Digestive system diseases

To the Editor: The potential upper gastrointestinal morbidity associated with non-steroidal anti-inflammatory drug (NSAID) misuse is well known.1,2 Recently, Frei and colleagues3 provided an overview of the morbidity and patient characteristics relating to opioid–NSAID misuse; however, they did not identify those patients with NSAID enteropathy (NE). NE is thought to occur via NSAID-induced reduction of endogenous prostaglandin via inhibition of both cyclooxygenase (COX)-1 and COX-2. The result is altered mucosal integrity, which thereby allows exposure to noxious luminal contents leading to inflammation, erosion and ulcers.1 We underscore the importance of identifying this group of patients presenting with anaemia, hypoalbuminaemia, weight loss or abdominal pain that relates to NE. The clinical presentation and small-bowel ulceration that is noted on investigations can often mimic Crohn’s disease.4 As the patient’s drug misuse is not immediately apparent, the diagnosis eludes the treating physician for some time, potentially at the expense of further morbidity from both ongoing medication misuse and the iatrogenic consequences of repeated presentations, investigations and medications that have been initiated to manage Crohn’s disease. Within the Townsville Hospital v(a 460-bed tertiary referral centre for North Queensland), we have observed an increasing number of cases where patients covertly self-medicate with large doses (up to 20 tablets per day) of codeine–ibuprofen analgesics, taken mainly for codeine addiction, subsequently developing small-bowel abnormalities. We present three cases that highlight this problem (Box). In each of these cases, the NSAID use was not immediately apparent. A recent search on the Adverse Drug Reactions Advisory Committee database did not identify any reports of such patients. This may represent significant underreporting of the issue due to lack of physician awareness. In mid-2010, the National Drugs and Poisons Schedule Committee implemented changes to how over-the-counter combination analgesics containing codeine can be accessed.5 Such medications must be accompanied by product and consumer medicine information, and a pharmacist must be involved at every sale to record the customer’s details. Despite these changes, there are still potential pitfalls, as there is no mechanism in place to stop patients from “pharmacy hopping”. It may be necessary to reschedule codeine as a prescription-only substance, and to create real-time databases of over-the-counter sales. While these drugs remain accessible over the counter, patients will continue to use them. Clinicians should therefore be vigilant for evidence of NSAID impact on the gastrointestinal tract. Three patients who self-medicated with large doses of a codeine–ibuprofen analgesic with small-bowel abnormalities consistent with NSAID enteropathy Patient characteristics Presentation Medications Investigations NSAID self-medication 42-year-old man with chronic ankle pain; hypogonadotrophic hypogonadism; diverticulitis with paracolic abscess; cholecystectomy; appendicectomy; excessive alcohol use; depression Recurrent severe hypokalaemia; vomiting, abdominal pain and weight loss; iron deficiency and hypoalbuminaemia; vitamin B12 deficiency Omeprazole 40 mg/day; mirtazapine 15 mg/day; oxycodone 5 mg 4–6 hourly as needed Gastroscopy: antral ulcers; colonoscopy: normal; capsule endoscopy: multiple jejunal ulcers with early structuring consistent with NE; CRP level within RI Ibuprofen 200 mg/codeine phosphate 12.8 mg: 10 tablets/day 41-year-old woman with previous diagnosis of Crohn’s disease elsewhere, not supported by small-bowel resection Abdominal pain, diarrhoea and vomiting; iron deficiency anaemia; hypoalbuminaemia Iron supplement Gastroscopy and colonoscopy: normal; capsule endoscopy: multiple web-like strictures with circumferential ulceration throughout the small bowel consistent with NE; CRP level within RI Ibuprofen 200 mg/codeine phosphate 12.8 mg: 20 tablets/day for 5 years 41-year-old man with Scheuermann’s disease; chronic back pain; melanoma; depression; excessive alcohol use Iron deficiency anaemia; hypoalbuminaemia Omeprazole 40 mg/day; amitriptyline 25 mg/day; as needed: buscopan 20 mg; paracetamol 500 mg/codeine 8 mg; paracetamol 500 mg/codeine 30 mg; tramadol 50 mg Upper endoscopy: small gastric ulcer; push enteroscopy: multiple jejunal ulcers consistent with NE; CRP level within RI Ibuprofen 200 mg/codeine phosphate 12.8 mg: 10–12 tablets/day for more than 5 years CRP = C-reactive protein. NE = NSAID enteropathy. NSAID = non-steroidal anti-inflammatory drug. RI = reference interval, < 5 mg/L.

Rozemary Karamatic · John Croese · Enrico Roche

A city specialist consulting in the country ponders the tyrannies of life, including health care, in the bush One of the many privileges I had while in clinical practice as a gastroenterologist was to work in the country. I consulted and did procedures in the beautiful regional city of Bairnsdale — in East Gippsland, about 3 hours’ drive from Melbourne — for 2 days in 1 week every month, for several years. The secretaries in my rooms in Melbourne used to dread my “Bairnsdale weeks”, because I would leave the office with a large suitcase half-full of files, and return with the same suitcase completely full of files, plus multiple dictation tapes. They also dreaded the letters, which were very long because they usually contained detailed information about the patients for the referring general practitioners, so that much of the management of the patients could be done without the need to see me again, given that I was not in Bairnsdale full-time. Bairnsdale is a lucky town when it comes to medicine. It has an outstanding collection of GPs, many of whom have worked in developing countries, so they have excellent skills in anaesthetics and obstetrics which they are keen to maintain. They are empathic, compassionate and strong advocates for their patients. Bairnsdale has a few specialists of its own, and used to have an unusually strong program of visiting specialists. But the Bairnsdale visiting specialist program has been cut back severely. People can get to the city, can’t they? Just give them a subsidised train fare. Apparently it is better to make 60 patients travel a 600 km round trip, rather than just one doctor. On my drives back to Melbourne I would have the feeling that I had done more good in 2 days’ regional practice than in a month of city practice. It felt similar to my thoughts on returning from a trip to the developing countries in which I had worked — Samoa and Zimbabwe, for example. The people of Bairnsdale, I gradually came to realise, faced multiple tyrannies, starting with the tyranny of distance. I remember once apologising to a patient for running late. “I’ve had a 3-hour drive this morning, from Melbourne”, I said. “Well so have I”, the patient shot back, “from Mallacoota” (240 km from Bairnsdale). Another patient commented to me somewhat bitterly that city folk were always reluctant to come to the country, but country people have no choice but to make trips to the city: “It’s a lot longer from Melbourne to Bairnsdale than Bairnsdale to Melbourne”. But it was not only the tyranny of distance: it was the tyranny of poverty. I could see its mark in many of the patients I saw. There were demographic patterns — the young drug users, now clean because they had moved away from “the valley” (the industrial Latrobe Valley, an hour’s drive to the west of Bairnsdale). There were the thin, careworn young mothers of four children by four different fathers, one child with autism, one or two with ADHD, and one with epilepsy. A history of childhood and domestic abuse seemed to be the rule rather than the exception. There were the toddlers destroying the consulting room — in the city, toddlers did not often come with their mothers; perhaps there was more support at home. And there were the young men with alcohol dependence, perhaps chronic pain syndrome, living in trailers in forestry towns, who could never come to Bairnsdale for review because of the cost of petrol. The tyranny of isolation meant that middle-aged farmers with body mass indices over 30, waist measurements over a metre, and abnormal liver function couldn’t walk for exercise because they didn’t have the time or company. Single mothers with chronic hepatitis C could not join an interferon program because there was no one to support them or help with the children. And then there was the tyranny of nature: in January 2003, many men and women, including all the orderlies in the hospital, had gone to fight bushfires, and the town’s economy was suffering. In February, Bairnsdale itself was threatened, the sky dark and the sun red. In March, a farmer with tears in his eyes told me about his cattle burning, and then — laughing sarcastically about government bushfire “relief” — that the authorities decided the new funded fences (replacing the burnt ones) had to be dingo-proof, with wires down to 10 cm from the ground. His farm had steep ups and downs, and this new fencing was “bloody impossible to build”, “bloody expensive” and “bloody stupid”. In April, his new fences all washed away into the Gippsland Lakes during floods. In my work in Bairnsdale, I know I changed peoples’ lives — people with gastro-oesophageal reflux disorder, hepatitis C and colitis. If I had not gone there, those people would still be suffering; they just could not, or would not, have come to the city. Subsidised train fares for them to come and see me in Melbourne would not have fixed their problems. However, many other specialties easily available in Melbourne are just not available in East Gippsland, even though we, in both the city and the country, all pay (and are effectively paid by) the same taxes. Overservicing in the city and no servicing in the country? Yes, it’s a long way from the city to the country, and distance is not the only tyranny.

Katrina J R Watson MB BS, FRACP, MPH

To the Editor: Despite the availability of clinical guidelines,1 management of patients with colorectal cancer is variable.2 The lack of a clear referral pathway can delay this journey3 and result in patients not receiving optimal care.4 To increase our understanding of factors influencing the referral of patients with colorectal cancer from general practice to specialists, we examined the views of 19 general practitioners in four focus groups — held in rural and urban New South Wales, rural Queensland, and urban South Australia. The relationships of these GPs with specialists not only helped expedite referral but also improved quality of care and feedback. The GPs considered that direct personal contact enhanced their relationships with specialists. This was cultivated over time and was seen as a measure of the GPs’ commitment to getting the best care for their patients. This was especially important for the GPs in rural and remote areas who advocated for patient needs, including travel for diagnosis and treatment and completion of follow-up care. The GPs felt that influencing the referral process required overcoming barriers within the public health system and/or facilitating referral to private providers. GPs preferred referral to the private health services compared with referral to the public system because of perceived delays and communication difficulties in the public system. GPs described a system of referral that was ad hoc and not informed by best practice guidelines or outcomes. They were most influenced by the ease of access to appropriate and timely consultations and the quality of feedback from specialists. Although this works well much of the time, we need a system in the public and private health sectors that identifies patients who may have cancer, investigates and treats them in a timely fashion, and delivers care that meets optimal standards. As patients of surgeons with higher caseloads tend to have better outcomes,5 GPs need better information about surgeon caseload. Finally, as we increasingly move towards working in multidisciplinary teams, it would be useful for GPs to have information regarding other support staff linked to surgeons.

Mark F Harris · Shane W Pascoe · Lisa J Crossland · Justin J Beilby · Craig Veitch · Allan D Spigelman

A 27-year-old woman was being treated with gastrojejunostomy feeding for severe anorexia nervosa. The position of the gastrojejunostomy tube was checked by fluoroscopy on the day of insertion (Figure, A, arrow). The next day, the patient presented with abdominal pain and “shortening” of the external portion of the tube. Repeat fluoroscopy showed migration of the tube (Figure, B, arrow). Computed tomography showed two segments of jejunojejunal intussusception (Figure, C, arrow and inset, and D, straight arrow) centred around the tube (Figure, D, curved arrow), with an intervening segment of normal jejunum (Figure, D, label J). The patient’s gastrointestinal tract was intact. The intussusceptions were reduced by applying traction on the tube under fluoroscopic guidance, and the patient resumed tube feeding without recurrence.

Uei Pua

Clinical record A 33-year-old woman was admitted to our service for investigation and management of acute hepatitis. She reported symptoms of nausea, fatigue, pruritus and right upper abdominal discomfort. The symptoms had first occurred 3 weeks earlier, resolving over 5 days, then recurred 2–3 days before presentation. The symptoms were temporally related to varicose vein sclerosing procedures, of which she had had three in total. The first procedure occurred 4 weeks before admission, with no subsequent side effects. It was after the second procedure, 1 week later, that symptoms first developed. The final procedure occurred a week before admission. During each procedure, the patient was given methoxyflurane as an inhaled analgesic administered from a 3 mL disposable cartridge. Other medications administered during the procedures were the sclerosing agent sodium tetradecyl sulfate and fexofenadine. There was no history of exposure to alcohol or to other prescription or over-the-counter medications. The patient had no risk factors for viral hepatitis, and there was no history of hepatitis or liver disease in her family. Clinical examination revealed jaundice and mild tender hepatomegaly only. Initial investigations showed hepatic enzymosis, with an elevated alanine transaminase level (2710 U/L [reference range, < 34 U/L]) and hyperbilirubinaemia (bilirubin 92 μmol/L [reference range, < 20 μmol/L]). Markers of liver synthetic function (albumin and prothrombin time) were within normal limits, as were full blood counts, electrolyte levels and renal function. Abdominal ultrasound demonstrated a normal-sized spleen and mild hepatomegaly, with an increased liver echotexture. Doppler sonography of the portal vein was normal. Serological tests for hepatitis A, B and C, Epstein–Barr virus, cytomegalovirus and HIV were negative. Iron and copper studies and levels of α-1-antitrypsin, antinuclear antibodies, antimitochondrial antibodies, anti-liver/kidney microsomal antibodies, anti-smooth-muscle antibodies and antinuclear cytoplasmic antibodies were all normal. Paracetamol was undetectable. Bilirubin levels continued to rise over the following 8 days (peaking at 202 μmol/L), although liver synthetic function remained normal throughout this time. A liver biopsy revealed evidence of resolving acute hepatitis with confluent perivenular hepatocyte dropout and bridging necrosis. There was no evidence of cholestasis or underlying fibrosis. The pathological diagnosis was of an idiosyncratic drug reaction, with the implicated drug being methoxyflurane. The patient’s condition continued to improve, with resolution of symptoms over 4 weeks and associated normalisation of liver enzyme and bilirubin levels. She has since remained well, and has been advised to avoid future exposure to methoxyflurane. Methoxyflurane, a short-chain halogenated ether, is a volatile anaesthetic agent. It was used for inhalational anaesthesia in the 1960s, but was withdrawn from use for this purpose when newer anaesthetic agents with more acceptable side effects became available.1,2 Methoxyflurane also has significant analgesic properties at subanaesthetic concentrations,3 and is thought to have minimal side effects in analgesic doses.4 These properties led to its adoption for use as an analgesic in a variety of settings for over 40 years.4 It is widely used by paramedic services in Australia,5 and has recently been studied for use in procedural analgesia in children and adults.4-6 It is provided in single-dose, pre-filled delivery devices (Penthrox, Medical Developments International, Melbourne, Vic), allowing accurate dosing and convenient delivery. In 2010, Penthrox was added to the Australian Schedule of Pharmaceutical Benefits as an item available free of charge for doctors’ bags. Although subanaesthetic doses of methoxyflurane (in the form of Penthrox) are used widely in Australia by ambulance services for prehospital analgesia, there is a paucity of data on its efficacy and safety. A recent observational case series and a review article found no significant side effects associated with its use for this purpose.4,5 Over three million inhalers have been dispensed in Australia since 1970,4 with the majority of doses administered for single-episode analgesia. Lessons from practice Taking a history of all medication exposures is important in assessing acute hepatitis. Repeated exposure to methoxyflurane may increase the risk of acute hepatitis. Reporting of suspected adverse drug reactions, such as this case, are important to raise awareness of possible rare side effects of commonly used medications. Hepatotoxicity resulting from the use of methoxyflurane as an inhalation agent in general anaesthesia is well described.1-3 However, hepatotoxicity associated with low doses of methoxyflurane for analgesic purposes appears to be rare. Three cases of hepatitis complicating methoxyflurane use (at subanaesthetic doses) during labour have been reported.7,8 In another case report, repeated exposure in the form of misuse of methoxyflurane was found to be associated with hepatotoxicity.9 The mechanisms of methoxyflurane-induced hepatotoxicity are unclear and may be multiple. Adverse effects of halogenated ethers are thought to be related to immune-mediated, direct toxic effects of metabolites and/or host idiosyncrasy.1 Reactive intermediates formed during metabolism of methoxyflurane can lead to tissue acetylation, with proteins modified by acetylation forming neoantigens that may trigger an immune response.1 Drug re-exposure has also been implicated as a factor contributing to methoxyflurane-induced hepatitis.2 Although unproven, it is possible that our patient’s repeated exposure to the drug may have contributed to the development of hepatitis through dose-dependent toxicity. In the prehospital setting, where methoxyflurane is being widely used, the side effect profile is minimal.5 It seems the exposure to methoxyflurane in our patient was the likely cause of acute hepatitis, and it may be that repeated exposure was a contributing factor. This observation has implications for the way methoxyflurane is prescribed, including its use for procedural analgesia in cases in which several procedures (and hence, repeated dosing) are required.

Kacey M O’Rourke BAppSc, MB BS · Stuart McMaster MB ChB, FRACGP · Karin M C Lust MB BS, FRACP

Clostridium difficile is the most common cause of health care-associated and antibiotic-associated diarrhoea. These guidelines are intended to provide advice to clinicians on the clinical assessment, diagnosis and management of C. difficile infection (CDI). Hypervirulent strains of C. difficile, including PCR ribotype 027 strains recently identified in Australia, have been associated elsewhere with epidemic spread and high rates of severe disease and death. Diagnostic tests include stool culture, polymerase chain reaction-based assays, cell-culture cytotoxicity assays and enzyme immunoassays detecting C. difficile glutamate dehydrogenase, and/or toxin A and/or B. To treat an initial episode and a first recurrence, metronidazole is the preferred antibiotic, with oral vancomycin reserved for severe disease and subsequent recurrences. Surgery should be considered for fulminant disease.

Allen C Cheng FRACP, MPH, PhD · John K Ferguson FRACP, FRCPA, DTMH · Michael J Richards MB BS, FRACP, MD · Jennifer M Robson FRACP, FRCPA, FACTM · Gwendolyn L Gilbert MD, FRACP, FRCPA · Alistair McGregor MB BS, FRACP · Sally Roberts MB ChB, FRACP, FRCPA · Tony M Korman MB BS, FRACP, FRCPA · Thomas V Riley MAppEpid, PhD, FRCPath

We report the first recognised case of infection with Clostridium difficile PCR ribotype 027 acquired in Australia. This pathogen has caused significant morbidity and mortality in widespread hospital-based outbreaks in the northern hemisphere. Clinicians need to be aware of the clinical picture, limitations of diagnostic tests, availability of further testing for epidemic strains, new therapeutic approaches, and in-hospital control strategies for this infection. (MJA 2011; 194: 369-371) Clinical recordAn 83-year-old Latvian man underwent an aortic valve replacement for aortic stenosis in late January 2010 at a hospital in Melbourne, Australia. He had a history of hypertension and chronic renal failure. He lived alone in his own home, and had not travelled outside Australia since September 2009 when he returned from a 3-month trip to Latvia. Between his return to Australia and the surgery, he had not received any antibiotics except for a single preoperative dose of cephalothin. His regular medications included various supplements, but no proton-pump inhibitor. He was admitted to the hospital the day before surgery. Two days after the surgery, he developed severe sepsis from a urinary tract infection, for which he received ticarcillin–clavulanate and a noradrenaline infusion. A coagulase-negative Staphylococcus was isolated from blood cultures, and he was given vancomycin. He later developed an infiltrate at the left lung base, but no change was made to his therapy. Five days after the surgery, he developed watery diarrhoea. Clostridium difficile was isolated from stool samples, although the results of enzyme-linked fluorescent assays (VIDAS, bioMérieux, Sydney, NSW) for C. difficile toxins were negative at this time. His leukocyte count was 9.5 × 109/L (reference range, 4.0–11.0 × 109/L) and his serum albumin concentration was 42 g/L (reference range, 35–50 g/L). Therapy with metronidazole (400 mg orally, 8-hourly) was commenced for presumed C. difficile infection (CDI), and the patient was placed under contact precautions. Alcohol-based hand rub was replaced with traditional soap and water hand washing (see below). Therapy with ticarcillin–clavulanate was subsequently ceased. After 9 days of metronidazole therapy, the diarrhoea became more frequent and vancomycin (250 mg orally, 6-hourly) was substituted. Repeat stool specimens were tested. This time, C. difficile toxins were identified by enzyme-linked fluorescent assay, and C. difficile was isolated again. Because of the patient’s deteriorating condition, the laboratory was alerted to the possibility of a hypervirulent strain. The isolate was tested for susceptibility to moxifloxacin (Etest, bioMérieux, Sydney, NSW) and found to be resistant, with a minimum inhibitory concentration of > 32 μg/L. The stool sample was positive by real-time polymerase chain reaction (PCR; GeneXpert, Cepheid, Sunnyvale, Calif, USA) when tested for the presence of C. difficile organisms carrying genes for toxin B (tcdB), binary toxin (cdtB) and an 18-base-pair deletion within the tcdC gene that is characteristic of the PCR ribotype 027 strain. These findings were confirmed by sequencing the tcdC gene, and this also identified a point mutation at nucleotide position 117, which is also characteristic of this strain. PCR ribotyping was undertaken using a previously published method1 that confirmed the isolate as PCR ribotype 027 (Box). Nineteen days after surgery, the patient’s condition deteriorated further. His temperature was 39.2°C, his leukocyte count was 31.2 × 109/L and his serum albumin concentration was 25 g/L. The diarrhoeal frequency fell to a single bowel action per day, and an abdominal x-ray showed a distended right colon. The oral vancomycin dose was increased to 500 mg, 6-hourly, and therapy with intravenous metronidazole was commenced along with vancomycin enemas (500 mg in 500 mL normal saline, 6-hourly). Ticarcillin–clavulanate therapy was recommenced. A surgical opinion was sought and subtotal colectomy discussed. As there was felt to be a high risk of mortality with surgery, medical management was preferred. After 5 days, the fever and diarrhoea improved. The enemas were ceased after 8 days and metronidazole therapy after 14 days. The patient subsequently recovered, and the diarrhoea had not recurred at 3-month follow-up. DiscussionAn epidemic strain of C. difficile (PCR ribotype 027) was first identified in Quebec Province in Canada in 2005, as a cause of hospital outbreaks of severe infection with high mortality rates.2 Retrospective analyses suggested that this strain had caused outbreaks across North America since 2000.3 The organism later spread to Europe, and cases have now been described in Asia and Central America.4 Increased toxin production by C. difficile PCR ribotype 027 may be responsible for its increased virulence,5 and fluoroquinolone resistance is likely to be contributing to its spread.6 Infection with this strain more often leads to severe disease, and is associated with more recurrences and a greater risk of death.2 Until now, only one case has been described in Australia in a patient who was thought to have acquired the infection in North America.7 This is the first case of hypervirulent CDI diagnosed in Australia with apparent local acquisition. Several factors support the conclusion that the infection was not acquired overseas. First, although the patient had travelled to Latvia 4 months before being admitted, the possibility that he acquired C. difficile PCR ribotype 027 then and remained colonised is remote. C. difficile does not colonise the normal adult gastrointestinal tract, and the patient received no antibiotics that may have disrupted his gut flora in the time between returning from Latvia and admission to hospital. Second, a recent publication from Latvia indicates that C. difficile ribotype 027 was not present in the country when our patient was there.8 Finally, there were at least two other subsequently confirmed cases of infection with C. difficile PCR ribotype 027 in the hospital at the time the patient developed symptoms of infection (it is not known where these cases were acquired). The case illustrates important features of hypervirulent CDI. The identification of severe disease is critical in guiding management. For surveillance purposes, severe disease may be simply identified as infections requiring ICU admission or surgery, or infections resulting in death, or a diagnosis of toxic megacolon.9 More sensitive diagnostic criteria for severe disease in addition to those above are required to guide patient care. While no such criteria have yet been prospectively validated, proposed markers of severe disease include age greater than 65 years, leukocytosis greater than 20 × 109 cells/L, deterioration of renal function, temperature greater than 38.3°C, serum albumin concentration less than 25 g/L and an elevated serum lactate concentration.10 Our patient met all these criteria except for the serum lactate concentration, which was not recorded. Although metronidazole remains the recommended first-line agent for mild to moderate CDI, oral vancomycin is now recommended for severe disease.9,10 Although there is no evidence that high-dose oral vancomycin (500 mg, 6-hourly) is any better than standard doses of 125 mg 6-hourly, higher doses are favoured by many clinicians. Evidence of benefit for vancomycin enemas is limited to case series; eight of nine patients with refractory severe disease had complete resolution with this therapy.11 In the setting of ileus with toxic megacolon, oral vancomycin will not reach the colon and intravenous delivery of metronidazole is preferable.12 Surgery should be considered if severe disease is unresponsive to medical therapy after 48 hours, or if there is bowel perforation or multiorgan failure.13 Elevation of plasma lactate to between 2.2 and 4.9 mmol/L has been identified in a retrospective review of a selected group of severely ill patients as a guide to when colectomy is most beneficial.14 Other strategies requiring further investigation for use in severe disease include intravenous immunoglobulin, alternative antibiotics such as tigecycline, and monoclonal antibodies. C. difficile spores are highly resistant to killing by alcohol and most other disinfectants. In outbreaks of CDI, health care workers should be instructed to wash their hands with soap and water in addition to using alcohol-based hand disinfection when caring for infected patients. Patients should be isolated and contact precautions with gowns and gloves are recommended. Environmental cleaning with hypochlorite-based solutions is necessary to eliminate the spores.9 Antibiotic stewardship is also an important element in control strategies, with studies of antibiotic restriction showing benefit.15 In Australia, laboratory diagnosis of CDI is most commonly made through detection of C. difficile toxins A and B using enzyme immunoassay (EIA) kits. EIA kits have reported sensitivities of 75%–95%, but most of the evaluations reporting these sensitivities use faecal cytotoxin detection (a flawed test) as the gold standard.16 In addition, the positive predictive value of these tests declines markedly in situations where the prevalence of disease is low.16 Poor sensitivity of the assay is the likely explanation for the initial negative result of the enzyme-linked fluorescent assay in our case. Despite this limitation, EIA kits remain widely used because of their simplicity and relatively low cost. Commercial real-time PCR testing for toxin genes (usually tcdB), has better sensitivity (93%) and specificity (97%),16 and is now available in several Australian laboratories. Toxigenic culture — isolation of the organism followed by toxin testing of the isolate — is extremely sensitive, but it is labour intensive and takes at least 3 days.16 There is currently great debate about the value of an algorithmic approach to diagnosing CDI, whereby a sensitive screening test is used to screen out negatives, thus improving the positive predictive value of a secondary test, particularly when the prevalence of infection is low.17 Distinguishing C. difficile PCR ribotype 027 from other strains of C. difficile does not affect individual patient management, but is important for surveillance purposes. Some commercially available PCR methods can presumptively identify PCR ribotype 027 based on detection of binary toxin genes and the characteristic 18-base-pair deletion in the tcdC gene. An alternative, less expensive, approach is to screen for moxifloxacin resistance by using a 5 μg moxifloxacin disc on a lawn culture of C. difficile on Mueller-Hinton agar. Worldwide, most PCR ribotype 027 isolates are resistant to moxifloxacin,2 while, in Australia, the prevalence of resistance in all strains of C. difficile is 1%. (T V Riley, B Elliot and colleagues, unpublished data). Zones of inhibition for resistant strains (potentially PCR ribotype 027) are > 16 mm while for susceptible strains, they are ≥ 16 mm (T V Riley and colleagues, unpublished data). Isolates of moxifloxacin-resistant C. difficile identified in this way can then be sent for further typing. Given the arrival of C.difficile PCR ribotype 027 in this country, periodic PCR ribotyping of a representative sample of isolates now needs to be performed at designated reference laboratories Australia-wide, and recurrent funding is required for this task. This will be an important adjunct to local screening measures, and will also detect the emergence of virulent PCR ribotypes other than 027. An Australian Commission on Safety and Quality in Healthcare recommendation for hospital surveillance programs in all states and territories to monitor C. difficile was approved by Australian Health Ministers in November 2008. As yet, the states and territories have not implemented this recommendation, and there has been no collation or analysis of national surveillance data. With the identification of the first case of PCR ribotype 027 C. difficile infection acquired locally, it is important that clinicians in Australia are aware of the clinical picture, limitations of diagnostic tests, availability of further testing for PCR ribotype 027, new therapeutic approaches,18 and in-hospital control strategies for this infection.19 The solution to the bigger problem of the emergence of virulent strains of C. difficile continues to lie in the basics of surveillance, antimicrobial stewardship, infection control and environmental cleanliness. Ribotyping pattern of the Clostridium difficile strain isolated from the patient compared with a reference and an unrelated strain Patient isolate Unrelated strain PCR ribotype 027 reference strain 100-base-pair DNA ladder PCR = polymerase chain reaction.

Michael Richards MB BS, MD, FRACP · James Knox BSc(Med), MB BS, DTM · Briony Elliott BSc(Hons) · Kate Mackin BA/BSc(Hons) · Dena Lyras BSc(Hons), PhD · Lynette J Waring MB BS, FRCPA · Thomas V Riley PhD, FASM, FRCPath

To the Editor: Interest in alternative therapies for Clostridium difficile infections (CDIs) is increasing as these infections become important causes of patient morbidity and mortality. Recurrent CDIs can be severe and difficult to treat. In-vitro data,1 followed by reports of the efficacy of tigecycline in the treatment of severe refractory cases of CDI,2 suggest that tigecycline should be considered as an alternative or adjunctive antimicrobial agent in these situations. To date, it has been used mostly as a “salvage” strategy in combination with other antibiotics in the face of clinical deterioration.2,3 We report the successful use of tigecycline monotherapy in the treatment of a patient with recurrent C. difficile colitis. An 83-year-old woman was admitted to hospital in July 2009 with acute diverticulitis. She was treated with intravenous cefotaxime (1 g three times daily for 6 days): her presenting fever and abdominal pain resolved but she developed watery diarrhoea. Despite positive stool cultures for toxigenic C. difficile, initial toxin testing by enzyme immunoassay (EIA [TechLab C. Difficile Tox A/B II]) of stool specimens was negative. After a 7-day course of oral metronidazole 200 mg three times daily, the diarrhoea abated. One month after discharge, our patient re-presented with anorexia, severe abdominal pain and diarrhoea. Six days of oral metronidazole, prescribed by her local doctor, had little effect. A computed tomography scan of the abdomen revealed diffuse thickening of the colon from the ileocaecal junction to the rectum, consistent with a pancolitis. Sigmoidoscopy showed grossly abnormal mucosa with pseudomembranes present. A diagnosis of C. difficile pseudomembranous colitis was made. After 10 days of oral vancomycin 250 mg, four times daily, her symptoms had resolved, and repeat sigmoidoscopy showed reversal of the mucosal changes. Six days later, the pseudomembranous colitis recurred. She rapidly responded to the recommencement of oral vancomycin, given as a tapering course over 6 weeks. Twelve days after completing the 6-week course of vancomycin, the patient presented with her third episode of colitis. Most reported strategies for recurrent CDI, such as faecal transplantation, probiotics or novel antimicrobials,4 were not practicable or available for timely use for our patient. Tigecycline, a broad-spectrum glycylcycline antibiotic, is available as part of the hospital formulary for the treatment of complicated skin and soft-tissue infections and complicated intra-abdominal infections. Encouraged by recent reports of success using tigecycline as adjunctive therapy for severe cases of CDI,2 we prescribed, as monotherapy, intravenous tigecycline 50 mg twice daily for 2 weeks. Our patient’s condition improved over 1 week. At 3-month follow-up, she remained asymptomatic, with repeat stool cultures and polymerase chain reaction (PCR) testing for C. difficile toxin negative at Days 75 and 107 following the last episode of colitis. Our case also highlights a diagnostic matter. In general, use of EIA to detect C. difficile toxin A or B is highly specific. However, in clinical settings where the prevalence of CDI is low, the positive predictive values for these assays are inadequate to rule in the diagnosis of CDI. Confirmatory laboratory testing using an alternative method (in this case, PCR) proved more reliable in the diagnosis of our patient’s recurrent CDI. Typing showed that our patient’s isolate was not PCR ribotype 027, a hypervirulent strain in Europe and North America associated with high mortality.5 We recommend consideration of tigecycline as a useful antimicrobial agent in the management of both recurrent and severe CDI.

Elaine Y L Cheong · Thomas Gottlieb

An estimated four out of five Australians with coeliac disease are undiagnosed — we need greater awareness and increased testing According to criteria published in 1990, which remain the most widely accepted, the diagnosis of coeliac disease is based on typical histological features of the small intestine of an individual on a gluten-containing diet: villous atrophy, crypt hyperplasia and intra-epithelial lymphocytosis.1 Serological tests for coeliac disease, such as for endomysial IgA or transglutaminase IgA, are predictive, but alone are not sufficient for diagnosis. The diagnosis of coeliac disease is confirmed by clinical, serological or histological improvement on a gluten-free diet.1 To become a member of a state coeliac society in Australia, a person requires a doctor’s letter indicating a medical need for a gluten-free diet. As a result, over 80% of members have biopsy confirmation of coeliac disease; this is also the case in the United Kingdom. Over the past 10 years, there has been a steady compound annual growth of a little less than 10% in new memberships for coeliac societies in the UK and Australia (Norma McGough, Head of Diet and Health, Coeliac UK; Graham Price, President, Coeliac Society of New South Wales; and Jane Davies, Executive Officer, Coeliac Society of Victoria, personal communication). Both countries have now developed active education programs for doctors in family medicine. It appears that these programs have been successful in increasing serological testing and reducing the “backlog” of symptomatic patients with coeliac disease who were previously unrecognised.2 Today, coeliac disease is very much a diagnosis made in adulthood; children under the age of 10 years make up only 11% of new members joining coeliac societies in the UK and Australia, while the median age of new members is 40 years. However, best estimates, based on there being about 1% prevalence of coeliac disease in Western populations, suggest that no more than one in five Australians with coeliac disease are now diagnosed.3,4 Finland, where about 0.5% of the total population have now been formally diagnosed with coeliac disease,5 is accepted as having the most coeliac-aware health system. Australia still has a long way to go to achieve the level of awareness present in Finland, where gluten-free Big Macs have been available for more than 20 years and restaurant menus routinely indicate whether food is gluten free. Although awareness of coeliac disease has generally been low in the United States, a recent report by Mayo Clinic suggested that in Olmsted County, the home of Mayo Clinic, as many as 0.35% of the local community have been formally diagnosed with coeliac disease, suggesting a 35% ascertainment rate.6 It was also reported that no additional mortality was observed in the residual group of individuals with unrecognised coeliac disease in Olmsted County, suggesting that aware physicians and prompt, appropriate diagnosis of symptomatic coeliac disease are effective in minimising serious complications.7 Conversely, very low clinical awareness of coeliac disease, observed by researchers of historical cohorts in Germany and the US, is associated with substantially increased mortality, usually caused by malignancies and infection.8,9 Experience in Finland also supports the principle that high levels of clinical awareness and diagnosis minimise morbidity and mortality among individuals with unrecognised coeliac disease.10 Three reports, including one published in July 2010, suggest that, because of the rise in the disease’s prevalence, progress in clearing the backlog of undiagnosed coeliac disease may be slower than we thought.5,8,9 In Finland, the prevalence of coeliac disease doubled from 1% to 2% between 1979 and 2000, while diagnosed coeliac disease increased from 0.03% to 0.52% of the population.5 In the US, Mayo Clinic researchers showed that the seroprevalence of coeliac disease rose almost five times, from 0.2% to 1%, between 1950 and 2000.8 Now researchers have shown that, in a cohort of mostly adult volunteers in Maryland, US, who were enrolled in 1974 and followed up in 1989, the seroprevalence of coeliac disease more than doubled from 0.2% to 0.5% in 15 years.10 Those who showed seroconversion between 1974 and 1989 were all adults, indicating that coeliac disease does not necessarily begin in childhood. Data from Finland also show that the prevalence of coeliac disease in older people is double that in children.11-13 Although confirmation of coeliac disease by biopsy is ideal, these new epidemiological insights are reshaping our understanding of coeliac disease and should better inform clinical practice. No longer can we assume that a single serological test for coeliac disease is adequate to exclude coeliac disease for life. The only test that seems capable of excluding coeliac disease for life is HLA-DQ genetic testing.14,15 Absence of genes encoding the susceptibility antigens HLA-DQ2 or HLA-DQ8 effectively excludes coeliac disease; however, over a third of European populations possess these genes, while only 1% to 2% of the population has coeliac disease.16 Increased testing for coeliac disease using transglutaminase IgA and the new generation “deamidated gliadin peptide” IgA and IgG, and more systematic collection of small bowel biopsy samples by endoscopists, will steadily define those patients with coeliac disease who have a clear medical need for a strict gluten-free diet.17,18 The popularity of the “fad” gluten-free diet might be peaking,19 but the medical need for gluten-free diets continues to rise.

Robert P Anderson MB ChB, PhD, FRACP

Unsatisfactory outcomes in medicine are too common. There are multiple causes, one of which is medical errors. In our society the response to medical error is typically legal, rather than investigative and remedial. This should be deplored by both the profession and the public. The clash between the legal and medical systems rarely leads to a decrease in the likelihood of future error. Rather, a defensive approach is fostered that encourages concealment of error and the attribution of blame. This balkanises the parties and makes solutions more difficult to find. The legal response to error and harm is reflective not only of our culture and history but also of the need for patients to ascertain information about the error and receive a financial remedy if loss has occurred. Given that this is the setting in which we find ourselves, the availability of the defence of “peer professional practice” (that an action is not negligent if the professional acts in a way that is widely accepted by his or her peers) gives some comfort. Mahar and Burke, in this issue of the Journal, draw attention to some important limitations of this defence (→ What is the value of professional opinion? The current medicolegal application of the “peer professional practice defence” in Australia). They point out that the defence is not a substitute for the need to properly warn patients of the material risks involved in a procedure. They also demonstrate that the requirement to practise according to widely accepted professional standards implies the need to be abreast of contemporary clinical practice. Surely this is the purpose of continuing professional education. Consequently, there is no justification for the practice of purely “defensive” medicine. Mahar and Burke’s article also highlights a negative interaction between the legal and medical cultures. In a recent case that relied on the peer professional practice defence, the testimony of one of the expert witnesses was discounted because, when forming his opinion, he consulted a colleague about her views on the case, which led the court to doubt the witness’s standing as an expert. In contrast, the medical view is that consultation in the face of doubt is protective of the patient and not a sign of weakness. As a doctor, the legalistic approach of the court in this regard reinforces the perception that the law is an ass, that it will never be understandable or reasonable, and that the solution to medical errors will never lie in the legal sphere. As a profession, this mandates that we make the study and minimisation of medical error and unfavourable outcomes our own. It is time to responsibly admit and embrace error and empower ourselves to grow. While “the truth will set you free”,* US President James Garfield was probably closer to the reality of the process when he supposedly added, “but first it will make you miserable”. * John 8: 32.

Annette G Katelaris MB BS, MPH, FRACGP

New ablative techniques can eradicate dysplastic Barrett oesophagus more effectively, but require longer-term follow-up to strengthen their evidence base Barrett oesophagus is a precursor lesion that can progress to oesophageal adenocarcinoma. Barrett oesophagus affects about 1% of the population and is believed to be due to chronic gastro-oesophageal reflux disease.1 Patients with Barrett oesophagus have a 30–40-fold relative risk of developing oesophageal adenocarcinoma, which usually occurs via progression through low-grade dysplasia (LGD) to high-grade dysplasia (HGD).2 Management of patients with non-dysplastic Barrett oesophagus comprises surveillance endoscopy and biopsies every 2–3 years, along with acid suppression. The traditional approach for treating LGD has been intensified endoscopic surveillance. A new trend has evolved in the management of patients with HGD and intramucosal cancer. Oesophagectomy has been standard treatment for these patients because of studies showing that cancer is discovered in about 40% of oesophagectomy specimens after a preoperative diagnosis of HGD.3 Oesophagectomy in high-volume centres now carries a mortality rate of around 1%; however, morbidity rates can be up to 30%.4 Recently, improved capacity to identify early cancers with modern endoscopes and advances in endoscopic resection and ablation techniques have resulted in excellent outcomes for individuals with HGD and intramucosal cancer treated with endoscopy alone. Staging dysplastic Barrett oesophagus requires meticulous endoscopic assessment, using the newest generation of high-definition endoscopes to identify nodules and subtle mucosal abnormalities that can harbour cancer. Biopsy samples are taken from visible abnormalities, and four-quadrant biopsy samples are taken from every 1 cm of Barrett oesophagus. New endoscopic technologies, such as narrow band imaging and confocal endomicroscopy, appear to aid identification of dysplastic areas and may reduce the need for random biopsies. Endoscopic mucosal resection is a technique to remove 10–15 mm areas of mucosa, to the depth of the submucosa. Larger areas, or the entire Barrett oesophagus up to 3–5 cm in length, can be completely removed by this method with several contiguous resections. Endoscopic mucosal resection of focal mucosal abnormalities is essential to identify and remove early cancers and to determine the depth of invasion. If dysplasia or cancer is confined to the mucosal layer, the chance of spread to perioesophageal lymph nodes is less than 5%. On the other hand, if cancer extends into the submucosal layer, the chance of lymph node involvement is about 30% and oesophagectomy is therefore indicated.5,6 In expert hands, focal endoscopic mucosal resection achieved complete removal of HGD and intramucosal cancer in 96% of 231 patients.7 However, metachronous lesions occurred in 22% of patients at mean follow-up of 61 months; incomplete removal of the residual Barrett oesophagus was the main risk factor for recurrence. This highlights the importance of removal of the entire Barrett segment.7 To address this issue, a few European centres have advocated stepwise complete resection of short segments of Barrett oesophagus. In a recent multicentre study, complete eradication of all neoplasia was achieved in 98% of patients (165/169) after median follow-up of 32 months.8 Endoscopic mucosal resection has a 1% risk of serious complications, such as major bleeding or perforation. Symptomatic stenosis requiring dilatation develops in up to 50% of patients following stepwise complete resection.9 Endoscopic ablation therapies rely on the fact that squamous mucosa will replace the ablated Barrett oesophagus in a non-acid environment. Older endoscopic therapies include argon plasma coagulation, photodynamic therapy and multipolar electrocoagulation. These techniques are limited by variable mucosal ablation and “buried Barrett” under squamous mucosa. The HALO radiofrequency ablation system (Barrx Medical, Sunnyvale, Calif, USA) consists of two devices for delivering radiofrequency energy to the Barrett oesophagus. The HALO360 device is a balloon that is inflated in the oesophagus to deliver a 3 cm circumferential burn, which can be repeated to treat long segments. The HALO90 is a flat device attached to the tip of the endoscope to ablate smaller areas of Barrett oesophagus. Energy delivery is automated, leading to a more predictable and uniform ablation, enhancing safety and efficacy compared with other ablative therapies. A randomised controlled trial of HALO radiofrequency ablation compared with a sham procedure has shown much higher rates of complete remission after 12 months in individuals with HGD (81%) and LGD (91%) compared with the control groups.10 The 2–3-year follow-up of patients who remained in the study has confirmed durability of response, with 95% of patients who achieved complete remission of Barrett oesophagus at 12 months remaining so at 2 years. Furthermore, 85% of those who failed to eradicate Barrett oesophagus at 12 months achieved complete eradication at 2 years with a mean of 1.2 further focal ablation sessions. Longer-term follow-up beyond 5 years is required to address maintenance of remission and reduction in cancer progression.10 The principle of combination therapy is to remove visible mucosal abnormalities that may harbour invasive cancer with endoscopic mucosal resection, then to ablate the remaining Barrett oesophagus with HALO radiofrequency ablation. Using this approach, 22 of 23 patients with early cancer or HGD achieved complete remission of Barrett oesophagus, with no neoplasia recurrence after 22 months.11 Endoscopic therapy with HALO radiofrequency ablation and/or endoscopic mucosal resection has now emerged as a credible alternative to surgical oesophagectomy and should be considered as a valid alternative to surgery for patients with HGD and intramucosal cancer. Our institution favours the combination endoscopic approach. The optimal management of patients with dysplastic Barrett oesophagus requires meticulous assessment and an individualised approach. Patients who undergo endoscopic therapy will need to be informed, motivated and compliant, as careful endoscopic surveillance after eradication is required to ensure that any recurrence is detected and treated early. Therefore, endoscopic therapy is best performed at tertiary centres with expertise in this evolving area.

Chatura S Jayasekera MB BS(Hons), FRACP · Finlay A Macrae MD, FRACP, FRCP · Paul V Desmond MB BS, FRACP · Andrew C F Taylor MB BS, FRACP, MD

Foreign body oesophageal obstruction is a medical emergency. It may be accidental, particularly in children, or deliberate, for example with suicide attempts. We present two cases illustrating accidental oesophageal foreign body impaction occurring after consumption of food that had been heated in a plastic container in a microwave oven, then cut and eaten directly from the softened container. To date, we are not aware of any similar reports. In view of potential complications, care needs to be taken when food is eaten directly from plastic takeaway containers. (MJA 2011; 194: 245-246) Clinical recordsPatient 1In April 2009, a 79-year-old woman was admitted to hospital with acute dysphagia. She had a history of hypertension, osteoporosis and hypercholesterolaemia. In the past she had also had a transient ischaemic attack. Her medications were felodipine, alendronate, atorvastatin and clopidogrel. Before presentation she had been eating quiche that had been heated in a plastic (polypropylene) container. At subsequent gastroscopy, a solid wedge-shaped piece of plastic 4 cm in length was found to be lodged in her upper oesophagus (Box 1). This was removed endoscopically with the aid of a stand ard Roth Net retriever (US Endoscopy, Mentor, Ohio, USA) (a snare with a mesh basket) leaving a longitudinal mucosal tear (Box 2). There was no evidence of oesophageal perforation and she made a rapid and complete recovery, being discharged after 48 hours on pantoprazole in addition to her usual medications. At follow up after 2 weeks, she remained well and pantoprazole was ceased. Patient 2In October 2009, a previously well 45-year-old woman presented with sudden onset of odynophagia and dysphagia localised to the lower oesophagus after eating fish that had been stored and reheated in a clear polypropylene container. Initial ear, nose and throat assessment showed no evidence of fish bones in the tonsil area or oropharynx. A subsequent chest and neck computed tomography (CT) scan identified an opaque, linear foreign body within the subcarinal region of the oesophagus. There was no extraluminal gas or mediastinitis. An urgent gastroscopy was arranged and revealed a superficial linear ulcer caused by a 3 cm × 2 cm plastic foreign body lodged in the mid-oesophagus. Attempted retrieval with grasping forceps failed and a Roth Net retrieval device was used to remove the piece of plastic through an overtube. A minor oesophageal mucosal tear was seen afterwards. The patient recovered uneventfully and was discharged after 24 hours. DiscussionForeign body impaction is an important cause of sudden-onset dysphagia and is a medical emergency. Foreign bodies can be classified either as food or true foreign bodies. In a recent retrospective series of 988 patients, the five most common foreign bodies resulting in impaction were food boluses (17.1%), coins (15.6%), fish bones (12.6%), dental prostheses (8.6%) and chicken bones (6%).1 The most common sites of impaction are the cricopharyngeus, aortic arch, left main branch bronchus and cardio-oesophageal junction, where physiological narrowing occurs. Objects greater than 2 cm have difficulty traversing the normal adult oesophagus.2 Risk factors for obstruction include young age, dentures, psychiatric disorders, neurological conditions such as motor neurone disease and strokes, developmental delay, impairment by alcohol and underlying oesophageal pathology.3 Oesophageal pathology includes inflammatory or fibrotic strictures, Schatzki rings, eosinophilic oesophagitis, malignancy and diverticula.4 Certain forms of obesity surgery, such as gastric banding, may also be complicated by dysphagia. Clinical manifestations of oesophageal obstruction include chest pain, dysphagia, odynophagia, regurgitation and hypersalivation. Swelling, tenderness and crepitus may represent oropharyngeal or proximal oesophageal perforation. It is crucial to assess for airway compromise such as stridor, choking and coughing. This may result when the impaction occurs at the level of the upper oesophageal sphincter leading to tracheal compression. Complications of foreign body ingestion include obstruction, perforation, aspiration, tracheo-oesophageal fistula, aorto-oesophageal fistula, and abscess formation.5 Imaging such as x-ray or CT scan may demonstrate the location of the foreign body. Fish and chicken bones, glass, plastic, or food boluses may not always be seen on plain x-ray. Most foreign bodies pass spontaneously, although up to 20% require intervention. Intravenous glucagon, which relaxes the oesophageal smooth muscle, may be administered before endoscopic therapy but is of limited value.6,7 Effervescent agents such as carbonated drinks are often given but evidence of their efficacy is limited and based on case series only. Management is determined by the patient’s clinical condition and the anatomical location of the ingested material. Airway compromise or obstruction at the level of the cricopharyngeus may require consultation with an ear, nose and throat specialist. Otherwise, flexible endoscopy is the mainstay of foreign body removal.8 Success rates of 94% have recently been reported.1 In all cases, removal within 24 hours is recommended to avoid pressure-induced ischaemia and to minimise the risk of perforation.9 Urgent endoscopic removal is required when a sharp object is ingested or if evidence of high-grade obstruction is present. The foreign body may be removed using various instruments or by the push technique.3 The latter involves pushing the foreign body into the stomach with the endoscope but carries an increased risk of perforation. Sharp objects represent a medical emergency due to the risk of perforation, which has been estimated to be as high as 35%.2 They are less common than other foreign bodies but more difficult to remove. Endoscopic removal with minimal mucosal injury can generally be achieved using a retrieval device such as a Roth Net, as in our cases, or polypectomy snares with use of an overtube.10 An algorithm for managing a suspected sharp oesophageal foreign body is outlined in Box 3. The two cases we describe involved inadvertent ingestion of plastic as a result of cutting food in a heated, softened food container, resulting in a sharp foreign body oesophageal impaction and subsequent mucosal tear. To our knowledge, there have not been similar case reports in the literature. Given that takeaway food containers are widely used, these cases highlight the need for care to be taken when heating food in such containers and then consuming directly from them. 1 Gastroscopy image showing a solid piece of plastic wedged in the patient’s upper oesophagus 2 Gastroscopy image after removal of the plastic foreign body, showing a longitudinal mucosal tear 3 Algorithm for managing a suspected sharp oesophageal foreign body

Marianne Guirgis MB BS, BPharm, FRACP · Robert Nguyen MB BS, FRACP · Christopher Pokorny MB BS, FRCP, FRACP

A 66-year-old woman presented to the emergency department with sudden-onset, severe thoracic back pain associated with dyspnoea and diaphoresis after consuming lunch. She was otherwise well, and her only medical history of note was gastro-oesophageal reflux disease. Examination showed a large right-sided pneumothorax, which was confirmed by chest x-ray. A pleural catheter was inserted, which resolved the pneumothorax, but the patient’s pain continued. A computed tomography scan showed a 2.7 cm transverse, linear foreign body in the patient’s oesophagus at the level of the aortic arch (Figure, arrow). This had caused perforation, pneumothorax, pneumomediastinum and pneumopericardium. The chicken bone was removed surgically, and the patient made an uneventful recovery.

Philippa J Bunting

An 82-year-old man presented to the emergency department with abdominal pain and vomiting. An abdominal computed tomography scan showed a whirl sign around the superior mesenteric vessels (Figure, arrow), suggestive of small bowel volvulus. A whirl is formed by the afferent and efferent loops of the volvulus, with the central portion consisting of tightly twisted bowel and mesentery.1 The latter create swirling strands of soft tissue shadow within a background of mesenteric fat attenuation, giving the appearance of a hurricane on a weather map. Caecal and sigmoid volvulus can also give rise to whirl signs. Laparotomy confirmed mid-gut volvulus with 360° rotation. The patient had an uneventful recovery following derotation of the mesentery.

Debasish Debnath · Peter Frecker

Does this colonic polyp not resemble a jelly baby?

D Brian Jones

Objective: To document presenting symptoms, investigations and management for Australian patients with oesophageal adenocarcinoma (OAC), gastro-oesophageal junction adenocarcinoma (GOJAC) and oesophageal squamous cell carcinoma (OSCC).Design, setting and participants: Cross-sectional study of a population-based sample of 1100 Australian patients aged 18–79 years with histologically confirmed oesophageal cancer diagnosed in 2002–2005, using data from cancer registries and treatment centres, supplemented with clinical information collected through medical record review in 2006–2007 and mortality information collected in 2008.Main outcome measures: Prevalence of primary symptoms, and staging investigations and treatment modalities used.Results: The primary presenting symptom was dysphagia, which was self-reported by 41%, 39% and 48% of patients with OAC, GOJAC and OSCC, respectively. Less common symptoms were reflux, chest pain, bleeding and weight loss. All patients underwent endoscopy, most had a staging computed tomography scan (OAC 93%, GOJAC 95% and OSCC 93%), and about half had positron emission tomography scans (OAC 51%, GOJAC 44% and OSCC 42%). Pretreatment tumour stage was reported in 25% of records, and could be derived from results of investigations in a further 23%, but the remaining half lacked sufficient information to ascribe a pretreatment stage. Curative treatments were attempted for 60% of OAC, 88% of GOJAC and 65% of OSCC patients. Surgery was performed on 52% of OAC, 83% of GOJAC and 41% of OSCC patients. About two-thirds of surgical patients received additional therapies.Conclusions: With anticipated increases in oesophageal cancer incidence, the resources required to diagnose and manage patients with oesphageal cancer are also likely to rise. Our data provide a baseline from which to plan for the future care of patients with cancers of the oesophagus.

Bernard M Smithers MB BS, FRACS, FRCS · Paul P Fahey BSc, MMedStat · Tracie Corish RN · David C Gotley MD, FRACS · Gregory L Falk FRACS, FACS · Garett S Smith MS, FRACS · George K Kiroff MB BS, MS, FRACS · Andrew D Clouston MB BS, PhD, FRCPA · David I Watson MD, FRACS · David C Whiteman MB BS,PhD, FAFPHM

To the Editor: Flitcroft and colleagues’ discussion of the National Bowel Cancer Screening Program provides a useful reminder of how political, institutional and financial issues can affect evidence-based policy.1 Bowel cancer is second to prostate cancer as the biggest cause of cancer death in Australian men, and men are more likely than women to be diagnosed with bowel cancer. There are no indications, however, that the screening program has sought to engage men as a target group. Men and women think about and act on their health in different ways and respond differently to messages, sources of information and modes of information delivery.2 Men are less likely than women to undergo preventive screening and are more likely to seek treatment at a later stage in a disease. A report for the Australian Government noted that, before receiving the Bowel Cancer Screening Pilot Program material, men were less likely to have been aware of preventive or pre-emptive behaviours “unless their GP had actually raised the subject with them, or a close friend had suffered, bringing the issue to a more personal level”.3 Further evidence indicated that fewer than one-third of men participated in the screening from mid 2006 to mid 2007, despite men aged 55 and 65 years being more likely than women to return positive results; among men aged 55 years, only 28% chose to participate.4 Participation rates during the 2-year screening period ending August 2008 were estimated to be 39.2% for men and 46.7% for women.5 Despite the considerable evidence that the “doing of health” is a highly sex-dependent activity, a population-based, “one size fits all” approach appears to have been adopted. Adding further insult to injury, men were blamed for their lower participation rate and for failing to understand “that screening for cancer saves lives”.6 A disappointing response to a free breast cancer screening initiative, on the other hand, prompted an investigation into the relationship between the wording of the screening invitation letter and the level of screening attendance.7 With around one in 19 men predicted to develop bowel cancer before the age of 75 years, men’s under-representation in bowel cancer screening is a serious problem. There is a need for more attention to be given to men’s attitudes and beliefs about risk and prevention, with a view to developing specific approaches to increase men’s participation in screening.8 It should not be too much to expect that Australia’s first National Men’s Health Policy, and an updated National Women’s Health Policy, will result in sex being taken into account in the design and implementation of national health initiatives.

Margo H Saunders · Anita Peerson

To the Editor: Flitcroft and colleagues’ historical report of bowel cancer screening in Australia is helpful to those new to this internationally accepted life-saving practice.1 One inaccuracy needs correcting. Lung cancer is the leading cause of cancer death in Australia — not prostate or breast cancer. Flitcroft et al appear to have quoted the Australian Institute of Health and Welfare data for new diagnoses, not cancer deaths.2 This error reflects the general lack of community focus or interest in the more than 7000 Australians who die each year from smoking-related lung cancer.3 An update is also warranted. Since submission of their article, once-only flexible sigmoidoscopy screening has joined faecal occult blood test (FOBT) screening in having randomised controlled trial evidence. Results of a recent British study point to the necessity of looking for this occult disease with flexible colorectal endoscopy.4 The study showed a massive 43% reduction in colorectal cancer mortality and a 50% reduction in incidence of invasive rectal cancer, owing to early flexible sigmoidoscopic diagnosis of colonic polyposis followed by polypectomy performed at subsequent colonoscopy. These techniques save thousands of lives worldwide each year. Flitcroft et al state that “A staged roll-out is a sensible approach”, but many of us who perform colonoscopic polypectomies on a weekly basis strongly disagree. Which is better — to be on a waiting list for a colonoscopy with a positive FOBT result, or to be ignorant of the possibility of a growing cancer in the colon? It is time to give people the opportunity of FOBT with or without further investigations. Flitcroft et al rightly point out that the National Health and Medical Research Council recommended that we should have at least biennial FOBT screening for individuals over 50 years of age.5 Australians have been very tardy in terms of adopting this recommendation. We don’t need an “age-specific cost-effectiveness analysis”. The argument should be about introducing flexible sigmoidoscopy. Like Semmelweis and hand washing back in 1847, history will judge our current generation harshly for ignoring the original life-saving FOBT research that was published in 19936 and allowing thousands of Australians to die unnecessarily from bowel cancer since then. It is time for us to take our heads out of the sand and introduce a proper national bowel cancer screening program. Thank you to Flitcroft and colleagues for helping us take another step in this direction.

Guy R Hingston

Liver abscess due to Klebsiella pneumoniae infection has been widely reported in Asia, but rarely reported in Australia until now. We describe four previously well Asian-born patients who presented across Australia with community-acquired K. pneumoniae liver abscesses. With prompt recognition, appropriate antibiotics and early drainage, outcome is significantly improved, although vigilance for metastatic complications is essential. Clinical recordsDuring 2008 and 2009, four patients (two men, two women) presented around Australia with community-acquired Klebsiella pneumoniae liver abscesses (KPLAs). All four patients were previously well and did not have diabetes. Patients 1, 2 and 3 were Australian residents who were born in Asia and had recently visited there; Patient 4 was visiting from China. All patients presented to hospital after several days of gastrointestinal and other symptoms. Liver abscess was shown on computed tomography scans, and K. pneumoniae infection was diagnosed following culture of abscess fluid or blood. Patients were treated with appropriate antibiotics and pigtail catheters for drainage; Patients 3 and 4 required surgical treatment. Patients 1, 2 and 3 were well at follow-up; Patient 4 returned to China and was lost to follow-up. Patient 3 suffered a recurrence about 10 months after her first presentation, but this was too remote to be clearly attributable to her short course of antibiotics (only 10 days). Box 1 summarises the clinical and microbiological details of the four patients. DiscussionA community-acquired Klebsiella pneumoniae primary invasive liver abscess syndrome has been recognised in Asia for more than 20 years, with almost 1000 reported presentations published by 2008; it has been reported less frequently in other regions.1 K. pneumoniae infection accounted for over 80% of primary liver abscesses reported from Taiwan in the 1990s.2 Increasingly, cases have been seen outside Asia, primarily among patients of Asian ethnicity, including in the United States.1,3 It has only rarely been reported in Australia until now.4,5 Of interest are an absence of prior hepatobiliary disease, an association with diabetes, and a risk of metastatic spread.6 Community-acquired KPLA has been associated with severe metastatic complications, including endophthalmitis. The reasons for the changing epidemiology away from Escherichia coli as the leading cause of pyogenic liver abscess are unclear, although selective pressure for Klebsiella through widespread amoxicillin use, to which it is almost universally resistant, has been postulated.7 A genetic predisposition is possible, given the disease is seen almost exclusively in patients of Asian ethnicity, even outside Asia, and very rarely in those of Caucasian origin.8,9 K. pneumoniae is frequently found as part of normal faecal flora, and spread to the liver is thought to occur from the intestines via the portal system.1 Ordinarily, any bacteria reaching the liver would then be phagocytosed and killed, and failure of this defence is presumed to lead to the formation of liver abscesses.1 Diabetes was present in about 50%–70% of patients reported from Taiwan,6 presumably conferring susceptibility by impairing neutrophil-mediated defence,10 and this also appears to be a risk factor for metastatic complications.6 It is interesting to note that none of the patients in our small sample had diabetes. Bacterial virulence is also of major importance, as the condition often affects previously healthy individuals. The presence of capsular polysaccharides of K. pneumoniae serotype K1 or K2 has been strongly associated with virulence through resistance to phagocytosis;10,11 our patients were all infected with one of these two serotypes. Commonly, K. pneumoniae strains causing liver abscess are hypermucoviscous, as defined by an unusual, highly mucoid colony appearance on culture, a feature strongly associated with the K1 or K2 serotype.11 This stickiness is the basis of the “string test”, which can be performed easily in the laboratory. The string test is a quick, useful investigation in this setting (Box 3).7 A colony that stretches more than 5 mm using a standard inoculation loop tests positive for hypermucovisosity.3 The geographical distribution of KPLA may be explained by the finding that K. pneumoniae isolates from Taiwan were far more likely to have a hypermucoviscous phenotype and to belong to K1 or K2 serotypes than those in other countries except South Africa, where invasive disease is also seen.12 Indeed, of the many K. pneumoniae capsular serotypes isolated from patients in an Australian tertiary hospital inpatient setting, K1 and K2 accounted for only 10 of 293 (3.5%) presentations.13 All our patients had recently been in Asia, which raises the possibility of exposure to these virulent strains of the organism. However, case reports from the US have involved emigrants from Vietnam and Korea who had not travelled home for some years.1 A third-generation cephalosporin such as ceftriaxone is usually an effective treatment, with good penetration of vitreous fluid and cerebrospinal fluid, allowing it to reach metastatic lesions in these locations.12 In the case of endophthalmitis, systemic antibiotics should be combined with intravitreal injections. Treatment is required until clinical state, biochemistry and radiology indicate resolution, often requiring antibiotics for 4 to 6 weeks. Another mainstay of therapy is computed tomography- or ultrasound-guided percutaneous abscess drainage. Surgical drainage may be necessary when percutaneous techniques have failed, as was seen in our Patients 3 and 4. Metastatic spread not uncommonly complicates KPLA; reports from Taiwan estimate the frequency of this at between 3.5% and 20%.12,14 Endophthalmitis, lung abscesses and meningitis are the more common complications. Ophthalmological and other organ review is therefore indicated when KPLA is diagnosed. Visual recovery in patients with endophthalmitis is often poor; a high index of suspicion and early intervention before visual changes are noted may improve outcome. Response to antibiotics and drainage is generally good. In contrast with patients with underlying biliary tract disease, long-term recurrence rates in patients with spontaneously occurring liver abscess appear to be low.15 Given the emerging global trend of K. pneumoniae liver abscesses, Australian clinicians should be mindful of this condition, particularly, but not exclusively, in patients of Asian origin with abdominal infection or whose cultures reveal this organism. In this setting, a hypermucoviscous isolate of K. pneumoniae may belong to serotype K1 or K2, and be associated with metastatic infection, particularly endophthalmitis, lung abscess and meningitis. 1 Clinical and microbiological details of four patients with community-acquired Klebsiella pneumoniae liver abscesses Patient 1 Patient 2 Patient 3 Patient 4 Year, state of presentation 2008, Victoria 2008, Victoria March 2008, Western Australia; Jan 2009, South Australia 2009, Northern Territory Demographics M; 33 y; Filipino-born; Victorian resident for 2 y F; 52 y; Malaysian-born; long-term Victorian resident F; 67 y; Malaysian-born; long-term SA resident M; 52 y; Chinese cargo ship sailor, passing through the NT Recent travel/contacts Lived with Filipino friends. Trip to Middle East via India 1 month prior Trip to Malaysia 6 weeks prior Trip to Malaysia between presentations Visiting from China Features on presentation 2 days of vomiting, myalgias, fevers and rigors; hypotension, mild epigastric tenderness, RUQ tenderness Several days of aches, rigors, diarrhoea; hypotensive, febrile 2008: 3 days of epigastric pain, low-grade fevers; 2009: 5 days of malaise, vomiting, RUQ pain 5 days of fever, jaundice, RUQ pain Notable investigations First abdominal U/S normal; CT of abdomen: 5 cm septate liver lesion (Box 2) Abdominal U/S: 9 cm multiloculated liver abscess; confirmed on CT of abdomen 2008: CT of abdomen: 3 cm liver lesion, near-resolved after 2 months; 2009: CT of abdomen: 6 cm liver abscess, progressed to 7.5 cm with central necrosis 1 week later CT abdomen: 8 cm multiloculated lesion Microbiology K. pneumoniae cultured on three sets of BC and abscess fluid; string test positive (Box 3) Resistant to ampicillin; sensitive to amoxicillin/clavulanic acid, ciprofloxacin, gentamicin K. pneumoniae BC and abscess fluid Resistant to ampicillin; sensitive to amoxicillin/clavulanic acid, ciprofloxacin, gentamicin 2008 and 2009: K. pneumoniae BC Resistant to ampicillin; sensitive to amoxicillin/clavulanic acid, cephazolin, ceftriaxone, gentamicin K. pneumoniae abscess fluid Resistant to ampicillin; sensitive to amoxicillin/clavulanic acid, cephazolin, ceftriaxone, gentamicin Serotype K1 K1 2008: isolate not serotyped; 2009: K2 K2 Drain/surgery Pigtail catheter Pigtail catheter 2008: no drainage; 2009: pigtail catheter then laparotomy for ongoing sepsis, with drainage of abscess and cholecystectomy Pigtail catheter, then laparotomy and chest drain Antibiotics Rationalised to ceftriaxone for 2 weeks; discharged on oral amoxicillin/clavulanic acid for 2 months Rationalised to ceftriaxone for 1 month; discharged on oral cotrimoxazole for 11 weeks (rash with ciprofloxacin) 2008: 1 week ceftriaxone then 5 days of amoxicillin/clavulanic acid; 2009: 3 weeks ceftriaxone then 1 week amoxicillin/clavulanic acid Initially timentin for 2 weeks; discharged on oral ciprofloxacin for at least 1 month Complications Brief acute renal impairment (creatinine to 180 μmol/L); 24 hours of septic shock requiring ICU 24 hours of septic shock requiring ICU 2009: 48 hours of septic shock requiring ICU Rupture through liver capsule and subphrenic collection and empyema, requiring laparotomy and chest drain BC = blood culture. CT = computed tomography. ICU = intensive care unit. RUQ = right upper quadrant. U/S = ultrasound. 2 Abdominal computed tomography scan showing a 5 cm abscess (arrow) in the right lobe of the liver in Patient 1 3 String test of a Klebsiella pneumoniae isolate demonstrating hypermucoviscosity Photo: Adam Jenney

James R Anstey MB BS · Timothy N Fazio · David L Gordon FRACP, FRCPA, PhD · Geoff Hogg BM BS, FRACP, FRCPA · Adam W Jenney MB BS, FRACP, PhD · Matthias Maiwald MD, FRCPA, D(ABMM) · Jonathan J Wilksch BSc(Hons)

To the Editor: Burger and colleagues reported the limitations of pre-August 2010 Pharmaceutical Benefits Scheme (PBS) criteria for subsidised anti-tumour necrosis factor-α (anti-TNF-α) treatment of perianal Crohn’s disease (CD).1 PBS-subsidised infliximab is now available for CD patients with a Crohn’s Disease Activity Index (CDAI) > 300 who have failed to achieve an adequate response to minimum doses of steroids and immunomodulators, and for patients with fistulising CD.2,4 In contrast with some Australian centres, our hospital has given infliximab to patients who fell outside these restrictions for indications for which clinical efficacy has been shown.1 We report on infliximab use and patient outcomes in patients with CD and ulcerative colitis (UC) since local PBS-subsidised use commenced in October 2008. Between October 2008 and February 2010, 57 patients at our hospital (44 with CD and 13 with UC) commenced infliximab treatment. Patients were assessed for remission status at 6–8 weeks after commencement of infliximab therapy (ie, after the induction course of three infusions). Twenty-four CD patients met PBS criteria. Of these, 12 achieved remission (CDAI < 150 [n = 8] or clinical remission on symptomatic grounds [n = 4]), eight showed clinical or endoscopic improvement justifying continued infliximab treatment, and four had no treatment response. Twenty CD patients did not meet PBS criteria. Of these, nine achieved remission (CDAI < 150 [n = 7] or clinical remission on symptomatic grounds [n = 2]), nine showed clinical or endoscopic improvement, and two had no treatment response. Reasons for not meeting PBS criteria were as follows: insufficient trial of prednisolone and an immunomodulator (10 patients, of whom 1 had no treatment response to infliximab); insufficient trial of an immunomodulator alone (7 patients, of whom 1 had no treatment response to infliximab); insufficient trial of prednisolone alone (2 patients); and CDAI < 300 (1 patient, who subsequently achieved clinical remission). Fourteen patients had perianal disease, of whom five did not meet PBS criteria. Of the 13 patients with UC, none were eligible for PBS-subsidised infliximab treatment. Six achieved, and remained in, clinical remission after a full infliximab induction course of three 5 mg/kg doses. Of the seven patients who did not, two initially responded but failed on reintroduction of treatment after an infliximab-free period. The other five had no response; three required colectomy. Our audit showed that less than half of patients receiving infliximab for inflammatory bowel disease fulfilled PBS guidelines for subsidised prescription, mostly because of relatively strict requirements for prior steroid and immunomodulator therapy, and the absence of UC as a listed indication. Furthermore, our CD patients who did not meet PBS criteria had similar treatment outcomes to those who did. Thus infliximab treatment can be of major benefit to patients with refractory disease whose only other treatment alternatives are experimental therapies or major surgery. Further revisions to PBS criteria for anti-TNF-α therapy, including relaxing restrictions for CD and providing access for patients with severe UC, are required.

Nicholas A Biehl · Janina Pawlik · Geoffrey M Forbes

Pancreatic exocrine insufficiency (PEI) occurs when the amounts of enzymes secreted into the duodenum in response to a meal are insufficient to maintain normal digestive processes. The main clinical consequence of PEI is fat maldigestion and malabsorption, resulting in steatorrhoea. Pancreatic exocrine function is commonly assessed by conducting a 3-day faecal fat test and by measuring levels of faecal elastase-1 and serum trypsinogen. Pancreatic enzyme replacement therapy is the mainstay of treatment for PEI. In adults, the initial recommended dose of pancreatic enzymes is 25 000 units of lipase per meal, titrating up to a maximum of 80 000 units of lipase per meal. In infants and children, the initial recommended dose of pancreatic enzymes is 500 units of lipase per gram of dietary fat; the maximum daily dose should not exceed 10 000 units of lipase per kilogram of bodyweight. Oral pancreatic enzymes should be taken with meals to ensure adequate mixing with the chyme. Adjunct therapy with acid-suppressing agents may be useful in patients who continue to experience symptoms of PEI despite high-dose enzyme therapy. A dietitian experienced in treating PEI should be involved in patient management. Dietary fat restriction is not recommended for patients with PEI. Patients with PEI should be encouraged to consume small, frequent meals and to abstain from alcohol. Medium-chain triglycerides do not provide any clear nutritional advantage over long-chain triglycerides, but can be trialled in patients who fail to gain or to maintain adequate bodyweight in order to increase energy intake.

James Toouli MB BS, FRACS, PhD · Andrew V Biankin MB BS, PhD, FRACS · Mark R Oliver MB BS, MD, FRACP · Callum B Pearce MB ChB, MD, FRACP · Jeremy S Wilson MD, FRACP, FRCP · Nicholas H Wray MND, BAppSc(ExSportSc), APD

IgG4-related systemic disease (IRSD) is a recently described entity with protean manifestations. We describe a patient who developed inflammation and fibrosis in multiple organs over 20 years, sequentially involving his pancreas, bile ducts, gallbladder, submandibular and lacrimal glands, and kidneys. He had an elevated serum IgG4 level. Retrospective analysis of biopsies showed strongly positive tissue immunostaining for IgG4, confirming the diagnosis of IRSD. This case illustrates the natural history of partially treated IRSD and its varied clinical presentations. Early diagnosis and treatment is important, as the condition is highly steroid-responsive. Clinical recordA 55-year-old man who abstained from drinking alcohol and was not taking any medications initially presented to a hepatobiliary surgeon in 1989 for recurrent abdominal pain and jaundice. On examination, he was icteric, with mild epigastric tenderness, but was afebrile and had no other signs of chronic liver disease. His serum amylase level was mildly elevated, and results of liver function tests (LFTs) showed abnormal levels of albumin (29 g/L; reference range [RR], 36–48 g/L), alkaline phosphatase (284 U/L; RR, 32–91 U/L), γ-glutamyltransferase (98 U/L; RR, < 38 U/L), alanine transaminase (50 U/L; RR, < 34 U/L) and bilirubin (102 μmol/L; RR, < 18 μmol/L). An abdominal computed tomography (CT) scan showed a 6 cm mass in the head of the pancreas consistent with a carcinoma. At laparotomy, his pancreas was noted to be hard and thickened. An intraoperative cholangiogram revealed multiple bile duct strictures. A cholecystectomy and side-to-side choledochojejunostomy were performed. Biopsy of the pancreatic mass showed mature fibrocollagenous connective tissue with scattered plasma cells, but no evidence of malignancy. The liver biopsy showed features consistent with large bile duct obstruction. Histological examination of the cystic duct and gallbladder showed diffuse lymphoplasmacytic infiltration, with intervening areas of dense fibrosis, causing marked wall thickening (Box 1, A). No gallstones were found. Rectal biopsies performed later were normal, excluding ulcerative colitis. A diagnosis of chronic idiopathic pancreatitis and primary sclerosing cholangitis (PSC) was made. His symptoms waxed and waned with no specific treatment. In 1993, the patient presented to a rheumatologist with dry mouth, without dry eyes, and was noted to have bilateral submandibular gland swelling and exophthalmos from bilateral lacrimal gland enlargement. He was otherwise well, with no history of rash, myalgia or arthritis. His erythrocyte sedimentation rate (ESR) was 29 mm/h (RR, 7–18 mm/h). No antinuclear antibodies or antineutrophil cytoplasmic antibodies were detected. A percutaneous Trucut biopsy of the submandibular gland showed a dense lymphoplasmacytic infiltrate and prominent fibrosis. Lymphoepithelial lesions were present without morphological features of lymphoma. A diagnosis of seronegative Sjögren’s syndrome was made, and the patient was given a trial of steroid treatment, starting with 30 mg of prednisolone daily. His exophthalmos and submandibular gland swelling resolved over 3 months, and no abnormality was seen on a repeat orbital CT scan. Incidentally, his abdominal pain resolved and his LFT results returned to normal. The prednisolone dose was reduced over 12 months to 5 mg/day. In 2002, with a serum creatinine level of 180 μmol/L (RR, 64–104 μmol/L) and a urea level of 13.5 mmol/L (RR, 2.5–8.3 mmol/L), the patient was referred to a nephrologist. Antinuclear antibodies were detected at a high titre of 1 : 640, and his ESR was 45 mm/h. The patient had eosinophilia (0.9 × 109 cells/L; RR, 0–0.5 × 109 cells/L), with an otherwise normal full blood count. His serum IgE level was normal. His spot urine protein–creatinine ratio was 89 mg/mmol (RR, 15–35 mg/mmol), consistent with proteinuria. A renal biopsy showed interstitial oedema; marked fibrosis with a dense infiltrate of lymphocytes, plasma cells and eosinophils; and moderate tubular atrophy, indicating severe active chronic tubulointerstitial nephritis. The patient’s prednisolone dose was increased to 60 mg/day, resulting in a dramatic improvement in renal function and normalisation of the spot urine protein–creatinine ratio. His steroid dose was tapered over the next few years. In 2009, the patient was referred to our gastroenterology clinic. His history of a benign pancreatic mass with biliary strictures was typical for autoimmune pancreatitis, and a diagnosis of IgG4-related systemic disease (IRSD) was considered. His IgG level was elevated (23.3 g/L; RR, 5.0–16.0 g/L), but IgM and IgA levels were in the normal range. In particular, the IgG4 subclass was markedly elevated, at 12.2 g/L (RR, 0.04–0.86 g/L). Levels of all other IgG subclasses fell within the normal range. The patient’s earlier biopsy samples were retrieved and immunostained for IgG4 using a recently commercially available monoclonal antibody (Zymed Laboratories Inc, San Francisco, Calif, USA). Strongly positive immunostaining for IgG4 was seen in the gallbladder, cystic duct (Box 1, B), submandibular gland (Box 2, A), lacrimal gland and kidney (Box 2, B) biopsies compared with control staining for total IgG. The proportions of IgG4-positive plasma cells (relative to total IgG-positive plasma cells) in the cystic duct, submandibular gland and kidney were 89%, 45% and 66%, respectively. These high proportions of IgG4-positive plasma cells (> 40%) confirmed the diagnosis of IRSD.1 DiscussionRecurrent abdominal pain and elevated serum amylase levels had first developed in our patient 20 years previously. He was given the diagnosis of chronic idiopathic pancreatitis, as the concept of autoimmune pancreatitis was not reported until 5 years later.2 Autoimmune pancreatitis may present with recurrent abdominal pain and jaundice, and a pancreatic mass indicative of carcinoma is commonly seen on imaging. The diagnosis of autoimmune pancreatitis can be suggested by an elevated serum IgG4 level3 and confirmed by biopsy showing a dense lymphoplasmacytic infiltrate with numerous IgG4-positive plasma cells.1,4 Patients usually respond well to treatment with steroids. Our patient’s cholestatic LFT results and biliary strictures were ascribed to PSC. However, gallbladder and cystic duct histology revealed a lymphoplasmacytic infiltrate rich in IgG4-positive cells with associated obliterative phlebitis, typical of lymphoplasmacytic sclerosing cholangitis.5 An elevated serum IgG4 level is seen in 75% of patients with this condition, and steroid therapy usually normalises LFT results and biliary strictures, a feature not seen in PSC.6 Our patient also had chronic sclerosing cholecystitis. Although our patient’s chronic sclerosing sialadenitis and dacryoadenitis were attributed to Sjögren’s syndrome, his exocrine gland histology was more consistent with Mikulicz’s disease, which differs from Sjögren’s syndrome both clinically and histopathologically. Mikulicz’s disease is associated with prominent infiltration of IgG4-positive plasma cells into lacrimal and salivary glands, as well as a favourable response to corticosteroid treatment.7 Also, lacrimal gland tear production is preserved in Mikulicz’s disease but not in Sjögren’s syndrome,8 as was noted in our patient. Tubulointerstitial nephritis is the most common form of IgG4-related renal disease. Characteristically, the renal tubulointerstitium is infiltrated by large numbers of IgG4-positive plasma cells and eosinophils, resulting in cortical fibrosis and tubular atrophy.9 This condition is frequently associated with eosinophilia and proteinuria, and responds well to high-dose corticosteroid treatment, leading to improved renal function and reduced proteinuria. IgG4-associated membranoproliferative glomerulonephritis has also been reported. IRSD can manifest in varied clinical presentations (Box 3), unified by characteristic histological findings of diffuse IgG4-positive plasma cell infiltration of multiple organs, resulting in obliterative phlebitis and tissue fibrosis.10 Our case illustrates the potentially chronic natural history of partially treated IRSD leading to presentations to different medical specialists over 20 years, emphasising the importance of diagnosing IRSD in order to institute treatment with steroids. Competing interestsNone identified. 1 Biopsy samples of the patient’s cystic duct A: Cystic duct biopsy sample showing thickening of the wall, with a diffuse dense lymphoplasmacytic infiltrate accompanied by fibrosis (haematoxylin–eosin stain; original magnification, × 20). B: Cystic duct biopsy sample showing numerous IgG4-immunopositive plasma cells (monoclonal antibody stain; original magnification, × 400). 2 Biopsy samples of the patient’s submandibular gland and kidney Biopsy samples showing numerous IgG4-immunopositive plasma cells (monoclonal antibody stain). A: Submandibular gland (original magnification, × 200). B: Kidney (original magnification, × 400). 3 Manifestations of IgG4-related systemic disease Autoimmune pancreatitis* Lymphoplasmacytic sclerosing cholangitis* Lymphoplasmacytic sclerosing cholecystitis* Chronic sclerosing sialadenitis* Chronic sclerosing dacryoadenitis* Chronic tubulointerstitial nephritis* Membranoproliferative glomerulonephritis Autoimmune hepatitis Riedel’s thyroiditis Interstitial pneumonia Pseudotumours of the lung Lymphoplasmacytic aortitis Hypophysitis resulting in hypopituitarism or diabetes insipidus * Feature was present in our patient.

Eu Jin Lim MB BS · Prithi S Bhathal MB BS, FRCPA · Peter P Tagkalidis MB BS, PhD, FRACP · Antony G Speer MB BS, FRACP

Identifying the emerging threats for which we must be vigilant In 1922, infectious diseases accounted for 15% of all deaths in Australia, but this rate declined dramatically to 1% by 2007 due to a combination of antibiotics, vaccination and public health measures. Yet infectious diseases continue to feature prominently in Australia. The Australian Institute of Health and Welfare has just released its biennial publication on the health of the nation, Australia’s health 2010 — a statistical and informed commentary that examines a variety of health issues dominating the national landscape.1 Here, I summarise the report’s chapter on infectious diseases to paint a picture of where we are today and the challenges we may well face in our future. Among vaccine-preventable diseases, invasive meningococcal disease remains one of the most feared. However, notification data continue to show a pleasing trend of decreasing cases annually.1 Much of this decline can presumably be attributed to the introduction of the meningococcal C conjugate vaccination program in 2003.2 Not surprisingly, cases of the B strain, for which there is no vaccine, dominate the notifications, although numbers have been stable and certainly haven’t increased. Similarly, rates of invasive pneumococcal disease remain steady and well below those seen before the introduction of universal infant vaccination in 2005.1 Concerns continue that there will be a surge of invasive pneumococcal disease due to non-vaccine serotypes — so-called serotype replacement — following introduction of the conjugate vaccination program that will offset any reductions from the program; however, this has not yet happened. Pertussis notifications reached unprecedented levels in 2008 and 2009, with a particularly large increase in the proportion of cases in 0–4-year-olds — the group most vulnerable to severe disease from pertussis.1 Yet it is likely that this increase in notifications can at least partly be explained by increased testing and easier access to better tests, such as polymerase chain reaction (PCR). The world experienced its first influenza pandemic in 41 years with the outbreak of pandemic (H1N1) 2009 influenza (popularly known as “swine flu”). There were over 45 000 laboratory-confirmed notifications of influenza in Australia in 2009, eclipsing those of previous years — by comparison, in 2007, the other severe influenza year in recent times, there were 10 445 notifications. However, there was undoubtedly more testing conducted in 2009. The figure shown in the Box elegantly demonstrates how the swine flu virus behaved like a typical pandemic strain, predominantly affecting adolescents and young adults, while the 2008 “standard” seasonal strain mainly targeted people at the extremes of age.1 Although pandemic influenza has had the highest profile in recent times, chlamydia, with over 62 000 notifications, was the most highly notified infection in Australia in 2009 and remains an important issue among the sexually active. However, as with pertussis and influenza, increased testing has almost certainly contributed to the large number of infections seen recently.1 From 2000 to 2009, there was a decline in rates of newly diagnosed hepatitis B and C infections. Particularly among adolescents and young adults, this decline may be due to factors such as a reduction in injecting drug use and a vaccination program for adolescents against hepatitis B infection. Despite this, however, chronic hepatitis B and C infections are looming as long-term challenges for Australia.1 One model predicts that the 2008 figure of 187 000 people living in Australia with chronic hepatitis B infection could markedly increase to 276 000 cases in 2017 if current practices and resources remain unchanged. This would be associated with a large increase in hepatitis B-related deaths, including those from hepatocellular cancer.3 It is estimated that 212 000 people were living with chronic hepatitis C infection in Australia in 2008, and these people are at risk of similar chronic sequelae as those with chronic hepatitis B infection.4 Challenges include increasing awareness of the diseases and improving access to treatment for affected people, many of whom are from marginalised groups (eg, non-English speaking migrants, Indigenous Australians and injecting drug users). The federal government has responded to these challenges by releasing its first national hepatitis B strategy and third national hepatitis C strategy.4,5 A dengue outbreak featured prominently in northern Queensland between November 2008 and June 2009. Around 1000 cases occurred during this 8-month period, matching the total for the preceding 9 years. The outbreak was characterised by all four strains of dengue circulating, including a virulent DENV-3 strain that had a shorter incubation period within both mosquitoes and humans.1 Hendra virus infection remains unique to Queensland, where outbreaks continue to occur, causing much angst among the public and communicable disease services alike. In 2008 and 2009, Hendra virus, which is transmitted to humans from infected horses, caused the deaths of two veterinary workers.1 There are two emerging infections of concern in Australia. First, hypervirulent Clostridium difficile (also known as PCR ribotype 027 or NAP1) infection has become well established in the health care systems of many northern hemisphere nations in recent years, with high case-fatality and bowel-resection rates. Although a milder form of the infection has been well established here for years, Australia had remained free of this particular hypervirulent strain until our first imported case was detected in Western Australia in 2009.6 This was followed in May 2010 by an outbreak among patients in a Melbourne hospital,7 raising concerns that it may become established in Victoria before spreading elsewhere. Second, the appearance of multiresistant gram-negative organisms such as Escherichia coli in returning travellers, especially those arriving from Asia, is of concern. Although colonisation with these organisms in the bowel is asymptomatic, the problem arises when they cause symptomatic illness, typically in the urinary tract. Few antibiotics are available to treat such infections, and they are often expensive (eg, carbapenems) or dangerous (eg, potential nephrotoxicity and ototoxicity from amikacin). One study found that, while 8% of travellers were colonised with multiresistant E. coli before leaving Australia, almost 50% were colonised on their return.1,8 (It appears that Customs officials may have to worry about more than concealed drugs in travellers’ bowels on their return to Australia!) The health inequities experienced by Australia’s Indigenous peoples are well recognised and apply to many infectious diseases. One example is acute rheumatic fever and rheumatic heart disease. Indigenous people in the Northern Territory have one of the highest rates in the world of these conditions and are around 20 times more likely to die from rheumatic heart disease than non-Indigenous Australians.9 Despite the advances in combating acute and chronic infectious diseases over the past century, both continue to present challenges to our health system, especially for certain Indigenous populations. Multiresistant gram-negative bacterial infections acquired from overseas and hypervirulent C. difficile infection are emerging threats in Australia for which we must be vigilant. This is in addition to infections caused by the already established multi-resistant nosocomial pathogens such as vancomycin-resistant enterococci. The need to isolate affected patients and use expensive antibiotics to treat them only further burdens the hospital system. A mandatory reporting system for certain hospital-acquired infections could be one way to address this. Although childhood immunisation programs have generally been successful, we need to be watchful for resurgent infections, such as pertussis, where immunity from childhood vaccination has waned. Finally, as last year’s swine flu outbreak demonstrated, a pandemic has the potential to consume considerable resources and generate widespread concern. While the 2009 influenza outbreak has passed, the potential for further pandemics and the need to prepare for them persist. Avian influenza, which continues to cause human infections overseas, immediately comes to mind in this regard. Age distribution of influenza notifications in a pandemic year (2009) versus a standard seasonal year (2008)* * Reproduced from Australia’s health 2010 with permission of the Australian Institute of Health and Welfare.1

Sanjaya N Senanayake FRACP, MAppEpid, MB BS

A 38-year-old woman presented with sudden onset of haematemesis and melaena. She had no abdominal pain or jaundice, and she had not taken drugs before the bleed. On examination, she had cutaneous features of neurofibromatosis (Figure, A). Upper gastrointestinal endoscopy showed a smooth polypoidal mass, with central umbilication, in the body of stomach (Figure, B). A contrast-enhanced computed tomography scan of the abdomen showed an exophytic mass confined to the stomach. Following another haematemesis, the patient underwent an emergency sleeve resection of the mass. Histopathological examination of the removed tissue revealed spindle-shaped neoplastic cells with elongated nuclei arranged in fascicles (Figure, C), and immunostaining (Figure, D) was positive for CD117 (c-KIT), confirming gastrointestinal stromal tumour (GIST). The prevalence of GIST in neurofibromatosis type 1 (NF1) varies between 4% and 25%.1 The clinical presentation of GIST associated with NF1 is similar to sporadic GIST but differs in being multiple; large, often involving the small intestine; and having a favourable prognosis.1 Several cutaneous syndromes are associated with gastrointestinal haemorrhage as a prominent feature. Prompt recognition of these disorders is required as early intervention can be life saving.

Pazhanivel Mohan · Mohan Kaduganoor Ramakrishnan · Jayanthi Venkataraman

Neuroendocrine tumours (NETs) are increasing in both incidence and prevalence and, as a group, are more prevalent than either gastric, pancreatic, oesophageal or hepatobiliary adenocarcinomas, or any two of these cancers combined. Clinical awareness of the protean and intermittent symptoms of NETs (eg, sweating, flushing, diarrhoea, and bronchospasm) is critical for timely diagnosis; however, the classical carcinoid syndrome is relatively uncommon. The most useful diagnostic test for gastrointestinal NETs is measurement of plasma chromogranin A (CgA) levels. Disease extent is assessed by both anatomical imaging, and nuclear imaging with radiolabelled somatostatin analogues. Pathological evaluation comprises tumour–node–metastasis classification, a minimum pathological dataset, CgA and synaptophysin immunostaining, as well as mitotic count or Ki-67 index (a marker of cell proliferation) to define grading. Resection of the primary lesion and as much metastatic disease as possible increases the efficacy of medical therapy. Other management strategies include hepatic embolisation and peptide receptor radionuclide therapy. Patients with tumours expressing somatostatin receptors should be treated with somatostatin analogues. Depending on the tumour grade, other effective agents include cytotoxics, tyrosine kinase inhibitors, and antiangiogenics. The overarching requirement for best management of patients with NETs is to ensure that they have ready access to experienced multidisciplinary clinician groups located within centres of appropriate subspecialty expertise.

Irvin M Modlin MD, PhD, DSc · Steven F Moss MB BS, MD, MRCP · Kjell Oberg MD, PhD · Robert Padbury MB BS, PhD, FRACS · Rodney J Hicks MB BS, MD, FRACP · Bjorn I Gustafsson MD, PhD · Nicholas A Wright MD, PhD · Mark Kidd PhD