Infectious diseases

To the Editor: Australian bat lyssavirus (ABL) has the potential to cause fatal encephalitis in humans exposed to infection through bat bites or scratches. There is no cure for rabies currently available, so postexposure prophylaxis with rabies vaccine and rabies immune globulin is recommended following potential human exposure, such as after bites or scratches. People who work with or handle bats should be vaccinated, should regularly monitor their rabies antibody levels to ensure maximum protection, and should seek immediate medical attention for all potential ABL exposures.1 We report the case of a 42-year-old man bitten by a black flying fox (Pteropus alecto) during the retrieval of the bat from a suburban Brisbane, Queensland, backyard. The bat had been found on the ground in the daytime, vocalising and acting aggressively. The patient was a member of a local organisation which cares for injured bats. The Logan and West Moreton Public Health Unit was notified the day after the incident. The patient reported that he had been vaccinated against rabies previously, and that his rabies virus-neutralising antibody titres were adequate. However, the patient’s available titres were below 0.50 IU/mL in 2002 and 0.43 IU/mL in 2008 (no boosters were given), both of which were below the World Health Organization recommended level that confers protection against rabies virus.2 The bat was euthanased for testing (because it had bitten a person, as per Qld Health protocol), and tests on the brain tissue showed it to be reactive for lyssavirus antigen (using an immuno-fluorescence antibody test) and lyssavirus RNA (using a TaqMan assay). In view of the patient’s recent serological tests indicating subprotective antibody levels and definite exposure to an ABL-positive bat, he was given postexposure prophylaxis comprising rabies immune globulin into the wound and five doses of rabies vaccine. He is currently well. The Public Health Unit determined that others were not potentially exposed to the bat. The prompt reporting of all potential ABL exposures to public health units is especially important because bat carers may underreport potential ABL exposures.3 Current guidelines recommend that bat carers with ongoing potential exposure to ABL should check their rabies virus-neutralising antibody titres every 2 years and have a booster if the titre is reported as inadequate (< 0.5 IU/mL). Alternatively, booster doses may be offered every 2 years without determining antibody levels.1 Further education of the bat-handling community and their doctors is necessary to maintain awareness and best practice to protect the people who do this potentially dangerous work.

Heidi J Carroll · Bradley J McCall · David Looke · Bruce Fraser

To the Editor: Recent media reports queried whether Australia could experience a serious outbreak of foodborne disease, such as the massive outbreak in May this year of Shiga toxin-producing Escherichia coli (STEC) serotype O104:H4 in Germany.1 Australia is potentially vulnerable to foodborne disease outbreaks from contaminated fresh produce, and health and food safety authorities need to plan for these events and assess our capacity to respond. Australian health agencies investigate 100–150 outbreaks of foodborne illness each year, although < 10% are associated with fresh produce.2 Australia has a very high-quality food supply, but we are still vulnerable to outbreaks. In 1991, norovirus-contaminated orange juice served by airlines infected 25 000 people, despite the juice being sourced from a single small factory.2 Foodborne outbreaks can become very large and spread internationally before health agencies identify a vehicle of transmission. In 2009–2010, an outbreak of hepatitis A infection in more than 400 people in multiple Australian states, France and the Netherlands was associated with consumption of semidried tomatoes from Turkey.3 The recent outbreak of STEC O104:H4 also occurred in other European countries and was associated with a common source of fenugreek seeds used for growing sprouts.4 Seed sprouts have caused many outbreaks of foodborne illness, including two outbreaks of Salmonella Oranienburg in Western Australia and Victoria in 2005–2006 where alfalfa sprouts were implicated.2 STEC outbreaks overseas have implicated seeds originating from Australia.5 Seeds may become contaminated during plant growth, particularly due to livestock and feral animal grazing, or during storage, neither of which can be effectively controlled by disinfection at sprouting facilities.5 In light of the recent European STEC outbreak, Australian food safety agencies should urgently assess the risks posed to the food supply by sprouted seeds. Australia does have well functioning plans to respond to multijurisdictional outbreaks and national food safety incidents,2 but has not had to respond to a massive outbreak. German investigators reported 3222 outbreak cases of STEC, including 810 cases of haemolytic–uraemic syndrome, in less than 2 months.1 The health system resources required to manage such an outbreak would be immense and costly. In Australia, treatment and other costs for two cases of haemolytic–uraemic syndrome totalled an estimated $14 000 each, despite neither patient requiring dialysis, developing end-stage renal disease or requiring a transplant.6 As with other national plans for responding to epidemics, government agencies need to ensure that possible impacts on the health system and industry are taken into account.

Martyn D Kirk

To the Editor: Echoing Scott and colleagues’ recent call for caution regarding the use of hospital standardised mortality ratios for benchmarking and public reporting,1 we have concerns about the use of infection rates as hospital quality indicators. The National Healthcare Safety Network (NHSN) at the United States Centers for Disease Control and Prevention defines central line-associated bloodstream infection (CLABSI) as occurring where the patient has “a recognized pathogen cultured from 1 or more blood cultures and organism cultured from blood is not related to an infection at another site”.2 This and other criteria (for organisms associated with skin contamination and in children) are also used as quality indicators by VICNISS (the Victorian hospital-acquired infection surveillance system) and the Australian Commission for Safety and Quality in Health Care. The infection prevention unit at Alfred Health in Melbourne recently assessed three cases of hospital-acquired bacteraemia as having met the NHSN/VICNISS definition of CLABSI. This assessment was disputed by Alfred Health’s intensive care unit and we sought further opinions from other infectious diseases physicians and infection control practitioners to adjudicate, in the absence of established criteria to determine whether the bacteraemia was due to infection at a site other than the central line. We received conflicting advice. These three cases would have comprised a third of the CLABSI cases at our hospital in the 6 months to April 2011, and thus significantly impact on our reported quality assurance indicators. Similar common situations may arise in considering cases of bacteraemia in patients who have central lines in the context of chemotherapy-related mucositis; in patients with extensive burns; where cultures are only taken from central lines (rather than from peripheral venepuncture); where there are single blood cultures of enterococci of doubtful clinical significance; and where there are unconfirmed clinical foci of deep infection.3 Previous published work suggests that interrater agreement remains poor, despite changes to the definition of CLABSI.4 Other infection rates are associated with other problems as outlined by Scott and colleagues.1 For example, the current NHSN risk stratification system for infection (http://www.vicniss.org.au/Resources/HCWType1Manual/Type1Manualv6_0708.pdf) related to coronary artery graft surgery is poorly discriminatory, as most patients fall into risk index categories 1 or 2, and statistical calibration of this system is poor.5 Interrater reliability of classification of superficial infections has also been shown to be poor.6 The relatively low rate of infections in patients undergoing coronary artery surgery may result in large stochastic variation, particularly in hospitals performing relatively few such procedures. Public reporting of infection rates is probably inevitable. However, such data should be restricted to indicators that have been shown to validly reflect preventable infections, using definitions that are reliable, and with the appropriate caveats regarding their limitations.

Allen C Cheng · Pauline Bass · Carlos Scheinkestel · Tim Leong

Objective: To review the uptake of seasonal influenza vaccination among hospital health care workers (HCWs) in Australia to date.Data sources: We searched MEDLINE and EMBASE (up to September 2010) and bibliographies of relevant reports for studies examining seasonal influenza vaccination (uptake, attitudes and/or programs) among Australian hospital HCWs. Studies relating to pandemic (H1N1) 2009 influenza vaccination or other types of health care facilities were excluded.Study selection: 15 articles were assessed, of which 10 met inclusion criteria.Data synthesis: The 10 studies were conducted between 1997 and 2008 and reported vaccination rates of hospital HCWs of 16.3%–58.7%. Two of three studies documenting uptake rates of > 50% were associated with active implementation of vaccination policies or interventions. Uptake rates by occupational group ranged from 29% to 58.3% for physicians, 19% to 56.4% for nurses, 23% to 57.7% for allied health professionals, and 18% to 66.7% for ancillary or support staff. Coverage rates in hospitals that provided the vaccine free of charge to staff (with or without an informational campaign) were no higher than in other hospitals.Conclusion: While seasonal influenza vaccination uptake was higher in hospitals with documented intervention programs, coverage is still low and does not appear to be affected by the provision of free vaccine to staff. State or institutional policies or mandates are likely needed to increase HCW uptake of seasonal influenza vaccination.

Holly Seale BSc, MPH, PhD · C Raina MacIntyre MB BS, PhD, FAFPHM

Low infectivity but high mortality: strategies to minimise spread until the vaccine arrives are the key Hendra virus (HeV) infection in humans is an emerging zoonotic disease that has a high mortality rate, but low infectivity. In all cases to date, the infection has been transmitted to humans from bats of the genus Pteropus (flying foxes) via an intermediate equine host. HeV and Nipah virus are the only known members of a new genus, Henipavirus, within the family Paramyxoviridae. HeV was first described after an outbreak of severe respiratory disease in horses that led to the deaths of 14 of 20 infected horses and the death of a horse trainer — one of two humans infected — in Brisbane in 1994.2 There have been seven cases of HeV infection producing pneumonic or encephalitic illnesses in humans. Four of these people died, three soon after exposure and the fourth from fatal encephalitis caused by HeV, which developed 13 months after full recovery from an initial aseptic meningitis.3 Of the three survivors, two made complete recoveries while the third experienced ongoing complications of the initial encephalitis.4,5 Subsequent serological testing for HeV in a large number of human contacts of the first three cases of HeV infection was completely negative.6 Before 2011, there had been 14 events of spillover of HeV infection from flying foxes to horses, and subsequent transmission to humans in five of these events. All events occurred in coastal Queensland except for one in northern New South Wales. Forty-four horses were infected; 34 of these (75%) died and the remaining 10 survived but were later euthanased. Seroepidemiological studies of more than 2000 horses and more than 5000 samples from 46 other animal species in Queensland did not identify HeV infection.7 Spillover events have occurred through most months of the year, but with increased frequency from June to September. The virus can survive under ideal cool and moist environmental conditions (eg, in bat urine at 22°C in the laboratory) for up to 4 days, but is generally thought to survive for only hours. Horses are thought to be infected by ingesting food or water contaminated by urine, saliva or birthing products of infected flying foxes. The virus amplifies within the horse, and humans who are exposed to a large amount of the secretions or blood from an infected horse can become infected. Laboratory studies have shown that horses may excrete virus for up to 72 hours before showing clinical signs.8 All seven humans infected with HeV to date had high levels of exposure to body fluids of infected horses, such as during unprotected autopsy or by direct contact with respiratory secretions or aerosols. Not all people with high-level exposure have contracted the disease or seroconverted. There is no evidence that prolonged close contact with flying foxes engenders a risk of HeV infection in humans.9 A wide range of mammals carry the appropriate receptor enabling them to be infected with HeV experimentally.10 Yet, although HeV infects the endothelium of blood vessels in many species in the laboratory, resulting in systemic vasculitis, outside the laboratory setting, only flying foxes, horses and humans are known to have been infected. One dog is known to have seroconverted without any clinical illness or detection of virus. Flying foxes were identified as the natural host in 1996, and antibodies to HeV have been found in archived samples of flying fox serum dating back to 1982.11 Flying foxes do not develop overt disease. All four species of flying fox in Australia, from as far north as Madang in Papua New Guinea to as far south as Melbourne, have been found to carry the virus.12 HeV is genetically stable, and there is no evidence that the virus has changed significantly since it was first isolated in 1994.8 This year has been a major year for the detection of spillovers of HeV into horses, with 14 events being notified by 17 August. Eight of these occurred in Queensland, with one being the first event notified west of the Great Dividing Range, in Chinchilla. Ten horses had been infected in Queensland and, for the first time, a dog has seroconverted, probably through contact with an infected horse. Six spillover events had occurred in northern NSW, with seven horses becoming infected. No humans have been infected this year to date, although not all of those potentially exposed have reached the end of their incubation periods; no one had a high degree of exposure to infected secretions. The incubation period in humans is 5 to 21 days. The clinical presentation has been variable, with both respiratory and encephalitic symptoms. There has been no transmission of HeV between people, but routine droplet precautions are advised. There is no known effective treatment for Hendra virus infection, and clinical management is based on treating symptoms as they arise. When a person has had high-level exposure to body fluids of infected horses, an experimental human monoclonal antibody (mAb) can be made available for postexposure prophylaxis. Henipavirus mAb has been shown to be effective in preventing infection in ferrets if administered within 12 hours of intrathecal injection of a high dose of HeV.13 However, this product has not yet been trialled for safety or efficacy in humans. It has been administered to three humans. The first person was late into the progression of severe encephalitis and subsequently died. The second two had moderately high-risk exposure, but no evidence of infection, and they did not develop illness or seroconvert. Currently, despite its unknown safety or efficacy, mAb is offered to people who have had high-level exposure to infected horse blood or secretions, after obtaining ethics approval and appropriate consent for each individual. Preventive measures are essential. Horse owners are advised to keep horses away from flowering and fruiting trees, and to remove feed and water troughs from under trees. Vets are advised to wear appropriate personal protective equipment when attending a sick horse or when performing invasive or aerosol-generating procedures on any horse. Horse owners and the public are advised to isolate sick horses from people, horses and other animals. The most promising prospect for controlling HeV outbreaks in humans is the vaccine for horses that is expected to be marketed in 2013.14

Jeannette R Young MB BS, FRACMA, FFPH · Christine E Selvey MB BS, MSc · Rick Symons DSC, PhD, MACVS

To the Editor: Kelly and colleagues are to be applauded for their call for a no-fault compensation scheme.1 If only such a scheme had been available in the early 1960s, when my sister (who has approved this letter) developed encephalitis secondary to a vaccinia inoculation. Then she, and our parents, would have been spared decades of struggling with the sequelae of this acquired brain injury in a “fault averse” system. The few who have been seriously harmed should not be forgotten by the millions who have benefited.

Mark R Nelson

Objective: To determine the prevalence of multiresistant organism (MRO) colonisation of reusable venesection tourniquets.Design and setting: A prospective study in a tertiary hospital to collect and analyse reusable venesection tourniquets for the presence of MROs — methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and extended-spectrum β-lactamase and metallo-β-lactamase-producing Enterobacteriaceae — using a sensitive enrichment method. Tourniquets were collected and tested during a 10-week period between September and November 2010.Main outcome measure: Prevalence of MRO colonisation of tourniquets.Results: The overall colonisation rate of 100 tourniquets randomly collected from general wards, ambulatory care areas and critical care areas was 78%. MROs were isolated from 25 tourniquets collected from a variety of hospital locations, including general wards, the intensive care unit, burns unit and anaesthetic bay. MRSA was isolated from 14 tourniquets and VRE from 19; both MRSA and VRE were isolated from nine tourniquets. There were no microorganisms isolated from 22 tourniquets.Conclusion: Reusable tourniquets can be colonised with MROs and may be a potential source of transmission of MROs to hospitalised patients.

Angie N Pinto MB BS, BSc, MPHTM · Thuy Phan BSc · Gabriela Sala BSc · Elaine Y L Cheong FRACP, FRCPA · Steven Siarakas BSc, PhD · Thomas Gottlieb FRACP, FRCPA

A 10-year-old boy from Papua New Guinea with multidrug-resistant tuberculosis and multibacillary leprosy developed acute glomerulonephritis while being treated as an inpatient at Thursday Island Hospital in the Torres Strait, Queensland. This is the first such case to be reported in Australia, where these diseases are uncommon and the combination is extremely rare, and it outlines important learning points regarding the aetiology of renal disease among patients with tuberculosis and leprosy. (MJA 2011; 195: 150-152) Clinical recordA 10-year-old boy from a remote village in Western Province, Papua New Guinea (PNG), presented to Saibai Island Primary Health Centre in the northern Torres Strait, Queensland, with a 4-year history of intermittent malaise, fevers, night sweats, recurrent skin sores and a cough productive of green sputum. He had received treatment for leprosy for 1 month the previous year at Daru Hospital (Western Province, PNG). There was a strong family history of leprosy and tuberculosis among both first- and second-degree relatives. On initial examination, the patient appeared cachectic. There was evidence of recent impetigo on both lower limbs and depigmented areas on his upper and lower limbs. He had thickened ulnar and posterior tibial nerves bilaterally, with normal sensation and motor function on repeated clinical assessments. His lungfields were clear to auscultation, but he had an ejection systolic murmur; he was also found to have hepatomegaly and enlarged inguinal, anterior and posterior cervical lymph nodes. He was transferred to Thursday Island Hospital for inpatient management. Slit skin smears were performed; phenotypic analysis of the right earlobe smear was positive for Mycobacterium leprae, confirming the diagnosis of multibacillary leprosy.1 An initial chest x-ray showed left upper lobe changes consistent with pulmonary tuberculosis; subsequent sputum samples and an aspirate of an anterior cervical lymph node cultured Mycobacterium tuberculosis resistant to rifampicin, isoniazid, streptomycin and ethionamide, in keeping with a diagnosis of disseminated multidrug-resistant tuberculosis (MDR-TB).2 HIV and hepatitis serological tests were negative. On admission, his serum creatinine level was 30 μmol/L (reference range [RR], 46–81 μmol/L). The patient was given intravenous amikacin and oral moxifloxacin, isoniazid, pyrazinamide, ethambutol, pyridoxine and rifampicin; cycloserine, aminosalicylic acid (mesalazine), dapsone and clofazimine were later added. One week after admission, the patient developed acute glomerulonephritis, which manifested as fluid retention (pulmonary oedema, peripheral oedema and ascites), hypertension (maximum blood pressure, 160/112 mmHg), haematuria, proteinuria (up to 9700 mg/L [RR, < 100 mg/L]) and impaired kidney function (serum creatinine level peaked at 69 μmol/L). He was treated with frusemide, nifedipine and prednisolone. There was serological evidence of recent infection with Streptococcus pyogenes (elevated antistreptolysin O and anti-DNAse B titres) and hypocomplementaemia (decreased complement component 3 [C3] concentration with normal complement component 4 [C4] concentration). The nephritic illness resolved slowly over the next few weeks. During this period, the patient developed painful, erythematous nodules over his upper torso and limbs (Box 1). His mother reported that he had experienced several such episodes in the past. The lesions measured 5–10 mm in diameter and were tender to palpation; in association with the cardiac murmur and elevated streptococcal serology there was some initial concern about the possibility of acute rheumatic fever and the patient was commenced on penicillin prophylaxis. However, expert consensus was that the lesions more likely represented erythema nodosum leprosum (ENL) — an immune complex-mediated inflammatory reaction that can occur in both acute and chronic relapsing forms among leprosy patients with a high mycobacterial load. Treatment options for this condition have historically included simple analgesics, steroids, non-steroidal anti-inflammatory drugs, clofazimine and thalidomide. A recent Cochrane review found a paucity of evidence for most treatments of ENL, and only a modest benefit from clofazimine and thalidomide.3 As the patient was already taking clofazimine, thalidomide was not considered to be a practical or necessary option in his case (given its significant side effects, the need for monitoring and the patient’s planned return to PNG); his several subsequent bouts of ENL were treated successfully with oral prednisolone. His renal function remained stable throughout these episodes, and an inpatient echocardiogram was normal. After three negative sputum smears, the patient was removed from isolation and continued treatment with intravenous amikacin. He was discharged home on oral therapy for both MDR-TB and leprosy, with follow-up planned at Saibai Island Primary Health Centre. Unfortunately, at the time of writing, due to unknown patient factors and unforeseen circumstances (such as the closure of the border and cancellation of outreach clinics), the patient has not been seen, nor his medications collected, for almost 6 months. DiscussionThe area encompassed by the Torres Strait and Northern Peninsula Area Health Service District in Queensland includes some of the most remote and isolated communities in Australia, and incorporates the porous maritime border with PNG. Thursday Island Hospital is the main referral hospital for the region and many PNG patients are seen in outer island clinics and treated as inpatients at Thursday Island Hospital. These include a significant number of patients with tuberculosis. Although accurate figures on the epidemiology of infectious diseases in PNG are difficult to obtain, it is likely that the rates of mycobacterial infections such as tuberculosis and leprosy in PNG are both underreported and among the highest in the world. The World Health Organization recently reported an annual incidence of 6.5 per 100 000 for leprosy in PNG,4 with historical prevalence of up to 3% recorded in some remote villages.5 For tuberculosis, PNG has reported an incidence of 233 per 100 000, of which about 25% may be MDR-TB.6 A recent literature review described only isolated case reports and small case series studies of concomitant infection with leprosy and tuberculosis over the past few decades.7 Most of these reported cases were from India, with documented co-infection rates (ie, the proportion of leprosy patients found to also have tuberculosis) in the order of 2.5%–7.7% in India and up to 13.4% in South Africa.8,9 Despite the relative dearth of published accounts of co-infection, it seems plausible that simultaneous infection with M. tuberculosis and M. leprae occurs more frequently than is described in published reports in regions with relatively high rates of both diseases (including countries in sub-Saharan Africa, South America, the Indian Subcontinent, and South-East Asia). Some postulated reasons for why rates of co-infection may nevertheless be lower than expected in high prevalence regions include improvements in the detection rate and treatment for both infections; the WHO’s initiative of providing free leprosy treatment in an effort to eliminate the disease; the effects of BCG immunisation; and the complex, possibly antagonistic interaction between the two strains of mycobacteria.7 Our patient developed acute glomerulonephritis as an inpatient receiving treatment for MDR-TB and leprosy; hence, a number of possible causes of his renal dysfunction were considered. Renal abnormalities occur among most patients with leprosy, particularly those with multibacillary disease (“borderline” or “lepromatous” disease using the Ridley–Jopling Classification of Leprosy), and renal failure is a frequent cause of death in patients with leprosy.10,11 Glomerulonephritis, nephrosclerosis, tubulointerstitial nephritis, amyloidosis and granulomas are the most common renal pathologies found on biopsy or autopsy of leprosy patients.12 Of the glomerulonephropathies, the proliferative glomerulonephritides are the most frequently described lesion among patients with leprosy.11,12 Hypocomplementaemia is a recognised association of renal disease in this setting, particularly among patients with multibacillary leprosy and ENL.12 Typical serum protein profiles seen among patients with renal disease associated with some selected infections are presented in Box 2. The pattern of hypocomplementaemia varies somewhat between the different forms of glomerular disease; low C3 with normal C4 (as in our patient’s case) tends to suggest either poststreptococcal or membranoproliferative glomerulonephritis.13 Evidence of streptococcal infection was found on biopsy from five leprosy patients with renal disease in India; the same case series reported two patients with microfilariae in peripheral blood samples, indicating the possibility of a range of concomitant infections contributing to renal disease in patients with leprosy.14 With respect to drug-induced nephrotoxicity, rifampicin (a common component of the pharmacological regimen for treatment of both leprosy and tuberculosis) has been implicated in acute renal failure, often associated with thrombocytopenia, immune haemolytic anaemia and intravascular coagulation.15 In our patient, however, the combination of oedema, hypertension, haematuria, hypocomplementaemia (in the pattern described), elevated streptococcal serological results and a history suggestive of recent skin infections is strongly supportive of a diagnosis of poststreptococcal glomerulonephritis, which is an uncommon form of renal disease in patients with leprosy. The patient did not undergo kidney biopsy as his condition was clinically improving and it was felt that this highly invasive procedure would not have yielded sufficient additional diagnostic information to make it worthwhile. It is also a moot point whether, given his nationality, this procedure would have been available to him. In summary, our patient had the misfortune to suffer simultaneous infection with multibacillary leprosy and MDR-TB (and may be the first such reported case in Australia), which was complicated by ENL and an acute glomerulonephritis that was probably poststreptococcal glomerulonephritis — a rare form of renal disease in a subset of patients among whom renal impairment is commonly due to other causes. 1 Erythema nodosum leprosum reaction, indicated by red patches 2 Serum protein profiles seen in renal disease associated with specific infections* Serum protein profile Group A streptococcus infection Acute glomerulonephritis Classic diffuse proliferative Decreased C3 Focal proliferative (IgA disease) Increased IgA Mycobacterium leprae infection Acute glomerulonephritis Proliferative forms Decreased C3 Cryoglobulinaemia (ENL) Decreased C3 and C4 Nephrotic syndrome Amyloid Increased AA Mycobacterium tuberculosis infection Nephrotic syndrome Amyloid Increased AA AA = amyloid A. C3 = complement component 3. C4 = complement component 4. ENL = erythema nodosum leprosum. IgA = immunoglobulin A. * The serum concentrations of certain proteins are altered in these conditions.

Lachlan J McIver MB BS, MPHTM, FACRRM · Shaun T Parish MB BS, DTMH, FACRRM · Samuel P Jones MB ChB, DTMH, JCPTGP · Alexander N Kippin MB BS, MPHTM · Timothy J Furlong MB BS, PhD, FRACP

To the Editor: In their article on the decline of infectious syphilis in the Australian Indigenous population from 2005 to 2009,1 Ward and colleagues conclude that it “might be the right time to move toward the elimination of infectious syphilis from remote Indigenous communities”. They note that another previously endemic sexually transmitted infection, donovanosis, has almost completely disappeared from Australia as a result of an elimination program.2 I strongly support their call to action and believe that syphilis can, and should, be next. It is likely that, outside of the small number of communities who have been able to implement a coordinated screening program, the decrease in syphilis in remote areas is an unintended benefit of the use of azithromycin for genital chlamydia and trachoma, and amoxicillin for gonorrhoea. Syphilis is only transmissible to sexual partners for a few weeks during the primary phase (when a chancre is present) and during the secondary phase (when mucocutaneous lesions may be present). Although syphilis is highly infectious during these stages, the relatively short duration of infectiousness partly explains why it is less common than other bacterial sexually transmitted infections. Because the painless ulceration of syphilis is easily ignored by men, or may go unnoticed by women with genital lesions, the diagnosis and treatment of latent (ie, subclinical) disease has been the main focus of syphilis control in remote areas. This approach has had only a limited effect on reducing the incidence of infectious syphilis. Indeed, as latent disease detection and treatment improves, there may be a paradoxical increase in the incidence of infectious cases because latently infected individuals become susceptible to new infection again after treatment.3 Therefore, detection and treatment of all cases of early, infectious syphilis must be the aim of an elimination program, but it will be extremely difficult to achieve this in a remote or rural setting using current diagnostic strategies that almost exclusively rely on serological testing. Serology is still the mainstay of syphilis diagnosis, despite the development of sensitive and specific polymerase chain reaction (PCR) tests for Treponema pallidum. Multiplex PCR tests that can also detect herpes simplex and donovanosis have been used to diagnose genital ulcerative disease in remote areas of Australia,4 but not to screen asymptomatic individuals. The validation of a syphilis PCR test that can be used to identify early, infectious syphilis should be a research priority — one that could be carried out as part of an Australian Government-funded, centrally coordinated but locally implemented, targeted syphilis elimination program.

Francis J Bowden

A 62-year-old woman with an autoimmune disease presented with panuveitis and was treated with immune suppression. She subsequently developed herpetic acute retinal necrosis and later died of herpes simplex encephalitis. Acute retinal necrosis usually occurs months to years after herpes simplex encephalitis. In our case, the ocular findings were present for 5 weeks before the encephalitis presented. To our knowledge, this is the first Australian case of acute retinal necrosis preceding herpes simplex encephalitis. (MJA 2011; 195: 87-88) Clinical recordA 62-year-old woman was referred to our hospital after a left-sided uveitis failed to respond to both topical and systemic steroids. She was known to have systemic lupus erythematosus (SLE) with severe arthritic changes, but had not received immunosuppressive therapy. She had right temporal lobe surgery in 1995 for a benign brain tumour. In 2005, she had Legionella pneumonia that had resulted in an intensive care unit admission with multiorgan failure and acute respiratory distress syndrome. As part of the diagnostic work-up during her previous admission, she was diagnosed as having herpes simplex virus (HSV) type 1 and was treated with aciclovir. She had no known history of genital or oral herpetic lesions. She had no significant ophthalmic history. When she was first reviewed at our hospital, she had been symptomatic for 3 weeks. She had been diagnosed as having an SLE-related panuveitis and had been treated with topical, regional and systemic steroids for 2 weeks with no response; on presentation, she was taking oral prednisolone, 1 mg/kg/day. She described a loss of appetite for 6 weeks but had no headache, fever, rash, pleuritic chest pain or shortness of breath suggestive of a lupus flare. Her initial visual acuity was 6/9 in her right eye and “hand movements” in her left eye. There was a relative afferent pupil defect in her left eye. Her anterior chamber had large mutton-fat keratic precipitates, fibrin and posterior synechiae — all indicative of a granulomatous uveitis. There was no fundal view of the left eye. An ultrasound scan of the left eye showed vitreous debris and a retinal detachment. Fundal examination of the right eye showed one or two small scattered intraretinal haemorrhages (Box 1, A). Fluorescein angiography (Box 1, B) of the right eye showed mild leakage from the disc and vessels in keeping with an early vasculitis. There was no view of the left fundus. An anterior chamber tap and vitreous biopsy were taken from the left eye. Bacterial and fungal microscopy and culture were negative; results of cytological analysis were normal. There was insufficient specimen for viral polymerase chain reaction (PCR). (This is a common occurrence for aqueous and vitreous samples, in which the amount taken averages 0.4 mL.) Blood sampling showed an antinuclear antigen positive to a titre of 1 : 2560 (> 1 : 160 considered positive for probable autoimmune disease), an erythrocyte sedimentation rate of 38 mm/hour (reference range, < 20 mm/hour for women aged > 50 years), and anti-DNA antibodies > 100 IU/mL (reference range, < 6 IU/mL); a white cell count and serum angiotensin-converting enzyme levels were normal, and human leukocyte antigen (HLA)-B27 was not detected. Serological testing was negative for syphilis and HIV. Blood culture was negative. An echocardiogram and chest x-ray were non-contributory. At this stage, the differential diagnosis included a masquerade syndrome (intraocular lymphoma), active lupus, or an endogenous, infective endophthalmitis. The patient was referred for a surgical vitreous biopsy. She continued to take oral prednisolone 1 mg/kg/day. Two days later, there was a marked deterioration in the patient’s vision. Her visual acuity was recorded as “no perception of light” in both eyes. She had no headache, but she was febrile. Her right eye now had anterior chamber and vitreous cells and widespread retinal haemorrhages (Box 1, C). Magnetic resonance imaging (MRI) of the patient’s brain showed an area of encephalomalacia in keeping with her previous surgery. Inflammatory changes and a retinal detachment were noted in the left globe. The optic nerves appeared normal. No orbital masses were noted, and no cavernous sinus pathological features were observed (Box 2, A). A surgical vitreous biopsy was performed on her left eye. The next day, she was found to have a deteriorating neurological status. She was delirious and seemed unable to hear and follow commands. She remained febrile. A lumbar puncture was performed. PCR of cerebrospinal fluid and vitreous fluid samples were positive for HSV type 1. In addition, the cerebrospinal fluid had 75 lymphocytes/mm3 and normal cytological features. She was commenced on intravenous aciclovir. A repeat MRI scan 8 days after the initial scan showed increased signal on flair involving the thalamus, occipital, temporal lobes and brainstem in keeping with an encephalitis (Box 2, B). She failed to improve clinically and died 3 weeks later. An autopsy was refused by the family, but the cause of death was pressumed to be herpes simplex encephalitis (HSE). DiscussionAcute retinal necrosis (ARN) associated with HSE has been well described. Most published reports describe the ocular findings following the encephalitis with a variable time course; the mean interval is 6 months but it can range between 10 days and 20 years.1-6 To our knowledge, there has been only one report published of HSE following ARN.7 When ARN follows HSE, it is assumed that a reactivated latent virus is axonally transmitted from the brain to the retina. A retrospective study published in 2008 examined the causative virus among 52 patients with ARN.8 It found that 14% had a history of previous HSE. There were no cases in which ARN preceded the encephalitis. In one case report, the authors noted that there have been 20 cases of ARN following HSE published in the past 20 years, and only one case of HSE following 3 weeks after ARN.9 HSE remains a serious illness with significant risk of morbidity and death. A high index of suspicion is required to diagnose HSE. Neurons undergo lysis associated with haemorrhage — a process similar to that seen in the eye with ARN. The exact mechanism of cell death is postulated to be a combination of direct virus-mediated and indirect immune-mediated processes.8,10 Without treatment, the brain undergoes severe inflammation and necrosis. ARN typically causes panuveitis with a distinctive pattern of retinal involvement. Patients may develop painful, severe visual impairment over a few days, or experience an insidious onset with mild visual symptoms such as floaters. Ophthalmic examination shows evidence of a granulomatous uveitis, vitritis, peripheral retinal periarteritis, retinal infiltrates, retinal necrosis, and sometimes retinal detachment. The posterior pole (macula) is usually spared until late; thus vision may remain fairly good despite surrounding necrosis. Diagnosis is made using PCR-based assays of aqueous and vitreous fluid. Treatment of ARN is intravenous aciclovir for 14 days followed by oral valaciclovir for 3 months. Systemic steroids are started a few days after initiation of antivirals to lessen the immune-mediated retinal necrosis. Our patient had a history of HSV years before the current presentation. There was, however, no history of preceding encephalitis. We hypothesise that the unguarded use of steroids may have caused reactivation of the virus and subsequent spread to the brain via retrograde axonal transport from the eye or from a generalised viraemia. This case highlights the importance of considering a viral aetiology in cases of atypical uveitis. ARN may herald systemic or cortical disease. Viral PCR should be performed before commencing systemic steroids. Herpetic disease may remain latent for many years before presenting in a previously uninvolved tissue. Intraocular inflammation remains a diagnostic challenge frequently encountered in ophthalmic practice. It remains imperative that all patients presenting with a possible uveitis be referred to an ophthalmologist. 1 Photographs of the patient’s right fundus A. Initial presentation of the right eye with small intraretinal haemorrhages. B. Fluorescein angiogram of the right eye at initial presentation. C. Two days after initial presentation. 2 Magnetic resonance imaging of the patient’s brain and orbits A. Old area of encephalomalacia on the right, and inflammatory changes in the left globe. B. Repeat scan showing increased signal on flair settings.

K Nadia Wittles MB ChB, FCOPHTH(SA), FRANZCO · Lucy A Goold MB BS · Jagjit S Gilhotra MB BS, MMed (ClinEpid), FRANZCO

Paediatric empyema thoracis occurs in 0.7% of pneumonias in Australia and general paediatricians may only see a few cases in their career. A recent survey demonstrated a lack of consensus in management across Australia, highlighting the need for a local guideline. Empyema is an accumulation of infected fluid in the pleural space caused by a disruption in the equilibrium of pleural fluid secretion and absorption by the pleural lymphatic drainage system. Children with empyema typically present with symptoms and signs of pneumonia. A persistent fever despite 48 hours of appropriate antibiotic treatment may indicate development of empyema. Children with empyema should be managed in a hospital with paediatric expertise — preferably by or in consultation with respiratory paediatricians, and in conjunction with paediatric surgeons (recommendation [R], strong; evidence [E], low quality). If feasible, children should be transferred to a tertiary paediatric centre; treatment of paediatric empyema is very different to that of adult disease. A chest x-ray should be carried out for children in whom empyema is suspected (R, strong; E, high quality); a routine lateral film is not needed. A lateral decubitus or erect film may be used to differentiate a simple parapneumonic effusion from an empyema if ultrasound is not available (R, strong; E, none). Daily x-rays are not necessary to monitor progress as changes on chest x-ray lag behind clinical status (R, strong; E, none). Ultrasound is the central investigation in the management of paediatric empyema; it should be used for all children with empyema as it is the best technique for differentiating pleural fluid and consolidation, estimating effusion size and grading complexity, demonstrating the presence of fibrinous septations and guiding chest drain placement (R, strong; E, high quality). A preoperative chest computed tomography (CT) scan should not be routinely performed (R, strong; E, moderate quality) but should be reserved for complicated cases in which the condition has not responded to treatment or there is concern that another pathological condition, such as a tumour, is involved. Blood tests such as blood culture (R, strong; E, high quality), full blood count and measurement of C-reactive protein level (R, strong; E, none) may help in supporting the diagnosis and monitoring the progress of the disease, but there is no role for routine blood tests. Children with empyema should receive high-dose, intravenous antibiotic therapy to ensure pleural penetration (R, strong; E, high quality). The majority of causative organisms in Australia are Streptococcus pneumoniae (in particular, serotypes 1, 3 and 19A), Streptococcus pyogenes, methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). In the absence of a positive culture result, the initial choice depends on the local hospital infection control policy for managing community-acquired pneumonia. Appropriate antibiotics should cover at least S. pneumoniae and S. aureus (R, strong; E, high quality). Consideration should be given to coverage of MRSA for children from communities with a high prevalence of MRSA (R, strong; E, high quality). Anaerobic infection should be considered in children who are at risk of aspiration. Macrolides should be used when Mycoplasma pneumoniae is thought to be the causative organism but should not be used routinely (R, weak; E, moderate quality). Moderate to large effusions require drainage. There is no role for diagnostic thoracocentesis. If there is a need to access the pleural cavity, the placement of a drain should be considered, thus ensuring that the child undergoes only one invasive intervention (R, strong; E, high quality). Pleural fluid should be sent for cytological testing, microscopic examination and culture, including culture for Mycobacterium tuberculosis (R, strong; E, high quality). Ideally, pleural fluid should be tested using enhanced molecular techniques such as polymerase chain reaction (R, strong; E, high quality). There is currently no role for pleural biochemical markers to guide therapy in children (R, weak; E, low quality). Chest drainage with a large bore drain alone is not recommended (R, strong; E, moderate quality). Instead, percutaneous small bore drainage with a fibrinolytic agent (preferably urokinase) or video-assisted thoracoscopic surgery (VATS) is recommended (R, strong; E, moderate quality). Open thoracotomy is not recommended as it has largely been superseded by the use of VATS. Children with an oxygen saturation level below 93% on room air should be given supplemental oxygen (R, strong; E, high quality). Other standard therapy includes fluid replacement (R, strong; E, none), use of antipyretic agents (R, strong; E, none specific to empyema) and analgesia (R, strong; E, none). There is no role for chest physiotherapy — apart from early mobilisation and encouragement of deep breathing and coughing, particularly after surgical intervention or tube drainage (R, strong; E, low quality) — and no indication for routine bronchoscopy in children with empyema (R, strong; E, weak). If a child has been afebrile for 24 hours, a change from intravenous to oral antibiotic therapy can be considered (R, weak; E, none). The choice of oral antibiotic depends on the organism identified (if any) or the class of antibiotic that was successfully used by intravenous therapy. There is no consensus on duration of oral antibiotic therapy, which varies from 1 week to 6 weeks (R, weak; E, none). A follow-up chest x-ray should be carried out 4–6 weeks after discharge from hospital to confirm that changes are resolving (R, weak; E, none). Further imaging is not required unless there are persistent clinical symptoms or complications (R, weak; E, none). There is no need for routine investigations to identify a possible underlying cause in previously healthy children without a history of recurrent infections (R, weak; E, very low quality). The full position statement is available at http://www.thoracic.org.au/ professional-information/position-papers-guidelines.

on behalf of the Australian Research Network in Empyema (ARNiE)

No-fault compensation, based on the ethical principle of redistributive justice, should form a cornerstone of Australia’s immunisation strategy Australia has an enviable reputation for its publicly funded vaccine program — a program that has benefited Australian children and adults over many years. In 2010, the National Immunisation Program funded 12 vaccines, twice as many as a decade previously. To monitor outcomes from this program, the Australian Childhood Immunisation Register, which commenced data collection in 1996, provides a detailed record of vaccine uptake by children.1 Funding for the register and for incentives to general practitioners to improve vaccine uptake are part of the total budget for Australia’s vaccine program, estimated to exceed $400 million annually.2,3 One area for improvement in the vaccine program is monitoring of adverse events following immunisation (AEFI). Another would be the introduction of a no-fault compensation scheme for serious adverse events which can be confidently attributed to vaccination. An investigation into the unexpectedly high number of febrile convulsions in children aged less than 5 years after they had received the influenza vaccine in 2010 — in some cases, with devastating consequences4 — provided a forceful reminder that timely vaccine safety monitoring is needed in Australia.5 More active adverse event surveillance is certain to uncover more AEFI but many of these will only be coincidental, while others will be of a transient or relatively trivial nature. On rare occasions, a serious AEFI with long-term sequelae will be recognised. A decision will then need to be made on whether the vaccine was responsible for that serious event. The World Health Organization defines four categories of serious AEFI: hospital admission or prolongation of an existing hospital admission; permanent disability; any event that is life threatening; or death.6 Using these criteria, 8% (193/2396) of the AEFI reported by passive surveillance in Australia in 2009 were judged to be serious.7 However, unlike many countries where compensation schemes exist for adverse events attributed to a vaccine, Australia has no routine approach to making the assessment of attribution. Parents of children or adults who believe they deserve compensation for a serious adverse event that they attribute to a vaccine are therefore required to make their case through the adversarial legal system. This requires the demonstration that an individual or an organisation was at fault. However, fault is often difficult to demonstrate and an adverse event may be caused by vaccination through no fault of the vaccine manufacturer, the regulator or the person who administered the vaccine. We have previously argued that a Queensland child who developed transverse myelitis after receiving oral polio vaccine was an example of an adverse event following vaccination where no fault was attributable to any party.8,9 Despite detailed epidemiological evidence that was consistent in this case with the causal criteria for an AEFI promulgated by the Institute of Medicine of the National Academies in the United States,8 and despite laboratory evidence showing that the polio virus recovered from this child was similarly pathogenic to a polio virus that has been accepted as causing vaccine-associated paralytic polio,9 the polio expert committee concluded that the evidence was insufficient to support a causal relationship between the oral polio vaccine and transverse myelitis. As causality has not been accepted, this child has received no compensation. The general principles associated with this case raise a number of pertinent questions for Australia. First, should a child who may have been injured by a vaccine, which was endorsed and paid for by the community, be compensated by the community when the serious adverse event may be attributed to the vaccine? Second, what are the criteria for accepting an attributable relationship between receipt of the vaccine and a subsequent adverse event? Third, what is the best method for financing a compensation scheme? Each question may highlight a potential barrier to the implementation of a no-fault AEFI compensation scheme in Australia. By 2010, 19 countries around the world had implemented no-fault AEFI compensation, implicitly answering “yes” to the question of whether the community owes a duty of care to an individual injured by a vaccine.10 There is also a strong ethical argument for this position, based on the concept of redistributive justice. Any person who is injured while helping to protect the community — for instance, by contributing to herd immunity, such that there are sufficiently many people immunised to prevent widespread disease transmission within the community — should not bear the consequences of injury alone. In essence, the community owes a debt of gratitude to that person. Temporal association of an adverse event with receipt of a vaccine does not establish causality and the underlying notion of causation used in most compensation schemes is similar to that used in epidemiology.10 The World Health Organization has published guidelines on causality for an AEFI.11 An adverse event considered to be very likely or certainly due to a vaccine would comprise a “Clinical event with a plausible time relationship to vaccine administration, and which cannot be explained by concurrent disease or other drugs or chemicals”.11 To simplify and expedite determinations of causality in the US, a vaccine injury table is used to predetermine causality if a vaccine injury is included in the table.10 However, determining causation is a complex issue. Recognising this, most countries have a designated committee, comprising medical and legal members, which deliberates on the attributable relationship between receipt of the vaccine and subsequent adverse event.10 Concerns about funding a no-fault compensation scheme is another of the probable barriers to its implementation in Australia. Schemes are currently funded by one of four methods: a vaccine levy; compensation for AEFI as part of a much broader injury compensation scheme; specific AEFI compensation funded through general tax revenue; and funding in association with industry.10 Funding through a vaccine levy has been self-sustaining in the US. Despite compensation payments having been made to 2580 claimants since 1989, the compensation fund there has a surplus of about US$3 billion.12,13 No-fault vaccine-injury compensation programs are based on the premise that any adverse event attributable to vaccination is not due to the fault of a specific individual or organisation, but due to an unavoidable risk that is acknowledged as being associated with vaccines. Germany has been operating a no-fault AEFI compensation scheme for 50 years.10 France restricts its compensation to serious AEFI, since these are likely to have long-term implications for the injured party.10 Restricting compensation to events with long-term consequences, above a nominated clinical threshold, may be an acceptable model for Australia. We have previously argued that Australia should follow the lead of other advanced countries and implement a no-fault compensation scheme.14 We continue to argue that such a scheme, based on the ethical principle of redistributive justice, should form a cornerstone of Australia’s immunisation strategy. Disclaimer The views expressed are those of the authors and have not been endorsed by any institution or organisation with which the authors are affiliated or by any committees of which the authors are members.

Heath A Kelly BSc, MB BS, MPH · Clare Looker MB BS, MPH · David Isaacs MD, FRACP, FRCPCH

A husband and wife became unwell after eating a fish from the Calder River in northern Western Australia. Gnathostomiasis was diagnosed, and treated with ivermectin and albendazole. Serological testing was positive for gnathostomiasis, and there has been no recurrence. These appear to be the first proven endemically acquired cases of gnathostomiasis in Australia, and demonstrate the difficulties in diagnosis and treatment. (MJA 2011; 195: 42-44) Clinical recordsPatient 1A 52-year-old man developed epigastric discomfort, nausea, diarrhoea and lethargy 10 days after eating a fish (identified by the patient as “black bream”, possibly Acanthopagrus berda or Hephaestus jenkinsi) caught from the Calder River in northern Western Australia (Box 1). The fish had been pan-fried whole over a camp fire, but the duration and thoroughness of cooking is unclear. The patient’s epigastric discomfort persisted, followed a week later by fevers and myalgia and then pruritic subcutaneous swellings and skin thickening over his chest and abdomen. He had no response to a prescribed course of antibiotics. His abdominal symptoms and myalgia continued and, over the next 2 months, multiple episodic swellings developed over his abdomen. The swellings progressed to involve both thighs and were associated with feelings of movement under his skin. Examination revealed right thigh oedema and skin induration with a “peau d’orange” appearance. Blood investigation showed marked eosinophilia (7.27 x 109/L; reference range, < 0.5 x 109/L). Doppler ultrasound examination showed no evidence of deep venous thrombosis, and results of computed tomography of the abdomen and pelvis were normal. Serological evaluation for vasculitis and autoimmune disease was unremarkable. A presumptive diagnosis of parasitic infection was made, and ivermectin 12 mg was prescribed. Rapid improvement occurred, with a reduction in the patient’s eosinophilia to 1.6 x 109/L. Serological evaluation for schistosomiasis, cysticercosis, filariasis, angiostrongyliasis and strongyloides was negative. Eight weeks later, recurrent swelling of the patient’s right leg was treated with ivermectin. Three months later, further cutaneous symptoms were treated with three doses of ivermectin, with a subsequent eosinophil count of 0.44 x 109/L. A serological test for gnathostomiasis was positive (24 kDa immunoblot test conducted by the Department of Helminthology, Mahidol University, Bangkok, Thailand) 8 months after initial onset of symptoms. A simultaneous enzyme-linked immunoabsorbent assay (ELISA) for Gnathostoma antibody was positive (titre, 0.901 at 1:20 dilution), and a repeat ELISA 14 months later showed a similar titre (0.823 at 1:20 dilution). No earlier blood sample was available to demonstrate seroconversion. There has not been any recurrence of symptoms or eosinophilia over the subsequent 6 years. Patient 2A 50-year-old woman (Patient 1’s wife) developed fevers and lethargy 12 days after eating the same fish as her husband. Vomiting and abdominal cramps followed, and settled down over 10 days. When she returned to Melbourne 4 months later, the patient’s blood samples revealed an eosinophilia of 1.6 x 109/L. A further 4 months later, a trial of ivermectin (12 mg weekly for two doses) was prescribed for gnathostomiasis, and 4 months later her eosinophil count was 0.23 x 109/L. Serological testing for amoebiasis, strongyloides, filariasis and schistosomiasis was negative. A test for gnathostomiasis (24 kDa immunoblot) was positive 8 months after initial symptoms. An ELISA for Gnathostoma was also positive 8 and 20 months after initial symptoms, with little change in titre (0.903 and 0.886, respectively). Sixteen months after the initial symptoms (9 months after ivermectin), a pruritic swelling over the upper right arm developed with associated eosinophilia. Eosinophilia and chronic symptoms resolved following a single dose of ivermectin 12 mg, and albendazole 400 mg twice daily for 21 days. Two months later, a transient pruritic swelling over the right buttock was treated with repeat ivermectin (12 mg weekly for two doses). Subsequently, the patient had recurrent swelling of the right deltoid muscle and was given three further ivermectin doses. Symptoms have not recurred during 5 years of observation. DiscussionGnathostomiasis is a foodborne zoonosis, a clinical syndrome caused most commonly by infection with the larvae of Gnathostoma spinigerum, but also by several other Gnathostoma species.1,2 Humans may become accidental hosts after ingesting third-stage larvae (Box 2). The larvae are unable to mature further in humans, and they migrate through visceral and cutaneous tissues. Larvae may be found in a range of intermediate and paratenic hosts including freshwater fish, snakes, frogs, snails and fowl.1,3 Consequently, the disease is endemic where these foods are consumed raw or undercooked, including South-East Asia and Japan, but more recently recognised in Latin America, China, India, Africa and in travellers returning from these areas.1,2 Locally acquired infection in Australia has not previously been confirmed.4 The Gnathostoma life cycle is illustrated in Box 2. Following ingestion of viable larvae, patients often develop fever, anorexia, abdominal discomfort, nausea and vomiting as larvae penetrate the gastrointestinal wall. This is usually associated with a marked eosinophilia. Subsequently, symptomatic disease may have either cutaneous or visceral manifestations depending on the larval migration pattern. Cutaneous disease is more common, typically presenting with intermittent migratory erythematous swellings, which may be pruritic or painful. Cutaneous symptoms usually occur within 4 weeks of larval ingestion, and last 1–2 weeks. In untreated patients, larvae may survive up to 15 years and cause recurrent symptoms, by which time eosinophilia may have resolved. Less common cutaneous manifestations include nodular lesions, skin abscesses, panniculitis or creeping eruptions. The main differential diagnoses include cutaneous larva migrans, larva currens, trichinosis and Calabar swellings secondary to loiasis. Visceral disease may involve almost any part of the body. Pulmonary disease may manifest as a cough, pleuritic chest pain, haemoptysis, lobar consolidation or pleural effusions. Gastrointestinal disease may be asymptomatic, but is more frequently associated with sharp abdominal pains or inflammatory masses, or may mimic an “acute surgical abdomen”. Ocular disease has a variety of manifestations and often allows direct visualisation of the larvae. Untreated, gnathostomiasis of the central nervous system (CNS) is associated with the highest mortality (8%–25%), and 30% of survivors have long-term sequelae.1 Typically, symptoms begin with acute radicular pain or headache, lasting up to 5 days, as the larva penetrates the CNS via spinal cord nerve roots. Focal paralysis and cranial nerve palsies usually follow, and may progress to eosinophilic meningoencephalitis or encephalomyelitis. Subarachnoid haemorrhage and other vascular complications are less common presentations of CNS gnathostomiasis. Imaging reveals the haemorrhagic migratory tracts of the larvae. The main differential diagnosis for CNS disease is Angiostrongylus cantonensis. Definitive diagnosis of gnathostomiasis requires parasite extraction and identification, however small parasite size (2–3 mm) makes this impractical, and thus is no longer recommended. Therefore, gnathostomiasis is a clinical diagnosis, supported by epidemiological history, blood eosinophilia (although alone not sensitive or specific) and serological testing. Serological tests have surpassed non-specific antigen injection techniques, and include immunoblot testing (which detects antibodies to specific L3 antigen with a molecular mass of 24 kDa) and ELISA (which detects IgG1 or IgG2 to the crude L3 antigen).6-8 The immunoblot test appears to be the most specific, but is difficult to perform.6-8 In a series of four patients with parasitologically confirmed gnathostomiasis, and 15 patients with a presumptive diagnosis of gnathostomiasis, the 24 kDa L3 antigen immunoblot test had a sensitivity of 100% for parasitologically confirmed gnathostomiasis and 33% for presumed gnathostomiasis.8 The authors commented that the lower sensitivity in presumptively diagnosed cases was probably due to initial incorrect diagnoses. In the same series, 64 patients with other parasitic infections and 19 healthy control subjects were also tested, with only one positive result, giving a specificity of 99%.8 An ELISA to detect subclass immunoglobulin levels for crude L3 antigen, avoiding the difficult purification step, has been proposed as an alternative diagnostic test. Detection of IgG1 has the greatest sensitivity (98%) making it an attractive initial test, and IgG2 does not appear to cross-react with other parasitic species, thus providing the best specificity (88%) for diagnostic confirmation of gnathostomiasis.7 Neither test is available commercially, but both the immunoblot and ELISA are performed at the Department of Helminthology, Mahidol University, Bangkok, Thailand. Nevertheless, serological investigations for gnathostomiasis have limited validation, making precise estimates of sensitivity and specificity difficult. Cross-reactions may occur, so caution with interpretation is paramount. In the patients described, an evaluation for other parasitic infections was made in order to reduce the possibility of a false positive result. Data comparing the outcomes of treatment regimens are limited to observational studies only. In a series of 49 patients treated with albendazole 400 mg twice daily for 21 days, over 93% achieved a cure at 6 months.9 In the same series, the efficacy was similar in 21 patients treated with ivermectin 0.2 mg/kg as a single dose.9 There are few data comparing combinations of ivermectin and albendazole. Longer observational studies indicate that treatment failures are common, as demonstrated in the two patients above, and thus repeat treatment is recommended if symptoms recur.10 Proven endemic human gnathostomiasis has not previously been reported in Australia, although cases suspected to have been locally acquired were described in the 1970s (non-specific antigen injection was used for confirmation).4 Gnathostoma infection of mammals has been described in Australia.11,12 Therefore, we believe these cases are the first confirmed cases of locally acquired human gnathostomiasis in Australia. The two patients had clinical syndromes compatible with gnathostomiasis, associated blood eosinophilia, positive serological results and supportive epidemiological history, and they responded to treatment. Importantly, neither of the patients had previously travelled outside Australia. Weaknesses of this report include that we were unable to definitively identify the fish species or determine how thoroughly the fish was cooked. Although it is a rare disease, gnathostomiasis needs to be considered in patients coming from endemic areas, and also in patients who have not left Australia, who present with migratory cutaneous lesions and associated peripheral blood eosinophilia. Visceral disease may be more difficult to diagnose due to the broad differential diagnoses, but gnathostomiasis must be considered in those with eosinophilic neurological syndromes due to the high mortality in untreated disease. 1 Calder River, West Kimberley region, northern Western Australia, where the “black bream” was caught 2 Gnathostoma life cycle5

Cameron J Jeremiah MB BS · Chanad S Harangozo MB BS, FRACP · Andrew J Fuller MB BS, FRACP, FRCPA

To the Editor: Young children are at increased risk of severe influenza compared with the general population. Routine vaccination of children using trivalent influenza vaccine (TIV) is recommended in the United States and Canada. The Western Australian government, with support from vaccine manufacturers, has been providing TIV free of charge to all children aged 6–59 months since 2008.1 In 2010, high fevers and an increased incidence of convulsions were observed in children aged < 5 years after administration of TIV. Most reports of adverse events were from WA, owing to higher uptake of vaccination associated with the free vaccination program. The national influenza vaccination program for children aged < 5 years was subsequently suspended,2 and high rates of fever and convulsions were confirmed.2,3 The majority of adverse events occurred after administration of Fluvax or Fluvax Junior (CSL Biotherapies). More than 50% of parents of children who were administered Fluvax or Fluvax Junior reported high fever after vaccination. The incidence of febrile convulsions after vaccination with Fluvax and Fluvax Junior was 4.4 per 1000 doses, significantly higher than expected.3,4 Fluvax and Fluvax Junior are not recommended for children aged < 5 years in the Australian 2011 influenza vaccination program.5 In response to these events, WA Health established an online registry for vaccine-associated adverse events — the Western Australian Vaccine Safety Surveillance (WAVSS). Health professionals are required and members of the public encouraged to report adverse events. In addition, a prospective safety study of the 2011 TIV in children aged < 5 years has commenced at Princess Margaret Hospital for Children and the WA Central Immunisation Clinic. From 15 March to 29 April 2011, 2227 doses of TIV were administered to children aged < 5 years in WA (2130 doses of Vaxigrip [Sanofi Pasteur]; 97 doses of Influvac [Solvay]). Adverse events in four children aged < 5 years have been reported via WAVSS: two with elevated temperature (≥38°C yet < 39.5°C) within 24 hours of vaccination, one with vomiting and diarrhoea after vaccination, and one with fever (not specified) and convulsions 4 days after vaccination (this child had a respiratory tract infection at the time of vaccination). All four children were administered other vaccines with TIV. In the safety study, 144 children were enrolled between 15 March and 29 April 2011. Adverse events after vaccination were reported in 10 children (7%), two of whom received other vaccines in addition to TIV. All 10 children had fever reported, and one child had a temperature > 39.5°C. Two children developed vomiting. No convulsions were reported and none of the children who had adverse events required assistance from a health care professional. These data demonstrate that the significant adverse events that occurred after administration of TIV in 2010 have not been observed in WA during early 2011. Ongoing surveillance is underway and will continue. Poor uptake of influenza vaccination in Australian children is likely to result in increased influenza-related hospitalisation, morbidity and mortality. Data such as those reported here are required to reassure the community of the safety of this vaccination program before the expected start of the 2011 influenza season.

Christopher C Blyth · Tracy Y Markus · Paul V Effler · Peter C Richmond

To the Editor: We read with interest the case by Nadeem and Khateeb of an elderly man with migratory lung lesions and the concurrent finding of mixed cryoglobulins.1 We are concerned about attributing this man’s symptoms to mixed essential cryoglobulinaemia. The clinical syndrome described in this patient is not typical of cryoglobulinaemia. The establishment of a diagnosis of essential mixed cryoglobulinaemia in this man is problematic, given a lack of cutaneous findings and no definite evidence of peripheral neuropathy and renal disease. Nerve conduction studies to establish the presence of peripheral neuropathy and renal biopsy to confirm membranoproliferative glomerulonephritis were not carried out. Given his age, the confirmation of membranoproliferative glomerulonephritis would potentially necessitate long-term and possibly intensive immunosuppression to prevent subsequent development of renal failure. The cryoglobulins reported in this case fulfil the criteria for type II cryoglobulins. However, they were of relatively low concentration (0.4 g/L of monoclonal IgM/kappa and 0.1 g/L of polyclonal IgG). As well as hepatitis C, type II cryoglobulins can be detected in association with hepatitis B and Sjögren’s syndrome.2 The absence of anti-Sjögren’s syndrome A and anti-Sjögren’s syndrome B antibodies by no means excludes the diagnosis of concurrent, subclinical Sjögren’s syndrome. In addition, hepatitis B and C have not been excluded as the cryocrit was not analysed for hepatitis B virus DNA and hepatitis C virus RNA. Furthermore, the relatively low concentration of cryoglobulin detected and the findings of chest opacities with very high levels of C-reactive protein (that fell to normal levels with antibiotic treatment) could also be due to an infective aetiology.3 We also note that the thermal amplitude of the cryoglobulins should be investigated in such cases, as it has been well described that cryoglobulins of higher thermal amplitudes are more likely to be clinically significant. In conclusion, given the long duration of this man’s admission, repeat cryoglobulin measurements after he was discharged would have helped to more clearly define the role of cryoglobulins in his disease. We therefore recommend caution when interpreting low levels of cryoglobulinaemia in patients who have a clinical syndrome that may or may not be consistent with clinical cryoglobulinaemia.

Carl A Kennedy · David Gillis · Richard C W Wong

Objectives: To report on the burden of disease in Australian infants with congenital cytomegalovirus (cCMV) infection in the era of neonatal hearing screening and improved diagnostic techniques.Design, setting and participants: National data were collected from across Australia via the Australian Paediatric Surveillance Unit (APSU) with monthly reporting by > 1000 clinicians between January 1999 and February 2009. For each reported case, data on investigations and epidemiological and clinical features were analysed. Detailed clinical reviews were performed on 42 infants in two Sydney tertiary paediatric infectious diseases clinics.Results: There were 195 infants with cCMV identified, including 126 definite and 69 probable cases. Of these, 175 (90%) were symptomatic and only 15 were treated with antiviral agents. Identification was delayed beyond 60 days of age in 30 cases (15%). During the period of study, neonatal hearing screening was introduced for most Australian infants. Detection of hearing loss increased from 19% of cCMV cases in 1999–2003 to 31% in 2004–2009. Of 42 infants whose cases were reviewed in detail, 33 (79%) had symptomatic disease. DNA detection of CMV, using polymerase chain reaction testing of newborn screening cards, was useful in retrospective identification, and was strongly correlated with the presence of clinical sequelae (15/18; 83%).Conclusions: Congenital CMV is underdiagnosed, infrequently treated, and often manifests as isolated hearing loss. Delayed diagnoses both before and after the introduction of neonatal hearing screening represent missed treatment and management opportunities and are likely to lead to poorer, life-long outcomes for these children. Retrospective analysis of newborn screening cards for CMV should be undertaken for infants with sensorineural hearing loss, to identify unrecognised cCMV.

Brendan J McMullan BMed(Hons), DTMH, DCH · Pamela Palasanthiran MB BS, FRACP, MD · Cheryl A Jones MB BS, FRACP, PhD · Beverley M Hall RN, RM, MPH · Peter W Robertson PhD · Jonathan Howard BSc(Hons), PhD · William D Rawlinson PhD, FRACP, FRCPA

Murine typhus (MT) occurs worldwide, but, in Australia, is only regularly diagnosed in south-west Western Australia. Meningoencephalitis is an uncommon complication of MT, often accompanied by rash or systemic involvement. We report a case of MT presenting exclusively with meningoencephalitis, raised intracranial pressure, papilloedema and bilateral 6th cranial nerve palsies. MT should be considered in patients with “aseptic” meningitis or meningoencephalitis, even in the absence of other typical features of a typhus-like illness. (MJA 2011; 194: 652-654) Clinical recordIn June 2010, a 20-year-old man who worked as an apprentice chef developed a progressively severe, non-pulsatile global headache without report of additional neurological symptoms, rash, fever or other constitutional features. After 3 days of headache he woke with severe headache and associated nausea and vomiting. A short time later, while standing in the shower, he developed paraesthesiae, starting initially in his fingers and toes, then spreading quickly up his limbs, trunk and finally involving his face and tongue. He subsequently collapsed onto the bathroom floor and was unable to move or speak, although he did not lose consciousness. While he was being transported to hospital, a speech disturbance was noted, with fluent but nonsensical speech. On initial assessment he was noted to be febrile at 39°C and confused, but without rash, organomegaly, lymphadenopathy or other signs on complete physical examination. There were no additional findings on neurological examination. This patient was normally well, had no prior significant medical history and took no regular medications or complementary therapies. He did not smoke, drank alcohol rarely and denied using cannabis or other recreational substances. He lived with his family on a small acreage in a rural area of the mid-north coast of New South Wales. Two dogs and two horses lived on the property, and an aviary containing parrots and an enclosure housing chickens were contained within the yard. There were no cats on the property. The patient reported that rats and mice were frequently seen around the chicken enclosure, but he had not been in its vicinity for several weeks before his illness. About a week before the onset of the headache, he had visited a friend who kept a pet rat indoors. He had never travelled outside NSW, and his travel within NSW was limited almost exclusively to infrequent travel between his home and Sydney. He did not recall any flea or other insect bites. He was diagnosed with meningoencephalitis after a lumbar puncture on the day of admission showed a predominantly lymphocytic pleocytosis of 180 lymphocytes/mm3 (reference range [RR], < 5 lymphocytes/mm3) with an elevated protein level of 1.7 g/L (RR, < 0.45 g/L) and a normal glucose concentration (Box 1). He was admitted to the intensive care unit (ICU) and remained there for a week because of fluctuating confusion and fever. During that week he had two further episodes like the one described before his presentation, including on Day 10 of admission requiring readmission to the ICU. Empiric treatment with a number of antimicrobial medications was commenced at standard doses in the following order: ceftriaxone (intravenously, Days 3 to 17 of illness); ampicillin (intravenously, Days 4 to 9); aciclovir (intravenously, Days 4 to 17); vancomycin, oseltamivir and azithromycin (intravenously, Days 10 to 17). Phenytoin therapy (1000 mg intravenous loading dose, followed by 300 mg orally, daily) was commenced on the day of admission owing to the possible seizure activity before presentation. He was discharged from hospital on Day 17 of the illness after the fever and headaches resolved. On presentation, the results of blood investigations including a full blood count, liver function tests, a C-reactive protein test, renal function tests and electrolyte level measurements were normal. A transient leukocytosis developed after admission and peaked on Day 6 of admission at 14.0 × 109/L, with a predominant neutrophilia. At no time was there significant derangement of liver function tests. Findings on brain imaging, including gadolinium enhanced magnetic resonance imaging of the brain on two occasions, magnetic resonance venogram and magnetic resonance angiogram were all normal. Serial lumbar punctures were performed (Box 1) showing the reducing white cell count and protein level. Cerebrospinal fluid (CSF) opening pressure was elevated to 30 cmH2O (RR, < 18 cmH2O) measured on Day 5 and this normalised by Day 27. Results of serological tests for human immunodeficiency virus, leptospirosis, Q fever, mycoplasma, brucellosis, psittacosis, and Ross River fever, which were performed during both the acute and convalescent phases of the illness, were negative. Repeated tests of the CSF for cryptococcal antigens were negative. CSF cultures for bacteria, fungi and mycobacteria were also negative, as was polymerase chain reaction testing for herpes viruses and enterovirus. Indirect immunofluorescence detecting total antibody against rickettsiae in the typhus group (Rickettsiae typhi and R. prowazekii), spotted fever group (R. honei and R. australis) and scrub typhus (Orientia tsutsugamushi) was performed in parallel on serum collected on Days 9 and 41. Antibodies against R. typhi were detected at a titre of 1/256 on Day 9, rising to ≥ 1/1024 on Day 41. Antibodies in each CSF specimen showed cross-reactivity with R. prowazekii at equivalent titres, but not with other rickettsial species. The patient first noticed diplopia and reduced visual acuity on Day 10, which peaked on Day 20 of his illness. At this point, bilateral partial 6th nerve palsies and papilloedema were noted. Because of persistent visual symptoms and papilloedema, therapy with 250 mg acetazolamide orally, twice daily was commenced on Day 26. Papilloedema was documented on Day 28 by ocular coherence tomography (OCT), a measure of retinal nerve fibre layer thickness and indicative of the degree of optic disc swelling (Box 2). The 6th nerve palsies resolved after Day 30 and regular fundoscopy and repeat retinal OCT showed the papilloedema continued to resolve (Box 2). Acetazolamide therapy was ceased on Day 35. The patient had not experienced recurrence of the headaches or neurological symptoms at 6 months after the onset of the illness. DiscussionWe present the first case of murine typhus (MT) reported in NSW since the 1940s. Perhaps even more notably, we have now reported the first case of MT causing proven, isolated meningoencephalitis with raised intracranial pressure (ie, rarely reported complications without other typical clinical features) in Australia. MT (endemic typhus) was first described in 1922 with a series of cases from South Australia.1 There have been further outbreaks in the Darling Downs region of south-east Queensland and south-west Western Australia.2 In each series, exposure to rodents was reported in a significant proportion of cases. MT has been reported worldwide in diverse geographic areas.3 Several areas continue to regularly report new cases including Perth in WA,4 South-East Asia,5 and Texas in the United States.6 The first case of MT in Victoria was recently reported,7 and no locally acquired cases of MT have been reported from NSW since 1944.8 The disease is caused by R. typhi, which is an obligate intracellular gram-negative bacterium with an incubation period of 7–14 days. There are two major sources of transmission. The major route of infection worldwide is the rat–flea–rat cycle.9 Rat fleas (Xenopsylla cheopis) transmit R. typhi to a roof or Norwegian rat (Rattus rattus and Rattus norvegicus, respectively). Humans are infected when flea faeces containing R. typhi are inoculated into the site of a flea bite. Alternatively, the organism may be inhaled from an environment contaminated with flea faeces. Another transmission cycle has been identified, which involves predominantly cats and opossums and their fleas (Ctenocephalides felis).10 In the case we present here, it is likely that the patient was infected as a consequence of close contact with rodents, with a respiratory route of infection being most likely. Although serological testing does not separate MT and epidemic typhus, MT has been distinguished by its milder course and the lower associated mortality.1 Fever is almost universal, and about 75% of affected patients complain of headache. Rash is observed in about 50% of cases, and is usually a macular or maculopapular rash that starts on the trunk and spreads to the extremities. A number of other features may accompany the illness, including myalgia, arthralgia, gastrointestinal symptoms, jaundice and hepatic dysfunction.11 Among the antibiotics given to our patient, azithromycin was the only one with activity against rickettsiae, and may have altered the course of the illness. However, without treatment, MT is usually a self-limiting illness, with symptoms resolving after 2 weeks.1 Neurological complications like those described in this report are uncommon in MT. Aseptic meningitis or meningoencephalitis has been reported in 2%–14% of cases.12,13 There is often a coexisting rash or other systemic features of typhus,12 and isolated meningitis or meningoencephalitis has been reported previously in only six patients.13,14 Papilloedema and raised intracranial pressure can occur with the meningitis, and 6th nerve palsy has been reported in a single case.13 Facial nerve palsy has also been described in association with meningitis in MT.14 Neurological dysfunction is usually reversible. but long-lasting deficits have been reported.13,15 In affected patients, the CSF typically shows a predominantly monocytic pleocytosis with variable elevation of protein concentration.13 The raised intracranial pressure and optic disc swelling in our patient were transient, and it is likely that intracranial pressure changes associated with meningitis are monophasic like MT infection generally. This has important implications for the extent and duration of treatment of associated raised intracranial pressure. This is the first report of MT causing proven, isolated meningoencephalitis with raised intracranial pressure in Australia. The clinical manifestations documented represent rarely reported complications of MT without other typical clinical features. The case illustrates that MT should be considered in the differential diagnosis of a patient presenting with “aseptic” meningitis or meningoencephalitis with or without raised intracranial pressure. This is particularly relevant in areas where MT is regularly observed, like south-west WA. However, it should also be considered in other areas of Australia. The absence of other typical features of a typhus-like illness such as rash should not preclude testing for R. typhi, as antibiotic therapy may reduce the duration and severity of the illness, and establishing the diagnosis of MT provides valuable information about the likely course and prognosis of the illness. 1 Serial findings on examination of the patient’s cerebrospinal fluid (CSF) Reference ranges: white cell count, < 5 cells/mm3; protein concentration, < 0.45 g/L; CSF opening pressure, < 18 cmH2O. 2 Serial ocular coherence tomography of retinal nerve fibre layer thickness showing improving papilloedema from Day 29 to Day 48

Neil G Simon MB BS(Hons), BSc(Med)Hons · Phillip D Cremer MB BS(Hons), PhD, FRACP · Stephen R Graves MD, PhD, FRCPA

Clinical records Patient 1 A 28-year-old man presented to the emergency department with a 2-day history of a right groin lump, scrotal discomfort and swelling. He was systemically well without urinary symptoms. The patient was born in Burma (Myanmar), and had migrated to Australia 6 years previously after living in Singapore for 2 years. On examination, there was an irreducible mass in the right inguinal canal, associated right scrotal swelling, and a normal testis. There was no peripheral blood eosinophilia. Ultrasonography showed a 1.1 cm heterogeneous right inguinal canal mass thought to be an incarcerated inguinal hernia. An inguinal incision was performed, and a mass attached to the spermatic cord was found and excised. Histopathology of the mass was consistent with filariasis (figure). Filarial serology (IgG enzyme immunoassay [EIA], Westmead Hospital, Sydney, NSW) was positive, but no microfilariae (filarial larvae) were seen on a blood film taken at 4 pm. The patient was treated with doxycycline 100 mg twice daily for 10 weeks and diethylcarbamazine 400 mg daily for 5 days, followed by 400 mg at 1 week and 1 month. Eighteen months later, the patient’s symptoms had not recurred. Patient 2 A 29-year-old Indian man who had migrated to Australia 7 years previously was referred as an outpatient with 10 episodes of penile swelling over 18 months. The episodes began abruptly with fever, chills and myalgias, soon followed by diffuse penile swelling. The systemic features typically resolved over 24–48 hours, and the penile swelling over 3 days. There was some inguinal discomfort, but no urinary symptoms. On examination, small, tender, bilateral inguinal masses were palpable. Ten months before presentation, while visiting India, the patient had sought medical treatment for the same problem. A diagnosis of lymphatic filariasis (LF) was made, and treatment with diethylcarbamazine 300 mg daily for 3 months was started, but did not lead to improvement. Upon review in Australia, despite negative filarial IgG EIA and examination for circulating filarial antigen by immunochromatographic testing (Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC), the clinical diagnosis of LF was thought to be correct. Twelve months after completing a 3-month course of doxycycline 100 mg twice daily the patient’s symptoms had not recurred. Patient 3 A 57-year-old Samoan man was referred by his general practitioner to the emergency department with 2 weeks of right leg and left scrotal swelling. The patient had migrated to Australia 16 years previously, and had recently returned from a 1-month holiday in Samoa. He began to experience chills and sweats 2 months after returning, followed by progressive right calf and left scrotal swelling, erythema and heat over 2 weeks. He did not have pain or urinary symptoms. A moderate-sized left hydrocoele with induration of the overlying scrotal skin, and associated right inguinal lumps, were found on examination. Blood examination revealed mild eosinophilia (0.6 × 109/L, reference range [RR] 0–0.5 × 109/L), although a blood film for microfilariae was not obtained. Ultrasonography showed movement within a left-sided 6.9 × 5.7 × 7.3 cm hypoechoic scrotal mass and associated hydrocoele. The initial working diagnosis was combined cellulitis and epididymo-orchitis. Treatment with intravenous antibiotics was commenced, with little response. The hospital’s infectious diseases service reviewed the patient and advised that the presentation was more consistent with LF. Treatment with doxycycline 100 mg twice daily for 10 weeks was commenced. Filarial IgG EIA serology was negative. The patient’s symptoms resolved, including the hydrocoele, and 12 months later he had not experienced a recurrence. Cross-sectional view of a filarial nematode in the spermatic cord, with surrounding intense eosinophilic inflammatory infiltrate (magnification, × 400). U = uterine tubes. M = musculature. I = intestine. C = cuticle. Lymphatic filariasis (LF) is caused by the filarial nematodes Wuchereria bancrofti, Brugia malayi and Brugia timori, which are transmitted between definitive human hosts by multiple mosquito vectors and have varying geographical distributions. LF is common in tropical and subtropical regions — an estimated 120 million people in 81 countries are infected, a third of whom have overt clinical disease.1-2 About one-third of those infected reside in India, a third in Africa, and the remainder in the Americas, South-East Asia and the Pacific, including many of Australia’s neighbours and countries with which Australia shares strong migration links.1 It is difficult to estimate prevalence accurately, but according to antigenic studies, prevalence of LF infection in India (the country with the greatest disease burden) is 5.66%.2 Endemic LF transmission in Australia has not been reported for over 50 years.3All three of the patients described were originally from countries endemic for LF, and their cases highlight the need for clinicians to be aware of the likelihood of LF being imported into Australia. The patients presented with recurrent inguino-scrotal pathology, with or without associated systemic symptoms, emphasising the difficulties of diagnosing this infection. LF manifestations may be acute or chronic. Acute adenolymphangitis, which is often recurrent, is characterised by fever, chills and lethargy, followed by focal and transient oedema, erythema and discomfort. Adult worms (macrofilariae) are usually concentrated in the inguinal and scrotal lymphatics, and thus lower-limb and inguinal symptoms are more common, although the upper limbs and breasts may be affected. Chronic LF infection is usually indicated by lower-limb lymphoedema, with or without ulceration. Other symptoms include hydrocoeles and chyluria. In non-endemic regions, clinically apparent LF, manifested as adenolymphangitis, hydrocoeles or lymphoedema, is uncommon. Mosquitoes are inefficient vectors for LF — infection is generally restricted to migrants from endemic regions rather than travellers.4 Key clinical features that may assist in making a diagnosis of LF include: history of residence in an endemic country for several years; self-limiting nature of attacks, in contrast to bacterial cellulitis, incarcerated hernias or testicular torsion; bilateral symptoms and signs, as described in Patient 3; recurrent episodes, as in Patient 2; palpable regional masses or lymphadenopathy. Interestingly, many infected people remain asymptomatic. Risk factors for symptomatic disease include duration and intensity of exposure to vectors, adult worm burden, frequency of secondary infections and the host immune response.5 The diagnosis of symptomatic LF requires strong clinical suspicion. Careful ultrasound may identify the random movement of adult worms in dilated lymphatics, known as the “filarial dance sign” (FDS). This is particularly useful in a patient with scrotal symptoms and is considered the gold standard investigation for detecting viable adult worms;6 however, in Patient 3 this did not lead to the diagnosis. A blood film and serological evaluation are alternative diagnostic options. In most endemic areas, circulating microfilariae (filarial larvae) exhibit nocturnal periodicity (coinciding with peak feeding of local mosquitos) and are best seen on blood films taken between 10 pm and 4 am. If nocturnal samples are not feasible, then provocation with diethylcarbamazine may enhance microfilarial detection 1–2 hours later. Pacific Island infections (except Papua New Guinea) are subperiodic, with maximal microfilaraemia in the late afternoon, and show unresponsiveness to provocation. Importantly, patients with the chronic manifestations of LF often have low levels of circulating microfilariae, resulting in lower blood-film sensitivity.7 Serological tests available in Australia include an in-house enzyme immunoassay (EIA) developed against the dog heartworm Dirofilaria immitis (Westmead Hospital, Sydney, NSW), and an EIA based on IgG4 antibodies to recombinant Bm14 filarial antigen (CELISA, Cellabs, Sydney, NSW).8 Estimates of D. immitis EIA sensitivity and specificity vary and have been limited by an absence of accurate comparators and cross-reactivity. The newer Bm14 test has shown promising sensitivity and specificity. Neither test can differentiate filarial species, or active infection from past infection. Two tests that may be performed throughout the day are available for filarial antigen detection, which is a measure of adult worm burden (BinaxNOW Filariasis ICT [immunochromatographic test], Alere, Brisbane, QLD; and Og4C3 EIA, TropBio, Townsville, QLD).7 Both tests have limited sensitivity for diagnosing chronic disease manifestations — compared with ultrasound for live adult worms, ICT has 67% sensitivity. Neither test detects antigen from B. malayi or B. timori.6,7,9 BRUGIArapid ICT (Malaysian Biodiagnostics Research, Selangor Bangi, Malaysia) detects antibodies to B. malayi and B. timori only, but must be imported from Malaysia. Biopsy may allow identification of adult worms, but, given the availability of less invasive tests, it is reserved for difficult diagnoses. In non-endemic areas, the objective of LF treatment is symptom improvement rather than transmission reduction. Traditional LF treatments target microfilariae and have limited activity against macrofilariae. Macrofilariae and the host immune response are responsible for many disease manifestations, but recent evidence has implicated the symbiotic, intracellular bacteria Wolbachia in pathogenesis.5,10,11 Filarial nematodes depend on Wolbachia for normal development and fertility.10 Doxycycline has been shown to clear filaria of Wolbachia symbionts, leading to microfilarial and macrofilarial death, and thus provides an attractive treatment option.11-13 Multiple clinical trials have demonstrated doxycycline’s efficacy in reducing adult worm viability (as measured by scrotal ultrasound), circulating antigenaemia (a marker of adult worm burden) and microfilaraemia.11-13 The degree of reduction of adult worm viability with doxycycline (75%–92%) appears to be far greater than that with any of the commonly used antifilarial agents. Further, doxycycline has significant effects on disease progression, bringing about improvement in lymphatic function, hydrocoele size, lymphoedema, circulating levels of lymphangiogenic factors and rates of lymphangitis.11 The extent to which doxycycline’s effects are mediated through activity against secondary bacterial pathogens has not been evaluated. The optimal dose and duration for doxycycline therapy is unclear, but studies using 200 mg daily for at least 6 weeks have shown the best results.11,13 Whether doxycycline should be used in conjunction with ivermectin, albendazole or diethylcarbamazine remains unknown. These additional drugs increase adverse events; however, few trials have compared combination regimens to doxycycline alone.12 Overall, the evidence suggests that in non-endemic settings doxycycline is the treatment of choice for symptomatic LF. All patients in this series demonstrated a good clinical response to doxycycline. Lessons from practice In non-endemic countries such as Australia, where lymphatic filariasis (LF) is uncommon and can masquerade as other illnesses, the diagnosis may be delayed or missed. A high degree of clinical suspicion should be maintained. Manifestations of LF include acute adenolymphangitis characterised by acute episodic inguino-scrotal or lower-limb swelling and discomfort, often associated with systemic symptoms and chronic lymphatic dysfunction. Diagnosis is largely based on clinical features, owing to the limitations of diagnostic investigations. There is growing evidence in support of doxycycline as an effective, well tolerated, affordable disease-modifying treatment that is active against Wolbachia, an essential filarial endosymbiont.

Cameron J Jeremiah MB BS · Craig A Aboltins MB BS, FRACP · Peter A Stanley MB BS, FRACP

To the Editor: In Natural history of infectious disease,1 Macfarlane Burnet emphasised that poliomyelitis was the one infective disease of advanced countries that had failed to respond to improvements in the standard of living, leading to epidemics in the first half of the 20th century that increasingly involved young adults, who developed severe paralyses. There was also an abnormally high death rate among young adults. However, in tropical countries where the poliovirus was endemic, the virus spread among infants “with a minimal number of paralytic cases”. Burnet therefore defined a “safe” period in the first year of life, when infection was not likely to lead to paralysis. Burnet also described the features of the “so-called ‘virgin soil’ epidemics” that occurred in remote islands and Arctic communities. In these places, the population had not been exposed to the virus in infancy, but the “brunt of the disease was borne ... by adolescents and young adults”. In an Eskimo community, the paralysis rate was 40% and the mortality rate 14% of the whole population.1 When, in 1988, the World Health Organization decided to eliminate the poliovirus using the oral, live attenuated virus Sabin vaccine, it apparently ignored Burnet’s observations, concluding that polio was in fact a serious disease in tropical countries. As a result of the vaccination program, the wild virus was eliminated from Africa, except in Nigeria.2 However, re-infection has occurred in several African countries, leading to epidemics since 1993 in which young adults have become severely paralysed and the mortality rate has been high,3 because the population’s first contact with the wild virus has no longer occurred in infancy. Burnet predicted that young adults aged between 15 and 25 years would be the main group affected in any polio epidemic.1 He based his observations on the natural history of the disease. The current approach to the epidemiology of polio infection has, however, relied on mathematical models and molecular biology. Both of these approaches have failed to predict that epidemics would occur.4,5 In fact, Anderson and May claimed that the decision to advocate vaccination was justified — that “programmes of mass immunization against poliomyelitis in developing countries are unlikely to do harm”.4 Nearly 40 years earlier, Burnet wrote: Any escape into circulation that was not immediately dealt with could grow into the almost unimaginable catastrophe of a ‘virgin-soil’ epidemic of poliomyelitis involving all the populous regions of the world. [...] The great epidemics represented the entry of virulent strains into populations containing a high proportion of older children and adults who had escaped natural immunisation infection.6 The loss of naturally acquired immunity to the wild virus as the result of oral vaccination could have disastrous results. While it is now too late to stop vaccination, it should be extended to young adults as well as children, because current epidemics are affecting this age group, as Burnet predicted.1

Colin L Crawford

As tuberculosis resistance increases linearly, the cost and complexity of managing these cases increases exponentially New Zealand’s first case of extensively drug-resistant tuberculosis (XDR-TB) is reported in this issue of the Journal.1 Even though the patient did not have transmissible pulmonary TB, the case highlights the complexity of managing such patients and draws attention to the long delay between suspecting TB and confirming XDR-TB. Two cases of XDR-TB have been reported in Australia, one in 20042 and one in 2010,3 but there have been many more cases overseas.4 Still, only three cases in our two countries — should we care? A quick revision of history can help us to understand why multidrug-resistant TB (MDR-TB), and now XDR-TB, are so important. Tens of thousands of Australians and New Zealanders died of TB during the 19th and early 20th centuries.5 For generations, TB engendered the same dark fear that we now associate with cancer. One face in the crowd provides a poignant example. Archie Jackson, who in 1929 became the youngest cricketer to have scored a test century against England, was also one of the youngest to die — he was just 23 when he died from pulmonary tuberculosis in 1933.6 The advent of safe and effective antibiotic therapy after World War II meant the end of the great fear, and TB seemed defeated. In fact, rates of TB were already falling before the age of antibiotics, partly due to improvements in nutrition and living conditions.7 However, it would be folly to assume “game over, TB”. TB notifications have stopped falling in Australia and New Zealand, although they remain very low by international standards (about seven new cases per 100 000 population per year).8 In contrast, drug-resistant TB is out of control in several regions of the world. In Burma (Myanmar), the country of origin of the patient described in the case report from New Zealand, there were an estimated 4250 cases of MDR-TB in 2006 alone.4 The reasons for the worldwide emergence of resistance include poverty, breakdown in public health systems following the fall of the Soviet Union,4 the interaction of TB with AIDS in Africa, and a laissez-faire attitude to antibiotic control in some increasingly wealthy emerging nations.9 Because of the biphasic biology of TB, whereby frequent asymptomatic infection is followed unpredictably by active transmissible disease, there is no practical way of isolating Australia and New Zealand from TB drug resistance. Infection with Mycobacterium tuberculosis is initially acquired by breathing but the risk depends heavily on the local prevalence of active TB. If a person lives for many years in a high-risk country, infection is likely, but usually remains silent and can only be detected by performing a Mantoux test or interferon-gamma release assay. Neither test detects bacterial cells directly, so will not reveal the resistance profile of the infecting strain. The silent stowaways then travel with refugees, overseas students and migrants who come seeking sanctuary or opportunity. Screening by chest x-ray allows early detection in some, but it is not always appreciated that people with normal chest x-rays may also carry latent M. tuberculosis. For example, as described in this issue of the Journal by Trauer and Krause, of 146 refugees arriving in the Northern Territory who were found to have latent TB infection (LTBI), only 6% had chest x-rays showing abnormalities.10 Those with LTBI were offered isoniazid preventive therapy in accordance with current guidelines, but this is unlikely to reduce future reactivation of antibiotic-resistant TB. Fortunately, most people with LTBI remain well, but a small group will develop active disease, often relatively soon after arrival. In Victoria, the median time between arrival in Australia and notification of TB was 2 years in a 10-year review of MDR-TB.11 About half of new cases of TB in Australia and NZ have transmissible pulmonary disease, mostly caused by the same strain of TB that they breathed in years earlier, antibiotic susceptible or otherwise.11 In this way, good public health practice at home can be undone by poor public health practice abroad. Why does resistance matter? First, there is the cost. The World Health Organization has estimated that the cost of treating a patient with MDR-TB is about 100 times the cost of treating fully susceptible disease.12 For the patient, there is a long and difficult 18–24-month treatment course. And then, there is the return of the age-old fear — although patients with XDR-TB can be treated too, resistance to the most effective second-line antibiotics increases the risk of treatment failure and death.13,14 Definitions of tuberculosis-related terms TB Tuberculosis — a clinically apparent disease caused by Mycobacterium tuberculosis that typically presents with one or more systemic symptoms (eg, night sweats, fever, loss of weight) and a local symptom indicating the site of active infection (eg, cough, headache, back pain, neck gland swelling). MDR-TB Multidrug-resistant tuberculosis — TB caused by M. tuberculosis that is resistant to at least rifampicin and isoniazid, the most active first-line antibiotics. XDR-TB Extensively drug-resistant tuberculosis — MDR-TB that is also resistant to any fluoroquinolone, and to at least one of three injectable second-line anti-TB drugs (capreomycin, kanamicin, or amikacin). LTBI Latent TB infection — an individual is infected but has no symptoms or signs of active disease. TB reactivation A person with LTBI develops active TB. The lifelong risk is thought to be about 5%, but is much higher in patients with HIV or who are medically immunosuppressed. Primary resistance Resistance in M. tuberculosis obtained from a patient with no history of treatment. Secondary resistance The development of resistance during treatment of drug-susceptible TB due to incorrect prescribing and/or poor patient compliance. Secondary case [of TB] A person who is infected by someone with active pulmonary TB before this initial diagnosis is made and the patient is isolated. So what is a rational response to this threat in low-risk countries such as Australia and New Zealand? Predicting where new cases of resistant TB will appear is very difficult. In Australia, there were only 153 cases of MDR-TB and one case of XDR-TB in the period 1995–2007.2 There have been about 2700 more cases of TB diagnosed since then,15 with an expected MDR-TB rate of about 2.5%.2 If you are a manager thinking that maybe you could put your TB funds to work elsewhere, think again. Resistant TB in a low-prevalence country is an example of a low-probability, high-impact event — a “black swan”, to borrow a concept recently popularised by the economist Nassim Taleb.16 A black swan is something too improbable to worry about, but then it happens and everything changes. For Europeans, swans had been axiomatically white for millennia. In 1697, a black swan was observed during the exploration of what is now Western Australia, and an axiom collapsed because of a single exception. Moreover, according to Taleb, such events are immediately rationalised and considered to have been obvious in retrospect.16 Consider the impact of a delayed diagnosis of pulmonary XDR-TB if the patient were an overseas-trained nurse or doctor working in a paediatric hospital. There is no proven postexposure prophylaxis; there is a risk of treatment failure and drug toxicity that would further distress already anxious parents; and the cost of successfully treating even one secondary case of XDR-TB has been estimated at US$600 000 in a Californian case series.17 Something like this will happen — we just don’t know when. Here are some suggestions for how we can try to out-swim the black swan. First, we must sustain and extend our existing overseas programs that support our neighbours in their struggle to control TB. This is not philanthropy, it is just common sense. One example involves clinics that have been providing treatment for MDR-TB to Papua New Guinea nationals who cross the Torres Strait to receive it. A recent decision taken on cost grounds by the Queensland and Commonwealth governments to close these clinics is unlikely to save Australia any money in the long run.18 Our next line of defence is the primary care clinician. Rapid diagnosis of pulmonary TB minimises secondary transmission, whatever the resistance pattern of the isolate. Then we need to strengthen our local TB public health services and recognise that as TB resistance increases linearly, the cost and complexity of managing these cases increases exponentially. Finally, we need to keep up to date with new technology. The latest molecular methods are now able to directly detect the presence of M. tuberculosis and rifampicin resistance simultaneously in primary specimens, including in some that are smear-negative (ie, acid-fast bacilli present but too few to be seen by microscopy).19 This is an important advance because rifampicin resistance is a marker for MDR and XDR-TB and the result could be available within just a few hours. Molecular diagnostics are not yet perfect — we will need to retain culture-based methods for a while yet — but they are now becoming widely available and progressively cheaper. We should embrace these new technologies and make molecular screening of primary specimens standard practice, even though the upfront costs will seem high initially. We need to be organised and up to date if we want to stay ahead of TB.

Paul D R Johnson MB BS, PhD, FRACP(Infectious Diseases)

Objectives: To assess the prevalence of latent tuberculosis infection (LTBI) in recently arrived refugees in the Northern Territory and to obtain comprehensive data for rates of treatment acceptance and completion for this condition.Design, setting and participants: Prospective data collection and follow-up of all 471 newly arrived refugees seen at the Centre for Disease Control, NT refugee health clinic from February 2006 to January 2009.Main outcome measures: Rates of LTBI determined by tuberculin skin testing; subsequent assessment and treatment compared with local protocols.Results: 458 of 465 eligible refugees were adequately assessed for LTBI, of whom 146 (31.9%) were diagnosed with LTBI. Older age, male sex and World Health Organization Eastern Mediterranean region of birth were associated with increased prevalences of LTBI. Of the refugees diagnosed with LTBI, 10 failed to attend for follow-up and 15 were not offered treatment. Isoniazid therapy was accepted by 93 of 121 refugees (76.9%), and 41 of these (44.1%) completed treatment. The most common reasons for discontinuation of therapy were medication-related side effects (most often gastrointestinal) and loss to follow-up. Increasing age was associated with failure to complete treatment.Conclusion: Outcomes of assessment and treatment for LTBI in newly arrived refugees in the NT are comparable to those for other target groups screened in developed countries. Loss to follow-up caused significant attrition in numbers, but complete data were obtained for a large proportion of eligible refugees. Most refugees who are offered treatment for LTBI accept, but less than half complete treatment.

James M Trauer MB BS · Vicki L Krause FAFPHM

In 2010, an immigrant from Burma was the first person to be diagnosed in New Zealand with extensively drug-resistant tuberculosis (XDR-TB). The strain of Mycobacterium tuberculosis is the most resistant reported to date in Australasia. Key difficulties of managing this disease in a low-prevalence country were delays from drug-susceptibility testing and in acquiring appropriate medicines, and a lack of evidence-based guidelines. Solutions are needed for New Zealand and the wider region as more cases of XDR-TB are likely to be encountered in the future. (MJA 2011; 194: 602-604) Clinical recordA 29-year-old man presented to his general practitioner in Otago, New Zealand, in March 2010 with discharge from an enlarged left anterior cervical lymph node (Box 1). He reported two episodes of night sweats but no weight loss, fever or chills. He was not coughing or producing sputum, and had no haemoptysis or chest pain. He was born in Burma (Myanmar) but had emigrated to New Zealand in 2006. At that time, chest x-ray screening did not detect tuberculosis (TB). He had no personal history of TB and no known contacts with TB. Fine needle aspirate that was collected in late March from the affected lymph node grew Mycobacterium tuberculosis after 30 days’ incubation. The isolate was sent to a reference laboratory for drug-susceptibility testing (DST). Eight days later, the isolate was reported to be “presumptively” resistant to isoniazid, rifampicin and ethambutol based on the results of broth-based DST methods. Resistance to pyrazinamide was also reported on the basis of a negative Wayne test. Additional DST was performed against the second-line drugs capreomycin, ethionamide, ofloxacin and amikacin. A further 10 days later, the isolate was reported to be resistant to all four of these second-line drugs and a report of “presumptive” extensively drug-resistant TB (XDR-TB) was issued. Because of the isolate’s unusually resistant profile on conventional phenotypic testing, molecular tests were used to cross-check these results by identifying gene mutations associated with resistance (Box 2). Fourteen days after the preliminary report of XDR-TB was made, and a total of 66 days after the sample was initially collected, a final laboratory report confirming XDR-TB was issued. Further DST performed by an international reference laboratory revealed susceptibility to cycloserine and para-aminosalicylic acid. DST was not performed against imipenem and clofazimine owing to a lack of standardised methods. After the isolation of M. tuberculosis, the patient was initially treated in the community with standard first-line drugs. On receipt of the preliminary DST results, his urgent admission to hospital was arranged, with provision for isolation to prevent airborne disease transmission. A chest x-ray at this time showed fibrosis in the left upper zone, and a computed tomography (CT) scan showed an enlarged lymph node in the left anterior cervical chain (Box 3). The patient’s HIV serology results were negative, and an induced sputum sample set for TB was negative for acid-fast bacilli. Treatment was instituted with cycloserine 250 mg orally twice daily, para-aminosalicylic acid 4 g orally twice daily, linezolid 600 mg orally once daily, moxifloxacin 800 mg orally once daily, imipenem 1 g intravenously twice daily, clofazimine 200 mg orally once daily and isoniazid 600 mg orally once daily. The hospital pharmacy had difficulty in obtaining cycloserine, clofazimine and para-aminosalicylic acid. A 2-week supply of these agents was obtained from Auckland, New Zealand, but the remainder had to be imported from the United States. After 5 weeks of treatment, the patient’s enlarged lymph node had reduced in size and the discharge had stopped. Treatment with imipenem was stopped and treatment with amoxycillin–clavulanate 625 mg orally three times daily was begun. Three further sets of induced sputum samples were negative for TB. The patient was discharged back to the community, as the risk of him passing on the infection was now low. He attended weekly follow-up by a respiratory specialist and was monitored for treatment adherence by public health staff. A follow-up CT scan of the neck 2 months after discharge showed further significant improvement. Initially, surgical removal of the lymph node had been planned. However, with resolution of the lymph node after 5 months of medical therapy, surgery was not required. Apart from transient nausea, the patient is tolerating the treatment well and it is planned to continue treatment for a minimum of 18 months. Public health contact tracing of people who had resided with the patient showed they did not have TB. DiscussionMultidrug-resistant TB (MDR-TB) is defined as M. tuberculosis infection that is at least resistant to both isoniazid and rifampicin. XDR-TB is defined as resistance to not only isoniazid and rifampicin but also any fluoroquinolone and one of the second-line injectable drugs (such as capreomycin, amikacin or kanamycin).1 This report describes the first case of XDR-TB in New Zealand; it also describes the most resistant strain of M. tuberculosis reported to date in Australasia. By 2009, 58 countries had reported at least one case of XDR-TB. Despite this, there has been no new drug licensed to combat TB for 40 years.2 Given the increasing frequency of travel and immigration from high-risk areas, New Zealand and other countries in the region are likely to encounter more cases of XDR-TB in the future. The current cost of our patient’s medication to the government is about NZ$10 000 per month. Burma is one of 22 countries with a high health burden due to TB; in 2004, 4% of new TB cases and 15.5% of those previously treated were of MDR-TB.3 No cases of XDR-TB have been reported in Burma, but this is likely to be due to underreporting secondary to resource and laboratory constraints.1 In New Zealand, the incidence of TB is about seven per 100 000 people annually, and the rate of drug resistance for TB has been very low;4 from 2000 to 2009 there were 22 cases of MDR-TB.4 Since 2009 there have been a further nine cases reported to date (unpublished data obtained by J T F). From a regional perspective with regard to XDR-TB, Australia reported one case in the period 2002–2005 and the Pacific Islands did not report any.5 A second case was reported in Australia in 2010.6 Our patient showed primary resistance, in contrast to secondary resistance which develops from inadequate or inappropriate therapy: he arrived in New Zealand with latent infection, having been infected with XDR-TB in Burma. DST provides key information for the management of XDR-TB. This case highlights the integral role of diagnostic laboratories in rapidly and accurately reporting results to guide appropriate treatment. In this case, commercially available molecular-based methods enabled highly unusual DST results to be cross-checked and confirmed once the results of conventional, broth-based phenotypic DST had become available. However, in principle, such assays could have been used before obtaining the results of conventional DST. This could potentially have resulted in a report of MDR-TB being issued 12 days earlier, and in second-line DST results and the XDR nature of the isolate being reported about 20 days earlier. Notably, this patient came from a geographical area known to have a high prevalence of MDR-TB. It may be that, in future, risk-based laboratory DST algorithms can be devised so that molecular DST can be selectively applied as the initial method of testing for patients at high risk of MDR-TB. However, the cost-effectiveness of such risk-based testing algorithms in low-prevalence settings would need to be established. Hypothetically, if the patient had active pulmonary TB, molecular DST could have been performed directly on a respiratory specimen rather than waiting for the culture to grow.7 Use of such a test in this scenario could have potentially reduced the turnaround time by over 60 days. There are limited data available to definitively guide the management of XDR-TB, but current regimens recommend the use of four or more effective medications, based on DST.8 This includes any first-line agent that is effective, a fluoroquinolone, a second-line injectable agent and any third-line agent to make up four to six medications. Pyrazinamide and ethambutol should be included if possible, as this improves survival.8 Kanamycin can be used in streptomycin-resistant cases, and amikacin if there is resistance to both kanamycin and streptomycin. Capreomycin and viomycin can also be considered. The fluoroquinolones have variable potency — moxifloxacin and gatifloxacin are more potent then ofloxacin and levofloxacin. Ciprofloxacin is not recommended as an antituberculous agent.9 Other second-line agents like ethionamide, para-aminosalicylic acid and cycloserine can also be used. Linezolid, meropenem and amoxycillin–clavulanate are not licensed for this use but can be added if no alternatives are available. Monitoring for adverse drug reactions is important.8-10 For pulmonary XDR-TB, treatment for at least 18 months is recommended after conversion to negative sputum cultures.9 Directly observed therapy should be instituted, and treatment success may be up to 60% in patients without HIV infection.10 Surgical resection in conjunction with medical management is useful in selected patients with XDR-TB.11 However, most surgical studies are focused on pulmonary XDR-TB. There is a lack of research on surgical outcomes for head and neck XDR-TB. Early recognition of cases, with isolation in negative pressure rooms and high efficiency particulate air filtration, is necessary to prevent spread, but standard chemoprophylaxis with isoniazid, rifampicin, or rifampicin and pyrazinamide for contacts is unlikely to be effective in XDR-TB.12 Although our experience indicates that there is potential for treatment success, definitive treatment guidelines are needed and more data are required to inform treatment and help contain spread. Further, it illustrates the importance of maintaining an adequate supply of second-line drugs in New Zealand. Confirming XDR-TB in a young man from Burma who had no history of previous TB treatment suggests that XDR-TB may be more common in Burma than has been widely believed, reinforcing the need for strengthening laboratory support networks and TB surveillance systems in South-East Asia. 1 External appearance of the patient’s left anterior cervical lymph node on presentation 2 Gene mutations identified in the Mycobacterium tuberculosis isolate, and associated known antibiotic resistance Gene Mutation Associated antibiotic resistance katG S315T Isoniazid rpoB S315L Rifampicin gyrA D94A Moxifloxacin rrs A1401G Amikacin and capreomycin embB M306I Ethambutol 3 Computed tomography scan of the patient’s neck on presentation, showing an enlarged left anterior lymph node

Tze Liang Goh MBChB · Cindy R Towns PhD, MBChB, BSc(HighHons) · Katharine L Jones BMedSci, BM BS, MRCP · Joshua T Freeman MBChB, FRCPA, PGDipID · Colin S Wong DM, FRACP

Objective: To determine uptake of treatment for hepatitis C virus (HCV) infection and predictors of deferral of treatment for HCV by using prospectively collected data from the Australian Chronic Hepatitis C Observational Study (ACHOS).Design, patients and setting: Cohort study involving interview and medical record review at enrolment and routine follow-up clinic visits of patients with chronic HCV and compensated liver disease attending a national network of 24 HCV clinics between April 2008 and December 2009. Eligible patients were those who had not been previously treated, were enrolled within 6 months of their first clinic visit, were eligible for treatment and had been enrolled for at least 6 months.Main outcome measure: Predictors of patients undergoing HCV treatment within the first 6 months of assessment.Results: 1239 patients were enrolled in ACHOS, of whom 406 met the criteria for inclusion in the subcohort for this study. Among this subcohort, 171 (42%) received treatment within 6 months of their first clinic visit. Current injecting drug use (odds ratio [OR], 0.26; 95% CI, 0.08–0.77), past and current treatment for drug dependency (OR, 0.34; 95% CI, 0.18–0.67, and OR, 0.42; 95% CI, 0.22–0.81, respectively) and alcohol use above 20 g/day (OR, 0.20; 95% CI, 0.08–0.46) were independent predictors of deferral of treatment. At least one of these factors applied to 41% of the subcohort. Clinical factors, including HCV genotype, HCV RNA level, and stage of liver disease were not associated with deferral of treatment for HCV.Conclusion: Factors related to drug and alcohol use, rather than clinical factors, influenced uptake of treatment for HCV. Further support for patients with drug and alcohol dependency is required to optimise treatment uptake.

on behalf of the ACHOS investigator team

Multidose vials (MDVs) for injectable therapeutic agents, including vaccines, pose a risk of infection to injected patients as a result of contamination of the vials. The Australian Government Department of Health and Ageing (DoHA) distributed the vaccine against pandemic (H1N1) 2009 influenza in MDVs. The distribution was accompanied by consent forms. The consent forms provided an inadequate basis for a discussion with patients about the risks associated with the use of MDVs. The High Court of Australia has previously held that medical practitioners who fail to explain the material risks of medical procedures to their patients might be held liable in negligence for any adverse sequelae of the procedures, even if the risks are very low. Medical practitioners, nurses, medical indemnity insurers and the DoHA should prepare now for the probable future use of MDVs by developing a consent form that would provide a solid foundation for a discussion of material risks with patients seeking vaccination.

Mark R Diamond PhD · Angela O’Brien-Malone PhD

With the expansion of the Second World War into the Pacific in 1941, and due to the deleterious impact of malarial infection on fighting capacity, the Australian Army devoted significant resources to new research into the prevention and treatment of malaria between 1943 and 1945 by forming the Land Headquarters Medical Research Unit in Cairns, Queensland. The documentation of this research became a significant subject for leading Australian artist Nora Heysen, when she was commissioned as the first female war artist by the Australian War Memorial in 1943.

Cherie L Prosser BSc, MA(Art History) · Ian A Clark BVSc, PhD, DSc