 0.08,1 which is not significant. This was without including smoking, which would undoubtedly have reduced the significance further as there were more smokers in the calcium group. Based on Bolland and colleagues’ suggestion, we reanalysed the data by removing the group receiving vitamin D but no calcium supplements in the NoNOF (Nottingham Neck of Femur) study,2 and using data for those treated with calcium monotherapy (18.5%) compared to placebo (16.3%) in the RECORD (Randomised Evaluation of Calcium Or vitamin D) study.3 The reanalysis still failed to show any evidence of an increase in mortality (relative risk, 1.05; 95% CI, 0.88–1.26; P = 0.56).

Benjamin M P Tang · B E Christopher Nordin

To the Editor: My attention was drawn to the Snapshot of an apical lung hernia published in the Journal last year.1 Persons with emphysematous hypertrophic lungs are often found to have clinically discernible supraclavicular swellings (Box). The finding of these swellings is a surprisingly common sign that is little remarked upon in clinical descriptions. These swellings are the bullous expansions of the apices of the lungs. Supraclavicular swelling in patients with emphysematous hypertrophic lungs A woman (A) and a man (B) with visible supraclavicular swellings.

George R Crowe