Infectious diseases

The complete, up-to-date guidelines can be found at: http://www.mja.com.au/ public/rop/cheng/che10661_fm.html Since the initial reports of H1N1 influenza (human swine influenza; caused by influenza A/2009/H1N1/swl) in Mexico and the United States in mid April 2009, many thousands of cases have been reported worldwide. At the time of writing, community transmission is becoming established in many areas in Australia, but the number of reported cases is likely to be an underestimate of the true incidence due to policies for testing. These guidelines provide advice to clinicians on the use of antiviral agents for this newly emerged influenza virus. A full version of these guidelines, including all references, has been previously published online (http://www.mja.com.au/public/rop/cheng/che10661_fm.html). Recommendations for diagnosis of influenzaIn areas with established community transmission, patients presenting with an acute febrile respiratory illness (fever with cough and/or sore throat) are considered to have H1N1 influenza 09 and testing is generally not recommended. Early in the course of the pandemic, timely influenza diagnostic tests can be used to enable targeted antiviral treatment, but will be less useful once community transmission is widespread. Health care workers performing nose swabs or other high-risk aerosol-generating procedures (eg, suctioning, bronchoscopy or intubation) should use a particulate respirator (N95, P2 mask or equivalent), eye protection, impervious gowns, gloves, and, where possible, carry out the procedure in a negative pressure room. The use of nasopharyngeal aspirates are not recommended because of the risk to staff. The use of a combined nose–throat swab is recommended for diagnosis. Specimens for viral nucleic acid detection and culture at reference laboratories should be taken for epidemiological surveillance and to monitor for drug resistance. Once the pandemic is established, this is best facilitated through existing sentinel surveillance systems. Recommendations for treatment using antiviral agentsAntiviral treatment has been shown to reduce the duration of symptoms and may also reduce the incidence of lower respiratory tract infection. Neuraminidase inhibitors (oseltamivir and zanamivir) are the antiviral agents of choice for H1N1 influenza 09. Dose recommendations for treatment and prophylaxis are provided in Box 1 and Box 2, respectively. The decision to treat an individual patient, particularly before the results of confirmatory testing are available, depends on three factors: An assessment of the likelihood of influenza, based on the known prevalence of infection in the region, a history of contact and the characteristics of the illness. An assessment of the likely benefits of treatment (Box 3), based on the presence of established complications, comorbidities and risk factors (Box 4), and the time since onset of the illness. The phase of the pandemic and the public health policies regarding distribution of the national stockpile (Box 5). Recommendations for treatment in adultsAntiviral treatment should only be given to patients with confirmed or suspected influenza within 48 hours of symptom onset, except in cases of severe influenza. Treatment should be prioritised for patients with risk factors for poor outcomes, such as the morbidly obese, pregnant women, those with chronic disease (including asthma, cardiorespiratory disease, diabetes and renal failure) or immunosuppression, and those presenting with severe disease. Recommendations for treatment in childrenAntiviral treatment can be given to children as young as 1 year. Parents should be warned of the possibility of rare neuropsychiatric symptoms related to oseltamivir use in children and adolescents. There is a concern regarding central nervous system accumulation of neuraminidase inhibitors in infants aged under 1 year, based on animal data; a treatment decision must balance the potential benefits of treatment with potential toxicity. Recommendations for treatment in pregnant womenAntiviral treatment should be offered to pregnant women with suspected or confirmed influenza because of the risk of severe disease in this group. Oseltamivir and zanamivir are in the Australian Drug Evaluation Committee category B1, with limited evidence suggesting safety. Recommendations for treatment of severe influenzaAntiviral treatment should be given to hospitalised patients with severe influenza infection (especially pneumonia), even if commenced more than 48 hours after the onset of symptoms. Antibiotic treatment should not be given routinely for influenza-like illness, but antibiotic treatment should follow established national guidelines for treatment of community-acquired pneumonia. Recommendations for prophylaxis with antiviral agentsLong-term prophylaxis can be given to first-responder health care workers for up to 6 weeks for oseltamivir and up to 4 weeks for zanamivir. Use of antiviral prophylaxis for these groups should be in the context of agreement to use the national stockpile. Antiviral prophylaxis can be given to health care workers and close contacts of patients with influenza following exposure, and to residents of institutions to terminate outbreaks. Contacts not provided with prophylaxis should have access to early treatment with antiviral agents, where indicated. Updated informationWe acknowledge that the evidence on which these recommendations are based is rapidly changing. In particular, estimates of disease severity and case fatality, and risk factors for severity are poorly defined at present and may influence clinical decision making. We therefore include some resources for further information. Updates to these clinical guidelines will be posted on the websites of the Australasian Society for Infectious Diseases (ASID) (http://www.asid.net.au), the Thoracic Society of Australia and New Zealand (TSANZ) (http://www.thoracic.org.au) and the MJA (http://www.mja.com.au). Australian resources for pandemic influenza, including links to clinical and infection control guidelines (http://www.flupandemic.gov.au) and current information on the H1N1 outbreak (http://www.healthemergency.gov.au and http://www.influenza specialistgroup.org.au). For information on accessing personal protective equipment and antiviral medication, see links below: http://www.emergency.health.nsw.gov.au/swineflu/professionals/index.asp (New South Wales) http://humanswineflu.health.vic.gov.au/practitioners/index.htm (Victoria) http://www.health.qld.gov.au/swineflu/html/hc_resources.asp (Queensland) http://flu.sa.gov.au/Swineflu/InformationforGPs.aspx (South Australia) http://www.public.health.wa.gov.au/3/952/3/human_swine_flu_health_providers.pm (Western Australia) http://www.pandemic.tas.gov.au/what_does_it_mean_to_you/health_sector (Tasmania) http://www.health.nt.gov.au/H1N1_Influenza/General_Information_Resources/index.aspx (Northern Territory) http://health.act.gov.au/c/health?a=da&did=11044035&pid=1242181681 (Australian Capital Territory). 1 Dose recommendations for treatment of influenza Treatment Dose, interval, duration Oseltamivir Adults; children > 13 years 75 mg, twice daily orally, 5 days Renal impairment* 75 mg, daily orally, 5 days Children aged 1–13 years < 15 kg 30 mg, twice daily, 5 days 15–23 kg 45 mg, twice daily, 5 days 23–40 kg 60 mg, twice daily, 5 days > 40 kg 75 mg, twice daily, 5 days Zanamivir Adults 10 mg (2 inhalations), twice daily, 5 days Children > 5 years 10 mg (2 inhalations), twice daily, 5 days * Creatinine clearance, 10–30 mL/min. 2 Dose recommendations for prophylaxis against influenza Prophylaxis Dose, interval, duration Oseltamivir Adults; children > 13 years 75 mg, daily, 10 days Renal impairment* 75 mg, alternate days, 10 days Children aged 1–13 years < 15 kg 30 mg, daily, 10 days 15–23 kg 45 mg, daily, 10 days 23–40 kg 60 mg, daily, 10 days > 40 kg 75 mg, daily, 10 days Zanamivir Adults 10 mg (2 inhalations), daily, 10 days Children > 5 years 10 mg (2 inhalations), daily, 10 days * Creatinine clearance, 10–30 mL/min. 3 Factors to consider in deciding on likely benefits of treatment for H1N1 influenza 09 (human swine influenza) infection Established complications Hospitalised patients Patients with respiratory compromise Patients with pneumonitis or secondary bacterial pneumonia High risk of complications Pregnant women Patients with morbid obesity Indigenous Australians Patients with chronic respiratory disease; other comorbidities (see Box 4) Potential for transmission to others Health care workers and first responders (eg, paramedics) Household contact or carer of high-risk patient Low risk of complications Healthy adults Low likelihood of benefit Presentation > 48 hours after onset of illness High prevalence of circulating influenza strains with resistance to neuraminidase inhibitors Potential risks of treatment Infants < 1 year 4 Patients at risk of complications from influenza infection* Pregnant women Indigenous Australians Patients with: chronic respiratory disease (including asthma and chronic obstructive pulmonary disease); cardiac disease; morbid obesity; chronic diseases (eg, diabetes, chronic metabolic diseases, chronic renal failure, haemoglobinopathies); chronic neurological disorders; or impaired immunity, including HIV infection Homeless people Residents of nursing homes and long-term care facilities Children aged 6 months – 10 years on long-term aspirin therapy Older people (> 65 years) Children < 5 years * Adapted from the Australian immunisation handbook.1 5 Indications for antiviral treatment and prophylaxis for H1N1 influenza 09 (human swine influenza) infection, depending on likelihood of benefit and stage of pandemic Pandemic phase Delay Contain Sustain Protect Epidemiological setting Little or no community transmission; cases identifiable via exposure history Limited community transmission; cases not identifiable via exposure history Community transmission in some regions Widespread community transmission Treatment Patients with established complications Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Groups at risk of complications* Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Health care workers, carers for patients at risk of complications within 48 h of onset of illness Clinically presumed or laboratory-confirmed Clinically presumed (if appropriate exposure history) or laboratory-confirmed Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Otherwise healthy adults and children > 5 y within 48 h of onset of illness Clinically presumed or laboratory-confirmed Laboratory-confirmed Clinically presumed (depending on rationing policy and virulence) Not generally indicated Infants < 1 y Depends on clinical scenario Depends on clinical scenario Depends on clinical scenario Depends on clinical scenario Low likelihood of benefit (> 48 h after presentation, known high prevalence of resistance) Not indicated, unless severe infection present. Consider zanamivir if oseltamivir-resistant Not indicated, unless severe infection present. Consider zanamivir if oseltamivir-resistant Not indicated, unless severe infection present. Consider zanamivir if oseltamivir-resistant Not indicated, unless severe infection present Prophylaxis following exposure Groups at risk of complications* Indicated Indicated Indicated (depending on rationing policies) Not generally indicated, except immunosuppressed patients and closed communities Health care workers, carers for patients with comorbidities Indicated Indicated Indicated (depending on policy for national stockpile) Not generally indicated (depending on hospital policy) Healthy adults and children > 5 y within 48 h of exposure Indicated Indicated Not indicated (depending on rationing policy and virulence) Not indicated Children < 1 y Not generally indicated Not generally indicated Not generally indicated Not generally indicated Low likelihood of benefit (> 48 h after exposure) Consider up to 7 days after exposure to prevent transmission Depends on observed incubation period and public health policy Consider early treatment if symptoms develop Not indicated * Such as pregnant women, patients with comorbidities or immunosuppression, and Indigenous Australians (Box 4).

Allen C Cheng FRACP, MPH, PhD · Dominic E Dwyer MD, FRACP, FRCPA · A Thomas C Kotsimbos MB BS, FRACP, MD · Mike Starr MB BS, FRACP · Tony M Korman MB BS, FRACP · Jim P Buttery MB BS, MSc, FRACP · Christine R Jenkins MD, FRACP · Vicki L Krause MD, FAFPHM, DTM · Paul D R Johnson MB BS, PhD, FRACP

What lessons can be learnt from Australia’s initial response to the outbreak? Given all the detailed planning and preparation that has gone into the Australian Health Management Plan for Pandemic Influenza (AHMPPI)1 over the past 4 years, Australians may be wondering how well the plan has performed in Victoria during the recent H1N1 (swine) influenza outbreak. As clinicians working in one of the main affected hospitals, we would like to offer four key observations. Firstly, the AHMPPI is a carefully developed medical and social management plan that was primarily designed to deal with a serious new strain of influenza, such as avian influenza, in which the case mortality (death rate) was expected to be up to 40%.2 It was developed by experts in virology, epidemiology and health policy based on computer modelling that used assumptions about disease transmission rates (infectiousness), disease severity and the likely effectiveness of a single drug — oseltamivir. In planning, there was only limited input from clinicians, and practical issues — such as the adequacy of the protective mask stockpile or the means of rapidly distributing drugs and equipment to the “front line” — do not appear to have been planned in detail.3 In reality, the severity of the 2009 swine flu outbreak has fallen well short of the worst-case scenario: instead of resulting in high mortality, swine flu has been associated with only a 1%–2% hospital admission rate and zero mortality in Australia (so far); early experience has shown that the clinical case definition (fundamental to accurate disease modelling) was not an accurate model for the swine flu epidemic; and drug and mask distribution has been extremely slow, especially to general practitioners, who are crucial to effective disease management and containment. But the AHMPPI has lagged in adapting to these circumstances. Instead of being flexible and responding to feedback from the medical front line in Victoria, the AHMPPI has continued to be rigidly based on past assumptions. The process has tended to focus on managing data and information flow, rather than managing the sick patients. Secondly, initial laboratory testing to confirm a case of swine flu was only allowed if a sick patient fitted the specific case definition — namely, the patient had to be a recently returned traveller from Mexico or North America, or a close contact of a proven case. Tests on all other patients who had a clinical illness suspected of being swine flu were initially refused or given low laboratory priority. This is the opposite of what should have occurred. To understand the full extent of disease spread, widespread testing without assumptions needs to occur so that the accuracy of the proposed case definition can be tested. The case definition should be used to guide clinicians, not the laboratory testing strategy. Otherwise it simply becomes self-confirming and does not identify the real extent of disease spread until it is too late — as has occurred in Victoria. Thirdly, public hospital testing capacity for viral diseases has been primarily concentrated, over the past three decades, on just one centre in Victoria — the Victorian Infectious Diseases Reference Laboratory. Although initially this made sense given the complexity of viral testing, technology has developed so rapidly in recent years that most public hospital laboratories now have molecular testing equipment available to accurately test for swine flu and other viruses. Thus, the present approach needs to change to reduce the current bottleneck whereby swine flu test results often take 3–5 days to come through. Meanwhile, the patient is not in quarantine and is generally not receiving antiviral therapy. If all hospitals had testing capacity and the rules for testing were not based on preconceived assumptions, the current influenza situation might have been different. Of course, confirmation of positive results by a reference laboratory would still be required, but its workload would be manageable (about 10%–20% of current levels). Finally, the AHMPPI depends on faith in oseltamivir — that it is totally safe and that its use will reduce disease severity and spread. However, to be effective, the drug should be commenced within 48 hours of disease onset.4 With laboratory results taking days to return, the only clinical solution would be to commence oseltamivir immediately influenza is suspected — in which case, at Austin Health we would be treating up to 80% of patients for a disease they do not have. Already it is known that the main seasonal influenza strain in the United States in 2008 was resistant to oseltamivir. The real nightmare scenario will be if the current swine flu strain also develops resistance in the face of widespread use of oseltamivir, leaving us with few treatment options. We are currently wasting oseltamivir on a mild illness when we are likely to need it next year, when the current strain could become more aggressive. Of course, some good things have come from the current outbreak. It is possible (but not certain) that people who caught swine flu this year may have some protection for next year’s possibly more aggressive strain. Secondly, the Acting Chief Health Officer in Victoria has done a great job in establishing new communication links with front-line clinicians and injecting some common sense into the AHMPPI debate. Finally, it has given Australia a chance to test its AHMPPI — what we need now is to critically evaluate its practical strengths and weaknesses.

M Lindsay Grayson MD, MSc, FRACP · Paul D R Johnson MB BS, FRACP, PhD

The swine influenza (H1N1 09) outbreak in Victoria has provided an excellent opportunity to review the Australian Health Management Plan for Pandemic Influenza (AHMPPI) and to assess its performance in practice. General practitioners play a major role in seasonal flu management, and it was expected that the AHMPPI would enable GPs on the front line to maintain this central role during the swine flu pandemic. The role of front-line GPs has been made extremely difficult by deficiencies in implementation of the AHMPPI, including resource supply failures, time-consuming administrative burdens, delays in receiving laboratory test results and approval for provision of oseltamivir to patients, and a lack of clear communication about policy changes as the situation progressed. We must use this experience to ensure timely and appropriate review of the AHMPPI and the way it is implemented. Better consultation with front-line clinicians, particularly GPs, is crucial and must occur as a matter of urgent priority.

Peter Eizenberg MB BS

We present the first six cases of H1N1 influenza 09 (confirmed by a polymerase chain reaction test from nasopharyngeal swabs) in patients requiring admission to intensive care in Australia (in three hospitals in the north-western suburbs of Melbourne). These cases highlight the small but significant risk of life-threatening respiratory failure associated with H1N1 influenza 09 infection. Clinical recordsPatient 1A 28-year-old obese woman (body mass index [BMI], 57 kg/m2) presented to the emergency department (ED) with a history of 5 days of sore throat, lethargy and myalgias, and a clear chest x-ray, followed by 2 days of dyspnoea, productive cough, and pleuritic chest pain. She was febrile (40°C), and had tachypnoea (respiratory rate, 36 breaths/min) and hypoxia (oxygen saturation measured by pulse oximetry [Spo2], 87% on 15 L/min oxygen via face mask). Her admission chest x-ray showed widespread alveolar infiltrates. She had a normal white cell count (WCC) of 6.3 × 109/L, but an elevated serum C-reactive protein (CRP) level of 221 mg/L (reference ranges shown in Box 1). She was admitted to the intensive care unit (ICU) and, after a brief trial of non-invasive ventilation (NIV), was intubated and treated with mechanical ventilation (MV) with a fraction of inspired oxygen (Fio2) of 1.0 and positive end-expiratory pressure (PEEP) of 20 cm H2O for the first 24 hours to maintain an Spo2 > 89%. She was treated with inotropes for septic shock and with renal replacement therapy for acute renal failure. Therapy with oseltamivir in addition to empiric broad-spectrum antibiotics was commenced. Bacterial cultures of blood, urine and tracheal aspirate were negative. The result of a test for urine pneumococcal antigen was negative. The patient was successfully weaned from ventilatory support on Day 14. Patient 2A previously well 24-year-old man (BMI, 22 kg/m2) was admitted to a regional hospital with a 1-week history of dry cough, fever, headache, abdominal pain, and vomiting. Thirty-six hours later, he was transferred to a metropolitan hospital because of worsening dyspnoea and hypoxia (Spo2, 88% on 15 L/min oxygen via face mask). He had tachycardia (110 beats/min), tachypnoea (respiratory rate, 34 breaths/min) and was febrile (39.9°C). He had a normal WCC (4.2 × 109/L) but an elevated CRP level (256 mg/L). A chest x-ray showed unilateral lobar consolidation. He was transferred to the ICU and treated with oseltamivir, broad-spectrum antibiotics, and NIV with an Fio2 of 1.0. After 96 hours, his hypoxia remained severe (partial pressure of arterial oxygen [Pao2] to Fio2 ratio, < 100), another chest x-ray showed bilateral alveolar infiltrates, and he was intubated and MV was commenced with an Fio2 of 1.0 and high-level PEEP (20 cm H2O) for several days. Bacterial cultures and urine pneumococcal antigen test results were negative. Oseltamivir therapy was continued for 7 days, and MV for 15 days. Patient 3A 26-year-old obese man (BMI, > 40 kg/m2) with a history of mild asthma presented after 2 days of nausea without vomiting, and no fever or cough. On the day of admission, he developed shortness of breath. He was found to be hypoxic (Spo2, 90% on an Fio2 of 1.0) with bilateral pulmonary infiltrates showing on a chest x-ray. His WCC was 5.6 × 109/L and CRP level was 137 mg/L. Therapy with broad-spectrum antibiotics and oseltamivir was commenced. He was intubated, and MV was commenced with an Fio2 of > 0.6 and high-level PEEP (15 cm H2O); the patient was successfully extubated after 10 days. Patient 4A previously well 41-year-old man (BMI, 30 kg/m2) presented with a 7-day history of cough, coryza, malaise, back pains and rigors. On the day of presentation, he became febrile (39.6°C) and developed tachypnoea (respiratory rate, 45 breaths/min) and severe hypoxia (Spo2, 84% on 10 L/min oxygen via face mask). His chest x-ray showed widespread pulmonary infiltrates. He had a WCC of 4.4 × 109/L and a CRP level of 166 mg/L. He was intubated in the ED and MV was commenced, and he was given oseltamivir and broad-spectrum antibiotics. He remained severely hypoxic (requiring an Fio2 of > 0.8) for 10 days, and was treated with MV in the prone position and inhaled nitric oxide. His condition gradually improved, and he was extubated on Day 13. Patient 5A 60-year-old man presented to hospital with an exacerbation of his severe chronic obstructive pulmonary disease (COPD). He also had severe peripheral and coronary vascular disease. On examination, he had tachypnoea (respiratory rate, 36 breaths/min) but no fever. He had no prodrome of coryza or myalgias, and a chest x-ray showed mild bibasal opacities. His WCC was elevated (11.4 × 109/L), but his CRP level was 12 mg/L. He was admitted to the respiratory ward and treated with oseltamivir, broad-spectrum antibiotics, and NIV. Two days later he was intubated, and MV was commenced for hypercapnic respiratory failure. Bacterial cultures were negative. His hypoxia was mild (requiring an Fio2 of < 0.5), but he required MV for 14 days. Patient 6An 18-year-old pregnant woman presented with a 4-day history of cough, fever, and persistent vomiting without diarrhoea. Oseltamivir therapy for possible H1N1 influenza infection was discussed with the patient, but not administered. After intravenous rehydration, she was discharged home, but she returned several hours later in premature labour. Her WCC was 8.2 × 109/L but her CRP level was high (90 mg/L). She was given steroids for fetal lung immaturity and transferred to a tertiary obstetric/neonatal hospital. Twenty-four hours after delivering a 26-week live infant, she developed hypoxic respiratory failure with tachypnoea (respiratory rate, 35 breaths/min) and bilateral pulmonary infiltrates. She required a high level of inspired oxygen therapy (Fio2, 0.6) by face mask, and monitoring in the ICU. The mother, but not her baby, had a positive polymerase chain reaction (PCR) test result for H1N1 influenza 09, and both were treated with broad-spectrum antibiotics and oseltamivir. DiscussionSince the emergence of the novel H1N1 influenza 09 (human swine influenza) in North America and Mexico in mid April, the number of confirmed cases has increased to over 55 000 across 105 countries.1 While most individuals will experience a mild clinical illness (coryza, fever, cough and myalgias), there have been 238 reported deaths (0.4%).2 A Centers for Disease Control and Prevention (CDC) report in May provided details of the 30 patients who were hospitalised in California, of whom six required admission to an ICU and four required MV.3 At the time of writing, there have been 3912 confirmed cases of H1N1 influenza 09 in Australia.2 Most reported illness has been mild, but 268 patients (6.9%) have been hospitalised, over 25 (0.6%) have been admitted to ICUs, and five deaths (0.1%) have been reported. Here, we presented the first six cases of H1N1 influenza 09 (confirmed by PCR test from nasopharyngeal swabs) in which patients required admission to intensive care in Australia. Admissions were to three hospitals in the north-western suburbs of Melbourne. These cases highlight the small but significant risk of life-threatening respiratory failure associated with H1N1 influenza 09 infection. All patients experienced a rapid (but reversible) decline in respiratory function, with most requiring complex respiratory support. The age distribution of these patients is consistent with other reports, and lower than that seen in previous influenza seasons.4,5 Four of the six cases we report had risk factors, including asthma, chronic lung disease, smoking, obesity, and pregnancy; these risk factors were similar to those identified in the CDC reports.3 Patients 2 and 4 had no identifiable risk factors. There are several possible explanations for the acute respiratory failure observed in these patients. Early onset of respiratory failure with widespread pulmonary infiltrates (Patient 3) suggests primary viral pneumonitis, whereas the delayed onset of fever with lobar signs (Patient 2) and pleurisy (Patient 1) suggest secondary bacterial pneumonia. A cytokine-mediated acute lung injury may also explain the late appearance of diffuse pulmonary infiltrates (Patients 4 and 6). The absence of a severe prodrome in Patient 5 suggests an exacerbation of the patient’s COPD. With the number of cases of H1N1 influenza 09 infection likely to increase, it is anticipated that further cases of severe respiratory failure associated with this influenza will be seen. Based on the cases reported here and other reports, we offer the recommendations shown in Box 2. A high index of suspicion that respiratory failure may ensue is warranted in patients who have risk factors5 or present with tachypnoea (respiratory rate, > 24 breaths/min) and/or hypoxia (Spo2, < 95% on supplemental oxygen), and early referral to hospital is warranted. Youth and prior good health do not preclude the possibility of severe respiratory failure. The Victorian Department of Human Services currently recommends nasopharyngeal swabs for a PCR test for influenza A in patients admitted to hospital with suspected influenza. Empiric therapy with antiviral agents (oseltamivir or zanamivir)5 should be considered in addition to antibiotic treatment for community-acquired pneumonia pathogens, in consultation with an infectious diseases specialist. Patients with suspected H1N1 infection should be isolated, preferably in a negative pressure isolation room.6,7 Where possible, antiviral filters applied to the expiratory limb of the ventilator circuit may further reduce the risk to health care staff. Oseltamivir (Tamiflu) and zanamivir (Relenza) reduce viral replication and shedding, and may reduce the risk of more severe illness. Their safety in pregnancy has not been investigated (Category B1 for use in pregnancy), but without treatment there may be a greater risk of premature labour (Patient 6).5,8 Increasing resistance to oseltamivir has been reported in other strains of currently circulating influenza A viruses, but, as yet, not in the H1N1 influenza 09 lineage.9,10 Any patient with respiratory distress or severe hypoxia (requiring an Fio2 of > 0.5) and pulmonary infiltrates on chest x-ray should be referred to an intensive care specialist for further assessment. Mechanical ventilation for these patients is complex, and requires expertise and specialised equipment. We used restrictive tidal volumes (6 mL/kg ideal body weight), high PEEP (15–20 cm H2O), pressure-limited modes of ventilation, alveolar recruitment manoeuvres, inhaled nitric oxide, and restrictive fluid therapy with apparent success. This is consistent with ventilation strategies used by others,11 and in keeping with strategies described by the Acute Respiratory Distress Syndrome (ARDS) Clinical Network.12 Extracorporeal oxygenation therapy has recently been used in other cases (G J D, personal communication). Based on the available data, we would not recommend NIV as the mainstay of respiratory support. The four patients who were given a trial of NIV in this series all required intubation and MV. This is consistent with published data for ARDS and pneumonia.13 NIV temporarily improves oxygenation and reduces the work of breathing, but does not necessarily alter the course of the disease.14 The need for NIV is an indication of severe disease and the likelihood of intubation and MV. For the most part, H1N1 influenza 09 is a benign disease, but it may lead to severe respiratory complications in a small proportion of patients. In our series, prompt diagnosis and intensive therapy was associated with favourable outcomes. 1 Reference ranges for white cell count and C-reactive protein level Reference range White cell count (WCC) 4–11 ×109/L C-reactive protein (CRP) < 5 mg/L 2 Summary of clinical recommendations for managing patients with possible H1N1 influenza 09 infection Maintain a high index of suspicion of possible respiratory failure in patients with risk factors such as asthma, smoking, pregnancy, obesity or chronic medical conditions.2,4 Refer patients to hospital if they have hypoxia (oxygen saturation measured by pulse oximetry [Spo2], < 95%) and/or tachypnoea (respiratory rate, > 24 breaths/min) or pulmonary infiltrates. Institute respiratory and contact precautions, including personal protective equipment.2,4-6 Conduct polymerase chain reaction tests for H1N1 influenza A in patients admitted to hospital with suspected influenza. Start antiviral therapy early; its benefits in pregnant mothers may outweigh the risks.4,7 Refer patients for intensive care unit assessment if a fraction of inspired oxygen (Fio2) of > 0.5 or oxygen at a rate of > 10 L/min is required to maintain the Spo2 at > 92%. Non-invasive ventilation is unlikely to improve the outcome; consider intubation and mechanical ventilation. Complex mechanical ventilation strategies are often required.

Melissa A Kaufman MB BS · Graeme J Duke MD, FJFICM, FANZCA · Forbes McGain FJFICM, FANZCA · Craig French FJFICM, FANZCA · Craig Aboltins MB BS, FRACP · Gary Lane FRACP, MMed(ClinEpi), MQIHC · Geoff A Gutteridge FJFICM, FANZCA

Objective: To assess the impact of introducing a publicly funded infant rotavirus vaccination program on disease notifications and on laboratory testing and results.Design and setting: Retrospective analysis of routinely collected data (rotavirus notifications [2006–2008] and laboratory rotavirus testing data from Queensland Health laboratories [2000–2008]) to monitor rotavirus trends before and after the introduction of a publicly funded infant rotavirus vaccination program in Queensland in July 2007.Main outcome measures: Age group-specific rotavirus notification trends; number of rotavirus tests performed and the proportion positive.Results: In the less than 2 years age group, rotavirus notifications declined by 53% (2007) and 65% (2008); the number of laboratory tests performed declined by 3% (2007) and 15% (2008); and the proportion of tests positive declined by 45% (2007) and 43% (2008) compared with data collected before introduction of the vaccination program. An indirect effect of infant vaccination was seen: notifications and the proportion of tests positive for rotavirus declined in older age groups as well.Conclusions: The publicly funded rotavirus vaccination program in Queensland is having an early impact, direct and indirect, on rotavirus disease as assessed using routinely collected data. Further observational studies are required to assess vaccine effectiveness. Parents and immunisation providers should ensure that all Australian children receive the recommended rotavirus vaccine doses in the required timeframe.

Stephen B Lambert MB BS, MAppEpid, FAFPHM · Cassandra E Faux MSc(ClinMicro) · Lisa Hall BTech(BiomedSc)(Hons), PhD · Frances A Birrell MPH, MAppEpid, GCSc(Stats) · Karen V Peterson DipT, BEd, MHlthSc · Christine E Selvey MB BS, MSc · Theo P Sloots BSc, GradCertMgt, PhD · Michael D Nissen BMedSc, FRACP, FRCPA · Keith Grimwood MD, FRACP

With the recent outbreak of swine influenza, the world may be facing this century’s first influenza pandemic. In Mexico, around 2000 patients have been hospitalised with respiratory illness and almost 150 people have died. Several other countries have reported smaller numbers of suspected and confirmed cases of swine influenza. This 2009 influenza A virus is a strain of the H1N1 subtype, and appears to be a human–avian reassortment swine virus influenza. It is likely that sustained human-to-human transmission of swine influenza has occurred, at least in Mexico. Despite there being so many hospitalised patients in Mexico, cases outside Mexico have demonstrated a mild influenza-like illness, with only one fatality to date. In contrast to the 1918 influenza pandemic, we now have a more robust public health system, with widespread global networks; vaccines can be developed rapidly; and there are antiviral medications to which the swine influenza A(H1N1) virus is sensitive. Many resources have been invested in pandemic preparedness programs in the health care and public health systems in Australia over the past few years.

Sanjaya N Senanayake MB BS, MAppEpid, FRACP

Australia can benefit from lessons learned in the epidemic of C. difficile infection in Europe and North America It is 30 years since Clostridium difficile was shown to be the cause of pseudomembranous colitis and many cases of antibiotic-associated diarrhoea in humans. In the interim, C. difficile has risen from relative obscurity to become a major hospital pathogen. Two factors were particularly important in its emergence during the 1980s. First, increased and inappropriate use of some broad-spectrum antibiotics, particularly cephalosporins, predisposed more patients to infection with C. difficile. Second, contamination of the hospital environment with C. difficile spores was, and remains, a significant problem, as the spore is likely to be the infective particle. The epidemiology of C. difficile infection continues to evolve, and developments overseas in the past decade threaten not only parts of Australia’s vast agricultural sector but also the country’s health care system. Since 2002, rates of C. difficile infection have escalated, with outbreaks of severe infection in North America and Europe caused by an epidemic strain — polymerase chain reaction (PCR) ribotype 027 (also known as North American pulsed-field type 1 [NAP1]). This strain is characterised by the production of greater amounts of toxins A and B and an additional, binary toxin, as well as resistance to fluoroquinolone antimicrobials.1 When this editorial was submitted for publication in January 2009, there was no evidence that this epidemic strain was present in Australia. However, C. difficile PCR ribotype 027 has now been isolated for the first time in Australia, as reported in this issue of the Journal2 (Riley et al). Although the patient most probably acquired the organism while travelling in North America, this case illustrates the ease with which it could be introduced into Australia. Thought to be driving the epidemic in humans in North America and Europe are the overuse of fluoroquinolones and fluoroquinolone resistance, but the ageing population and improved case ascertainment may also be contributing to the dramatic increase in cases. Other factors may also be important, such as the increase in prescription of proton-pump inhibitors, which coincided with the emergence of epidemic C. difficile.3 Several recent observations from overseas have broad relevance for Australia. First, there has been an apparent increase in community-acquired C. difficile infection in the absence of classic risk factors such as antibiotic exposure, leading to suggestions that all patients with community-acquired diarrhoea should be tested for C. difficile.4 Assertions that community-acquired C. difficile infection is a new disease4 are not correct — it has been recognised in Australia for over 15 years but is underdiagnosed.5 Therefore, it is difficult to determine whether this increase is a true increase or rather reflects better case ascertainment. Nonetheless, the suggestion that C. difficile infection should be considered more than just a hospital problem is valid, and general practitioners need to be aware of this change in epidemiology. The prevalence of binary toxin-producing C. difficile in human disease is also increasing, and there is an association between binary toxin-producing isolates and community acquisition.6 Second, it is speculated that C. difficile is part of a zoonosis, and that transmission of infection via spores may be foodborne.7 There is compelling evidence for the former, but none for the latter. C. difficile is known to colonise many animals.8 Indeed, as in humans, it probably colonises the gastrointestinal tracts of most infant animals until weaning. There was alarm at a report that 20% of a small sample (n = 60) of retail beef in Canada contained C. difficile.9 Equally disturbing are reports that many pig herds in the United States are infected with C. difficile. The overall prevalence of C. difficile in piglets from 10 herds in North Carolina was 48%, and ranged from 0 to 97% across the herds. Mortality for piglets with C. difficile infection is 15%, and animals that survive are 10% underweight when they go to market.10 Most animal isolates of C. difficile produce binary toxin, and both pigs and cattle harbour PCR ribotype 078 — a strain that, like ribotype 027, produces increased amounts of toxins A and B, in addition to binary toxin. In the Netherlands, the prevalence of human C. difficile infection with ribotype 078 strains has increased since 2005; these infections were in a younger population and more frequently community-acquired than infections with ribotype 027 strains. In the eastern Netherlands, where more than 90% of the country’s pig farms are located, over 20% of human isolates are now ribotype 078, and human and pig strains of C. difficile are highly genetically related.11 In Australia, little is known about the prevalence of C. difficile in pigs. A small study in 2007 found C. difficile in 10 of 37 samples (27%) from piglets with diarrhoea, but none of the isolates were ribotype 078 (unpublished data). Why is C. difficile infection increasing in pigs in Europe, and what are the implications for Australia? The use of antimicrobials for growth promotion was banned from 2006 in Europe, and even earlier in Denmark, starting in 1995. However, since 2000, the use of therapeutic antimicrobials in production animals has increased in Europe in general, and specifically in Denmark, a big producer of pork. Of real concern is evidence of greater use of cephalosporins in animals. While the number of pigs in Denmark increased by 50% in the past 15 years, the amount of penicillinase-susceptible penicillins used increased by 400%, and cephalosporins by 1000%. Most of this increase was in piglets and sows.12 Although the total amount of cephalosporins used remains small, this is a worrying trend. If the situation is similar in the Netherlands, and anecdotal evidence suggests that it is, then this may be analogous to the situation in humans in the 1980s when there was a dramatic increase in C. difficile in many hospitals, driven by cephalosporin use.13 The overlap between the location of pig farms in the Netherlands and the occurrence of human ribotype 078 infections suggests a common source.11 This is likely to be the environment. The Netherlands has one of the highest population densities in the world. If infection rates in pig farms in the Netherlands are as high as those in the US,10 then it is likely that a large proportion of the Dutch population comes into contact with C. difficile spores every day. Individuals are at risk of infection if they are taking antimicrobials or any other medication that perturbs the gut flora. The good news for Australia is that, with our very low population density, a similar risk to humans is unlikely to develop. However, this is no reason for complacency. Every effort should be made to stop epidemic C. difficile from becoming established in our production animals. Unfortunately, the mere perception of C. difficile infection as a foodborne disease will damage the industry. Even before the first isolation of C. difficile PCR ribotype 027 in a patient in Australia, health care practitioners were becoming justifiably concerned. A proposal for C. difficile to be made notifiable in all states and territories of Australia was approved at the Australian Health Ministers’ Advisory Council meeting in November 2008. Australia’s conservative policies on fluoroquinolone use in humans and animals may offer some protection. However, if cephalosporin use is driving C. difficile infection in animals overseas, then additional efforts to target cephalosporin use in veterinary medicine may be needed in Australia. The solution to these problems continues to lie in surveillance for the emergence of virulent strains of C. difficile, promotion of judicious use of antimicrobials in both human and veterinary medicine, and environmental cleanliness, the latter perhaps easier said than done outside health care facilities.

Thomas V Riley MAppEpid, PhD, FRCPath

We report the first isolation in Australia of a hypervirulent epidemic strain of Clostridium difficile, PCR ribotype 027. It was isolated from a 43-year-old woman with a permanent ileostomy, who appears to have been infected while travelling in the United States. The isolate was positive for toxin A, toxin B and binary toxin, and resistant to fluoroquinolone antimicrobials, and had characteristic deletions in the tcdC gene. All diagnostic laboratories and health care facilities in Australia should now be on high alert for this organism. Clinical recordA 43-year-old woman was admitted to a Perth hospital at the end of October 2008. She had been diagnosed with ulcerative colitis 8 years previously and, in 2002, underwent proctocolectomy and permanent ileostomy. Since then, she had experienced a number of stoma problems requiring surgical repair or local revision. On this occasion, computed tomography (CT) showed a parastomal small-bowel herniation, with a normal appearance on ileoscopy. The herniation was repaired with intraperitoneal mesh. After the operation, the patient developed small-bowel ileus and was placed on total parenteral nutrition. She then developed a central-line infection, with both Serratia marcescens and Staphylococcus epidermidis isolated from a central venous catheter tip, for which she was treated with intravenous cefepime and vancomycin (each, 1 g 12-hourly) for 10 days. A subsequent ileoscopy did not show any mucosal abnormality. Culture and faecal cytotoxin testing of the stoma fluid for Clostridium difficile was negative before her discharge from hospital at the end of November 2008. The patient subsequently travelled to the United States and, while in New York City on Christmas Day, became unwell with high ileostomy output, cramping abdominal pain and vomiting. Despite progressively worsening symptoms, she travelled to Hawaii via Vancouver, Canada. On arrival in Hawaii, she required hospitalisation and was admitted to an intensive care unit in Honolulu on 6 January 2009 with a diagnosis of complicated C. difficile infection with generalised sepsis and acute renal failure. An ileoscopy showed diffuse inflammation and ulceration of the ileal mucosa. She recovered slowly after treatment with oral vancomycin (250 mg 6-hourly), and was discharged after 14 days. On her arrival back in Australia, the symptoms recurred. An ileoscopy on 4 February 2009 showed a single inflamed ulcerated area close to the stoma, and biopsy specimens of this area were reported as consistent with pseudomembranous enteritis and C. difficile infection (Box 1). Culture of the ileostomy fluid again resulted in the isolation of toxigenic C. difficile. The isolate was determined to be positive for toxin A (tcdA), toxin B (tcdB), and binary toxin (CDT) by polymerase chain reaction (PCR) testing for toxin genes (tcdA, including the repetitive region, tcdB, and both the cdtA and cdtB binary toxin genes).1,2 The antimicrobial susceptibility profile of the isolate on E-strip testing (AB bioMérieux) indicated fluoroquinolone resistance: penicillin, susceptible (S) (minimum inhibitory concentration [MIC], 0.75 mg/L); clindamycin, S (MIC, 2 mg/L); metronidazole, S (MIC, 0.38 mg/L); levofloxacin, resistant (R) (MIC, > 32 mg/L); moxifloxacin, R (MIC, 16 mg/L); and vancomycin, S (MIC, 0.38 mg/L). The tcdC gene (which encodes a negative regulator in toxin production) was sequenced and found to contain an 18-base-pair deletion, as well as a single nucleotide deletion at position 117,3 characteristic of the epidemic C. difficile strain, PCR ribotype 027. On the basis of these findings, the patient’s isolate was PCR ribotyped,4 which confirmed it to be C. difficile PCR ribotype 027 (Box 2). Because of the severity of the patient’s initial illness, she was treated with a further 14-day course of oral vancomycin (250 mg 6-hourly). Her condition improved, and she has remained well since, with two negative cultures for C. difficile since cessation of vancomycin. DiscussionA hypervirulent, epidemic strain of C. difficile, PCR ribotype 027, has been responsible for outbreaks of severe disease in North America and Europe. This organism is characterised by production of increased quantities of toxins A and B, plus an additional, binary toxin (actin-specific ADP-ribosyltransferase), and fluoroquinolone resistance. Overuse of fluoroquinolones is probably driving epidemic spread of this strain in North America and Europe, and attributable mortality in people aged over 60 years who are infected has been over 10%. There has been concern in Australia because of the lack of suitable surveillance systems to detect the entry of epidemic C. difficile into this country;5 this is the first report of such an occurrence. This case is unusual because infection apparently occurred while the patient was travelling. Travel-associated C. difficile infection is extremely rare and, to our knowledge, acquisition of C. difficile during travel has never been proven. However, C. difficile is known to cause diarrhoea in travellers, as a result of antibiotics given either as prophylaxis before the journey, or as treatment for traveller’s diarrhoea afterwards. Indeed, in 1995, we reported three cases of laboratory-proven C. difficile infection following doxycycline administration for malaria prophylaxis.6 All three patients apparently acquired the organism outside Australia, although this could not be proven as no cultures for C. difficile were performed before travel. Six cases of C. difficile infection were recently reported in Spain in travellers who took antibiotics to treat an acute diarrhoeal episode and subsequently presented with prolonged or recurrent gastrointestinal symptoms, including diarrhoea.7 Interestingly, the first isolation of C. difficile PCR ribotype 027 in Austria was from a British tourist who was admitted to a hospital in Tyrol with a 5-day history of nausea, watery diarrhoea and lower abdominal pain. She was reportedly taking antibiotics prescribed by her physician to treat bronchitis, and the authors believed she acquired the strain in Great Britain before travel.8 We believe our patient most likely acquired C. difficile infection in New York City. According to the US Centers for Disease Control and Prevention, C. difficile PCR ribotype 027 has now been detected in 40 US states, including New York.9 It is less likely that she was infected while passing through Canada, even though PCR ribotype 027 is thought to be endemic in the western part of that country.10 In either case, as she had not been in contact with the health care system at that stage of the trip, community acquisition is most likely. Recent reports suggest that community acquisition of C. difficile is increasing worldwide.11 The lesions associated with C. difficile infection in humans are generally restricted to the colon, but pseudomembrane formation has been described in patients with an ileostomy.12 Our patient may have been at risk of C. difficile infection for two reasons. First, in ulcerative colitis, the intestine is known to be more readily colonised by C. difficile, and much of this colonisation occurs in the community rather than the health care setting.13 To what extent that risk is modified by colectomy is not known. The upper gastrointestinal tract microflora in patients with an ileostomy is similar to that of the colon 1 to 3 weeks after the ileostomy.14 Second, our patient had completed a course of antibiotics about 1 month earlier, and the “normal” microflora may not yet have re-established enough to provide any protection. We were fortunate that this patient was seen at an institution that routinely cultures for C. difficile. Currently, most laboratories in Australia do not culture for C. difficile, instead relying on either enzyme immunoassays or PCR tests. As molecular typing is required to identify C. difficile PCR ribotype 027, at a minimum, all patients with severe, suspected C. difficile infection should have specimens cultured, and any isolates should be sent to a laboratory with expertise in identifying epidemic strains. General practioners and diagnostic laboratories need to be reminded that patients presenting with community-acquired or travel-related diarrhoea may have C. difficile infection. Periodic targeted surveillance with molecular typing of C. difficile isolates should be funded by government, as suggested previously,5 until more rapid molecular diagnostic tests to identify epidemic strains are developed. We were also fortunate that the patient was seen as an outpatient on her return to Australia, and did not require hospital admission, minimising the possibility of contamination and spread of epidemic C. difficile within the hospital setting. However, this case exemplifies the ease with which this organism could be introduced into Australia. The conservative policies on fluoroquinolone use in this country may afford some protection against the establishment of epidemic C. difficile. Ciprofloxacin and moxifloxacin are the only fluoroquinolones available in Australia; levofloxacin, gatifloxacin and others are not. Nonetheless, all diagnostic laboratories and health care facilities in Australia should now be on high alert for the epidemic strain of C. difficile. 1 Ileal biopsy specimen from the patient, February 2009 Mucosa adjacent to the ulcer showed acute inflammation, with neutrophils invading the surface mucosa (stain, haematoxylin and eosin; original magnification, × 400). 2 PCR ribotyping of the Clostridium difficile strain isolated from the patient in February 2009 Polymerase chain reaction (PCR) amplification of ribosomal RNA intergenic spacer regions results in specific banding patterns (ribotypes), which can be used to genetically fingerprint strains of Clostridium difficile. Ribotyping showed the similarity between the patient’s isolate (lane 4) and the epidemic 027 strain (lane 3). Key to lanes: L = molecular weight ladder 1 = reference strain, VPI 10463 2 = ribotype 014 (the most common ribotype in Australia [unpublished data]) 3 = ribotype 027 (epidemic strain) 4 = patient’s isolate.

Thomas V Riley MAppEpid, PhD, FRCPath · Sarah Thean BSc(Hons) · Graham Hool MB BS, FRACS · Clayton L Golledge MB BS(Hons), DTMH, FRCPA

To the Editor: A 70-year-old woman presented to the emergency department with intense pain, erythema, oedema and haemorrhagic bullae of the right lower leg. Twenty-four hours earlier, she had fallen into warm seawater on the south coast of New South Wales, sustaining a penetrating wound by an unknown object. She reported developing excruciating pain and the noted leg changes within hours of the injury. She had a history of systemic lupus erythematosus (SLE), managed long-term with 7.5 mg oral prednisone daily. Soon after presentation, she rapidly developed septic shock, becoming hypotensive, tachycardic, hypoxic and confused. She was experiencing rigors and required inotropic support. On examination, there was marked cellulitis of the right lower leg with purpura and bullae. No crepitus was detectable in the tissues. There was no clinical or laboratory evidence of disseminated intravascular coagulation. Broad-spectrum empirical antibiotic treatment with intravenous gentamicin, cephazolin and metronidazole was commenced, and urgent, extensive surgical debridement of the lower limb was performed (Box). Wound culture swabs and tissue samples were sent for microbiological and histopathological examination. On Day 2, blood cultures taken at initial presentation were positive for Vibrio vulnificus, as were tissue swabs. Based on susceptibility testing, antibiotic therapy was reduced to a single agent, intravenous ciprofloxacin 400 mg twice daily. The patient’s postoperative clinical recovery was slow, but her SLE did not flare up, and on Day 23 she was transferred to a tertiary referral centre for lower-limb skin grafting. Cellulitis is a common presentation to emergency departments, and common organisms are usually implicated. However, in some cases, the presence of more unusual pathogens, such as V. vulnificus, should be considered. V. vulnificus is a virulent halophilic (salt-loving) gram-negative bacterium associated with seawater temperatures (usual range, 18°–24°C). It has two distinct clinical presentations.1,2 The first, well recognised, is septicaemia after ingestion of raw or undercooked seafood, such as oysters, causing acute gastrointestinal disease. The second, not always considered, is necrotising wound infections, as in this case. Open wounds can be directly inoculated with V. vulnificus from seawater containing the organism. “Vulnificus” is a Latin term meaning “inflicting wounds”. Hippocrates described perhaps the first recorded case of a fisherman with pain in the foot, fever, delirium and blistering skin.3 Patients with primary wound infections caused by V. vulnificus develop painful, rapidly progressing cellulitis. More unusually, our patient developed fulminant sepsis from an open wound infection. Patients who are immunocompromised, especially those with alcoholic liver disease, hepatitis B or hepatitis C, have a higher risk of infection with V. vulnificus, as well as patients, like ours, who take long-term steroid therapy.2 Management requires timely recognition, antibiotic therapy and prompt surgical review. Cellulitis of right lower leg caused by infection with Vibrio vulnificus

Tamara C Preda · Veronica A Preda · Allan P Mekisic

To the Editor: A 27-year-old man who had recently emigrated from Sudan was admitted to our department with a 7-hour history of constant peri-umbilical pain. Physical examination revealed inconstant voluntary guarding of the lower abdomen. Full blood and electrolyte examinations were unremarkable. Urinalysis showed protein and traces of blood. A condition requiring surgery was considered unlikely and further investigations were undertaken. Significant bladder calcification was noted from an abdominal x-ray. A computed tomography scan confirmed this finding (Box), and also revealed circumferential distal ureteric calcification, appendiceal thickening with appendicolith, and adjacent fat stranding. Repeat abdominal examination demonstrated right iliac fossa tenderness with a positive Rovsing sign. Acute appendicitis was diagnosed and an inflamed, thickened, retrocaecal appendix was removed laparoscopically. The patient was discharged 2 days later, but did not attend his post-operative review. Histological examination of the appendix demonstrated transmural neutrophil infiltration, without eosinophils. Within the lumen there were numerous oval-shaped helminth ova, some with terminal spines, consistent with acute appendicitis caused by schistosomiasis. The patient did not have a general practitioner, therefore a referral to an infectious diseases clinic was made. He was thereafter lost to follow-up. Infection by schistosomes leads to chronic granulomatous inflammation in many body systems, including the gastrointestinal tract. Adult worms are not usually harmful to the host — eggs provoke a Th2-mediated immune response.1 Three major species of Schistosoma cause schistosomiasis in humans, of which two are endemic in sub-Saharan Africa — Schistosoma mansoni and Schistosoma haematobium. S. haematobium migrates against portal venous flow to the vesical venous plexus, causing urinary tract calcification through chronic inflammation and fibrosis. This species has also been described as a cause of appendicitis.2 Examinations of appendices removed from patients with acute appendicitis in endemic areas have demonstrated schistosomiasis in 2.3%–4.2% of samples, with 2.7% having histological evidence of acute schistosomal appendicitis in one study.3,4 Schistosomiasis can be diagnosed by histological analysis, or urine and stool microscopy. Serological testing cannot be used to differentiate past and present infection, however positive serological results are the basis for treatment of patients in endemic areas. After diagnosis, praziquantel should be prescribed. It is assumed that our patient did not receive praziquantel. He thus risks significant morbidity and mortality from possible gastrointestinal, hepatic, urinary, pulmonary and neurological complications related to chronic schistosomal infection. Surgeons and pathologists should be aware of the atypical pathology of acute schistosomal appendicitis. The number of immigrants arriving in Australia from endemic areas has increased markedly in recent years and further presentations may occur. Non-contrast computed tomography scan of a 27-year-old man with schistosomal appendicitis Calcification of the bladder (black arrow) and distal ureters (white arrows) is evident.

Jordan K Webb · Graeme Thompson

To the Editor: A 4-year-old girl presented with a flyblown scalp to a district aid post outside Madang, Papua New Guinea (PNG). Coincidentally, we were present at the aid post in our capacity as students and lecturers in the tropical paediatrics module of the James Cook University Masters in Public Health and Tropical Medicine course. The child was otherwise healthy, and her scalp had been normal until about 2 days previously, when her mother noticed two developing “sores”. These had deteriorated into circular, foul-smelling ulcers about 1.5 cm in diameter and 2 cm apart on the crown of her head (Box, A), in which live maggots could be seen squirming. The child’s mother had extracted some maggots with a pair of toothpicks (Box, B), and about 10 more were removed at the aid post with tweezers. When no further movement was apparent in the wounds, they were covered with petroleum jelly to suffocate any “stragglers”. No dead larvae were seen the following morning, and the wounds healed rapidly. We believe the most likely culprit was Chrysomya bezziana, or Old World screw-worm fly, although we were unable to preserve a larva for formal identification (by “curing” in very hot water and transporting in 70% ethanol). Old World screw-worm fly is an obligate myiasis-producing fly endemic in PNG. Its larvae are found only in living vertebrate tissues. The child’s mother had not noticed a prior lesion, and we assumed entry was through a graze on the scalp. Although screw-worm fly is endemic throughout tropical and subtropical regions of Asia and Africa, it is not found in Australia. If it became established here, it could devastate the livestock industry, particularly by striking the umbilical region of newborn calves and infesting their abdominal contents.1 The fly is known to be able to travel 100 km,2 further than the distance between the islands of Torres Strait, but has not yet migrated from PNG to Australia. It could also be introduced in livestock vessels returning from Asia or the Middle East; the Australian Quarantine and Inspection Service has strict regulations to prevent this, with all returning vessels thoroughly cleaned before reaching Australian waters. This is justified as it has been documented that sheep shipped from Australia arrived in Bahrain with fly infestation. Presumably, flies were attracted to the ship as it passed the coast of Oman or the United Arab Emirates.3 Infestation is self-promoting, as ovipositing females are particularly attracted to the odour of an existing myiasis, resulting in expansion of the lesion. In our patient, the application of petroleum jelly to the lesions fortuitously covered the odour, reducing the likelihood of reinfestation. Ivermectin is useful in treating affected animals,4 as well as humans5 when the larvae cannot be physically extracted. Scalp of a child with fly infestation A: Circular ulcers on the child’s scalp. B: Removal of larvae with toothpicks.

John S Whitehall · Richard Speare · Heidi E Best · Philippa J Price · Deborah J Mills

To the Editor: We report a case of reactive arthritis with an unusual cause in a previously well 47-year-old male landscape gardener. The patient presented with acute onset of left ankle arthritis. He had a 10-day history of a productive cough associated with mild fever, back pain and arthralgias. His temperature was 37.7°C and occasional crackles were audible at the lung bases. His left ankle was tender, with decreased range of movement. The provisional diagnosis was atypical pneumonia with reactive arthritis. A chest x-ray was normal. Laboratory tests showed an elevated white cell count of 11.93 × 109/L (reference range [RR], 4–11 × 109/L), with a C-reactive protein level of 326 mg/L (RR, < 3 mg/L). Arthrocentesis showed increased white cells but was negative for crystals and bacteria. Serological tests were positive for Chlamydia psittaci (IgM, IgA and IgG were all elevated and increased during illness), and the patient was also positive for human leukocyte antigen (HLA)-B27. He was initially treated with meloxicam for the arthritis. Oral prednisone was added when his joint symptoms became more disabling. Weaning of prednisone was attempted, but symptoms recurred. Sulfasalazine was subsequently added. Symptoms took about 8 weeks to resolve. Sufferers of psittacosis are infected by inhaling the obligatory intracellular bacterium, Chlamydia psittaci, from the faeces of infected birds in soil or grass. As a landscape gardener, our patient was at risk. Clinical presentations of psittacosis vary considerably, but patients usually present with flu-like and respiratory symptoms.1 Reactive arthritis is unusual, being more commonly associated with pathogens such as Salmonella, Shigella, Campylobacter and Yersinia spp.2 Although reactive arthritis usually involves asymmetrical large joint oligoarthropathies, patients with Chlamydia psittaci infection usually have a polyarticular pattern.3 HLA-B27 has a high association with spondyloarthropathies, including reactive arthritis. Contact with infected birds is often not obvious, making the diagnosis challenging. Microimmunofluorescence (showing a fourfold increase in antibodies or IgG titre greater than 16) has become available for diagnosis. Differential diagnosis of reactive arthritis includes other causes of arthritis such as sepsis and crystal deposition. Management of Chlamydia psittaci reactive arthritis includes early use of the antibiotics doxycycline or erythromycin, or possibly ceftriaxone.4 Anti-inflammatory drugs are the mainstay for symptomatic treatment of all reactive arthropathies. Intra-articular steroid injections may be helpful. There is conflicting evidence regarding the benefit of systemic corticosteroids. Sulfasalazine may be a helpful adjunct.5 For gardeners, preventive measures include the use of masks, gloves and lawnmower catchers.

Peter N Gonski · Bobby Chan

Clinical cases in infectious diseases: a public health approach. Sanjaya Senanayake. Sydney: McGraw-Hill, 2007 (x + 398 pp). ISBN 978 0 07 471662 5. In the preface to this text, Sanjaya Senanayake quotes the introductory voiceover to the television series “Law and Order” about the connecting roles of the police and district attorneys in criminal law. This analogy is particularly apt for the practice of infectious diseases, and this book, by an infectious diseases physician with experience in public health, attempts to bridge the divide between clinicians and public health practitioners. Clinical cases in infectious diseases provides a useful insight into 22 examples of infectious diseases that encompass a diverse range of epidemiological and clinical features. They are set out almost as a TV script, interspersed with referenced facts about each disease. At first I found this style a little irritating, particularly as the doctors in the scenarios seem to inhabit a parallel universe where they diagnose botulism and Bairnsdale ulcer within the first page. However, with the more realistic and common scenarios, the style works well to enliven what might otherwise be a dry subject. Some of the diseases included are rare in Australia, whereas others, such as influenza and tuberculosis, are common. A strength of the author’s approach is his focus on answering the practical questions — specific tests and treatments, the period of infectivity, isolation measures and responses. As such, this easily read book succeeds as an introductory text for medical students and junior doctors, public health staff and laboratory microbiologists. It is necessarily difficult for a book of this nature to be complete, and it does not pretend to be a textbook of infectious diseases. However, notable omissions are sexually transmitted infections, particularly HIV. Other more controversial issues could also be considered, such as the ethical implications of quarantine of infectious patients or dealing with reckless conduct. Yet this should not detract from what is an entertaining and informative read for junior staff interested in the interface between clinical practice and public health practice.

Allen C Cheng

Objective: To determine the rate of perinatal hepatitis B virus (HBV) transmission in an Australian setting and to identify maternal virological factors associated with highest risk of transmission.Design, participants and setting: A prospective, observational study of perinatal transmission of HBV. Participants were pregnant women attending Sydney South West Area Health Service antenatal clinics who tested positive for hepatitis B surface antigen (HBsAg), and their babies. All babies were routinely offered hepatitis B immunoglobulin (HBIG) and HBV vaccination. Babies positive for HBsAg at 9-month follow-up underwent further virological testing, including HBV DNA sequencing. The study was conducted between August 2002 and May 2008.Main outcome measures: HBV DNA levels and demographic characteristics of HBsAg-positive pregnant women; proportion of their infants with active HBV infection at 9-month follow-up; maternal characteristics affecting transmission rate; HBV DNA sequencing of infected infants and their mothers.Results: Of 313 HBsAg-positive pregnant women, 213 (68%) were HBV DNA-positive and 92 (29%) were positive for hepatitis B “e” antigen (HBeAg); 138 babies born to HBV DNA-positive mothers were tested for HBV infection (HBsAg positivity) at about 9 months of age. Four cases of transmission were identified. All four mothers had very high HBV DNA levels (> 108 copies/mL) and were HBeAg-positive. Three of the four infants were infected with wild-type HBV strains, with identical maternal/infant isolates. The fourth mother–infant pair had an S gene variant, HBV D144E, which has been previously reported in association with vaccine/HBIG escape. (Unfortunately, HBIG was inadvertently omitted from the immunisation schedule of this infant.) Transmission rates were 4/138 (3%) from HBV DNA-positive mothers overall, 4/61 (7%) from HBeAg-positive mothers, and 4/47 (9%) from mothers with very high HBV DNA levels. No transmission was seen in 91 babies of mothers with HBV DNA levels < 108 copies/mL.Conclusion: In this cohort, HBV perinatal transmission was restricted to HBeAg-positive mothers with very high viral loads.

Elke Wiseman MB BS, FRACP, PhD · Melissa A Fraser RN(Hons), GradDipInfectCont · Sally Holden · Anne Glass RN · Bronwynne L Kidson RN · Leon G Heron MB ChB, FRCPA, FAFPHM · Michael W Maley MB BS, FRCPA, FRACP · Anna Ayres BSc(Hons) · Stephen A Locarnini BSc(Hons), MB BS, PhD · Miriam T Levy MB BS, FRACP, PhD

About 13 000 refugees are currently accepted for migration into Australia each year, many of whom have spent protracted periods living in extremely disadvantaged circumstances. As a result, medical practitioners are increasingly managing recently arrived refugees with acute and chronic infectious diseases. The Australasian Society for Infectious Diseases has formulated guidelines for the diagnosis, management and prevention of infection in newly arrived refugees. This article is an abridged version of the guidelines, which are available in full at <http://www.asid.net.au>. All refugees should be offered a comprehensive health assessment, ideally within 1 month of arrival in Australia, that includes screening for and treatment of tuberculosis, malaria, blood-borne viral infections, schistosomiasis, helminth infection, sexually transmitted infections, and other infections (eg, Helicobacter pylori) as indicated by clinical assessment; and assessment of immunisation status, and catch-up immunisations where appropriate. The assessment can be undertaken by a general practitioner or within a multidisciplinary refugee health clinic, with use of an appropriate interpreter when required. The initial assessment should take place over at least two visits: the first for initial assessment and investigation and the second for review of results and treatment or referral.

on behalf of the Australasian Society for Infectious Diseases Refugee Health Guidelines Writing Group

A 49-year-old health care worker received varicella vaccine in accordance with current Australian guidelines. She developed streptococcal toxic shock syndrome, complicated by acute atraumatic dislocation of the right wrist secondary to poststreptococcal reactive arthritis — to our knowledge, the first report of spontaneous wrist dislocation as a complication in this condition. Vaccination was accompanied by prolonged viraemia with the varicella vaccine strain — also, we believe, the first report of this in an immunocompetent patient. Clinical recordA 49-year-old female hospital employee received varicella vaccination, in accordance with the guidelines of New South Wales Health for varicella-seronegative health care workers.1 She presented 17 days after the second vaccine dose (38 days after the first dose) with a 12-day history of joint pain and swelling, predominantly affecting the upper limbs and knees, along with myalgia and lethargy. These symptoms had worsened over the preceding 48 hours. There were no noticeable skin lesions, and no local reaction at the vaccination site. The patient’s past medical history was unremarkable except for depression treated with venlafaxine, the only medication she was taking at the time of admission. At presentation, she was afebrile, with a blood pressure of 95/60 mmHg, and pulse rate of 96 beats/min. The dominant clinical finding was gross peripheral oedema of the upper limbs, including the hands (Box 1). Initial investigations showed raised total white cell count (13.1 × 109/L; reference range [RR], 3.9–11.1 × 109/L) and neutrophil count (12.1 × 109/L; RR, 2.0–8.0 × 109/L) and abnormal liver function (bilirubin, 51 μmol/L [RR, < 21 μmol/L]; concentration of alanine aminotransferase [ALT], 152 U/L [RR, < 33 U/L]; aspartate aminotransferase [AST], 112 U/L [RR, < 45 U/L]; γ-glutamyltransferase [GGT], 112 U/L [RR, < 30 U/L]; alkaline phosphatase [ALP], 308 U/L [RR, 30–115 U/L]; and albumin, 32 g/L [RR, 35–53 g/L]). The possibility of varicella hepatitis complicating vaccination was considered. Forty-eight hours after admission, the patient became confused and hypotensive, with a systolic blood pressure of 70 mmHg. Streptococcus pyogenes was isolated from blood cultures. Her blood pressure did not increase in response to intravenous resuscitation with normal saline (1 L) and colloid (2 L). She was transferred to the intensive care unit, where she received inotropic support with noradrenaline for 22 hours. She developed streptococcal toxic shock syndrome, with renal impairment (concentration of sodium, 126 mmol/L [RR, 135–145 mmol/L]; potassium, 4.3 mmol/L [RR, 3.2–5.0 mmol/L]; urea, 23.4 mmol/L [RR, 2.5–6.1 mmol/L]; creatinine, 195 μmol/L [RR, 50–110 μmol/L]), thrombocytopenia (platelet count, 86 × 109/L [RR, 150–400 × 109/L]) and continuing impairment of liver function (bilirubin, 76 μmol/L; ALT, 78 U/L; AST, 58 U/L; GGT, 72 U/L; ALP, 237 U/L; and albumin, 22 g/L). After 4 days, the serum albumin concentration had dropped to 17 g/L, and gross oedema persisted. The source of the S. pyogenes infection was not established, but the organism was cultured from a small skin lesion in the right cubital fossa. The isolate was subsequently identified as S. pyogenes serotype M11. Varicella zoster virus (VZV) genotyping of serum showed the presence of the Oka vaccine strain of VZV.2 Nucleic acid testing by quantitative polymerase chain reaction (PCR) using primers that target VZV open reading frame 62 revealed a serum load of 480 000 VZV DNA copies/mL 2 days after admission and 19 days after the last varicella vaccination. Tests on admission for VZV-specific IgG were positive. The patient was treated with high-dose intravenous benzylpenicillin (1.8 g 4-hourly) for 10 days and aciclovir (10 mg/kg 8-hourly) for 7 days. Ten days after admission, serum albumin levels had risen to more than 30 g/L. Although the peripheral oedema resolved gradually, both wrists and the left knee remained swollen. The patient had no fever and no clinical features of septic arthritis. Ultrasound examination of the joints and a technetium-labelled bone scan did not suggest joint fluid or adjacent osteomyelitis. Nineteen days after admission, the patient showed signs of bilateral median nerve compression. The right wrist appeared clinically deformed, with palpable synovitis (Box 2A ). Imaging showed disruption of the right wrist and carpus to a degree usually associated with high-energy trauma (in the absence of any history of trauma), with dislocation of the distal radioulnar joint (DRUJ), and wide diastasis of the scapholunate interval (Box 2B). The left wrist and carpus showed lesser disruption. The following day, the patient underwent aspiration of the left knee effusion, and bilateral carpal tunnel decompression and flexor synovectomy. Extensive synovitis was observed around the flexor tendons of both wrists (Box 2C), with rupture of the right lunotriquetral ligament. The right DRUJ was reduced and held in a supination splint, avoiding the insertion of metalware until infection had been excluded. Fluid from the knee contained 85 000 polymorphonuclear cells/mL, but no organisms were seen. Fluid and synovial tissue from the right wrist and left knee showed no bacterial growth on culture, and were negative for VZV by quantitative PCR (although the patient had received no antimicrobials in the 21 days before surgery). Histological examination of synovial tissue showed an acute and chronic inflammatory cell response and granulation tissue-type reaction, consistent with poststreptococcal reactive arthritis. The patient was negative for HLA-B27 antigen. The supination splint did not adequately control the right DRUJ. K-wiring of the joint was required, with subsequent fusion of the wrist joint and stabilisation with a tendon graft. Symptoms were initially treated with non-steroidal anti-inflammatory drugs, with the later addition of systemic corticosteroids. Quantitative varicella PCR was performed weekly for 4 weeks. A decrease in varicella DNA concentration in serum from 480 000 to 3400 copies/mL was shown 5 days after admission to hospital. Levels stabilised at 9600 ± 2100 copies/mL, and had decreased to 800 copies/mL before discharge. The Oka vaccine strain of VZV was still detectable by quantitative PCR in the blood 54 days after vaccination, but had become undetectable just over 2 months after vaccination. The timeline of events is outlined in Box 3. DiscussionThis is the first report, to our knowledge, of prolonged viraemia after varicella vaccination in an immunocompetent patient, and also of spontaneous wrist dislocation as a complication of poststreptococcal reactive arthritis. Varicella vaccine contains live attenuated virus (Oka/Merck strains), and has been used in Australia since 2000.3 Although the Oka vaccine strain has been detected in patients with varicella or zoster-like rashes after VZV vaccination,4 its persistence and load in blood after vaccination of immunocompetent adults has not been established. In a study of primary varicella infection, wild-type virus was not detected more than 8 days after the onset of rash, nor in any patient who received aciclovir.5 Another study was unable to detect virus more than 14 days after onset of illness.6 In contrast, in our patient, viraemia persisted for 54 days and the Oka VZV strain was detectable after aciclovir treatment. S. pyogenes infection has long been recognised as a sequelae of chickenpox.7-9 A study found that up to 50% of cases of invasive group A streptococcal infections in children were associated with recent VZV infection.7 However, in previous cases, varicella infection was clearly apparent, and skin lesions were present from which secondary bacterial infection was presumed to arise. Our patient had no clinically apparent chickenpox-like skin lesions, and, in her case, the association between the varicella vaccination and streptococcal infection cannot be clearly defined. The frequency of poststreptococcal reactive arthritis complicating streptococcal septicaemia is difficult to determine because of the heterogeneity of the condition and lack of well accepted diagnostic criteria.10 Although palmar flexor tenosynovitis is described,11 acute atraumatic wrist dislocation has not been documented previously as a complication of poststreptococcal reactive arthritis. Occasional reports of atraumatic dislocation of the wrist have been in the setting of a pre-existing connective tissue disorder or had unknown aetiology.12,13 The M11 serotype of S. pyogenes isolated from our patient has been reported previously in invasive streptococcal disease, although M1 and M3 are the most commonly isolated serotypes.8 However, we believe this is the first report of the M11 serotype as a cause of poststreptococcal reactive arthritis,14 possibly reflecting a more virulent strain. This case highlights the possibility of prolonged high-level viraemia following varicella vaccination and the possible association with invasive S. pyogenes disease. However, this must be considered in the context of the benefits of varicella vaccination in preventing transmission of disease to health care workers15 and susceptible individuals. 1 Gross oedema of the patient’s hands at presentation 2 The patient’s wrist 19 days after admission A: Clinical deformity of right wrist. B: Posteroanterior and lateral x-rays showed carpal disruption, dislocation of the distal radioulnar joint and wide diastasis of the scapholunate interval. C: At surgery, synovitis was apparent around the flexor tendons. 3 Timeline of events Day Event 0 First dose of varicella vaccine 21 Second dose of varicella vaccine 26 Onset of symptoms 38 Admission to hospital 40 Serum VZV DNA level 480 000 copies/mL Admission to intensive care unit with streptococcal toxic shock syndrome 57 Bilateral median nerve compression 68 Median nerve decompression, flexor synovectomy, and knee aspiration. No evidence of infection, clinical picture suggestive of reactive arthritis 75 Serum VZV 800 copies/mL by quantitative PCR 89 Serum negative for VZV by quantitative PCR VZV = varicella zoster virus. PCR = polymerase chain reaction.

Claire M Italiano MB BS · Cheryl S Toi PhD · Simon P Chan MB BS, FRACS(ORTH) · Dominic E Dwyer MD, FRACP, FRCPA

To the Editor: Controlled breathing is a fundamental principle of marksmanship. I describe an effect of viral lower respiratory tract infection on small arms training that was unexpectedly prolonged. The patient (myself) had abrupt onset of respiratory infection, 1 day after a marksmanship training session on an electronic firing range. During the session, I obtained satisfactory scores from several firing positions (best score, 66 mm grouping for five shots and 126 mm grouping for 20 shots, at 200 m, prone firing position). The illness progressed rapidly from a non-specific prodrome to a flu-like illness with fever, malaise, muscle aches, lethargy, slowed cognition, cough, sore throat, rhinorrhoea, persistent lacrimation and a 24-hour period of prostration. Recovery began after 48 hours, allowing a return to light work at 72 hours and full working duties by Day 7. On Day 14, during another marksmanship training session, my accuracy was severely decreased. I failed to obtain satisfactory scores in any position because of persistent erratic breathing and occasional involuntary coughing (best score, 235 mm grouping for 20 shots at 200 m). Spirometry later that day showed a reduced peak flow rate (310 L/min) (see Box). Serological tests were negative for IgG and IgA for all respiratory agents assessed. Nasal swabs were positive for parainfluenza virus type 3 by polymerase chain reaction testing. Involuntary coughing, particularly towards the end of the day, and decreased exercise tolerance persisted for a further 2 weeks, by which time peak flow had increased to 500 L/min. A third marksmanship session the week afterwards showed an improvement in scores, but they were still worse than those obtained pre-infection. Notably, grouping deteriorated rapidly after the first series of 20 shots, and could not be regained even after short rests. Replay of the recorded laser beam pattern for the session indicated that the breathing pattern remained erratic, although peak flow had risen further to 550 L/min. In the aftermath of the First World War, the joint head of Germany’s forces, Ludendorff, claimed that the failure of his 1918 spring offensive was ultimately caused by epidemic influenza.1 The epidemic affected German troops later than the allied forces, in June 1918. By July 1918, there were an estimated 500 000 German influenza casualties. Ludendorff’s initial successes were a result of new, highly mobile type infantry tactics — the forerunner of today’s “fire and movement” — which require physical fitness, stealth and accuracy of rifle fire. My case demonstrates that the tactical consequences of a viral lower respiratory infection can last much longer than medically explicit morbidity. Prolonged effects in my case included persistent involuntary cough, loss of exercise tolerance and loss of marksmanship, weeks after the initial acute illness. Ludendorff’s claim may be not so far off the mark. Marksmanship scores* and peak flow rates over time after onset of a respiratory tract infection * Lower scores for shot grouping indicate better marksmanship (shots are more closely grouped).

Timothy J J Inglis

Chromobacterium violaceum infection is uncommon but potentially fatal, with a clinical picture similar to melioidosis but with different antibiotic sensitivities and treatment. This infection can involve any organ, but we believe this is the first reported case of C. violaceum endocarditis. Clinical recordA 40-year-old woman was admitted to hospital with a 1-week history of general malaise, fever, rigors, lower back pain and headache. She reported swimming in a freshwater lake in Litchfield National Park in the Northern Territory a week previously, during the wet season, at which time she had sustained a graze on her thorax from a tree branch. On admission, the patient’s temperature was 38.5°C, her pulse was 113 beats/min, blood pressure was 105/64 mmHg, respiratory rate was 22 breaths/min, and oxygen saturation was 98% on room air. A small resolving skin lesion was noted on her thorax. She had a grade 2/6 pansystolic apical murmur. Findings from the general examination were otherwise normal. Haematological investigations found her haemoglobin level was 130 g/L (reference range [RR], 110–165 g/L), white blood cell count was 10.2 × 109/L (RR, 3.5–11.0 × 109/L) with neutrophils at 8.96 × 109/L (RR, 2.0–8.0 × 109/L), and C-reactive protein (CRP) level was 300 mg/L (RR, < 2.5 mg/L). Results of liver function tests peaked between Days 17 and 20 at the following levels: alkaline phosphatase, 193 U/L (RR, 42–98 U/L); γ-glutamyltransferase, 101 U/L (RR, < 38 U/L); alanine aminotransferase, 117 U/L (RR, < 34 U/L); and aspartate aminotransferase, 78 U/L (RR, < 31 U/L). Normal results were obtained for urea, creatinine, electrolytes, lumbar puncture, urinalysis and a chest radiograph. Serological tests for Burkholderia pseudomallei, Leptospira spp., rickettsiae, Q fever, hepatitis A, B and C viruses, dengue virus and HIV were negative. T-cell subsets and immunoglobulin levels were normal. Intravenous aciclovir and ceftriaxone were commenced, and a diagnosis of melioidosis was considered. On Day 3, patient temperatures up to 40°C were recorded, and motile gram-negative bacilli were detected in the two initial sets of blood cultures after 28–39 hours of growth. Intravenous gentamicin was added to the patient’s antimicrobial regime. On Day 4, a computed tomography (CT) scan of the abdomen and pelvis showed multiple discrete hypodense lesions measuring up to 1.7 cm throughout the liver, and a bulky spleen (Box 1, A). Deep-purple and black colonies grew on Mueller–Hinton blood agar and antibiotic sensitivity plates. Chromobacterium violaceum, sensitive to ciprofloxacin, meropenem and co-trimoxazole, but resistant to gentamicin, was identified, and confirmed by testing on the VITEK 2 system (bioMérieux, Durham, NC, USA). B. pseudomallei, the causative organism of melioidosis,1 is not usually pigmented. The patient was commenced on intravenous meropenem. Abatement of symptoms was slow, but the patient’s CRP level fell to 17 mg/L on Day 13. A repeat CT scan of the abdomen and pelvis on Day 10 showed generalised reduction in size of the liver abscesses. A transthoracic echocardiogram on Day 11 revealed mild mitral regurgitation. A contrast CT brain scan performed on Day 13 showed no abnormalities. A transoesophageal echocardiogram (TOE) performed on Day 15 demonstrated a small, 8 mm × 1 mm, linear mobile echodensity arising from the left ventricular outflow tract between the commissures of the left and right coronary cusps, consistent with a small vegetation (Box 1, B). An electrocardiogram was normal. The patient was discharged home in Week 5 and continued on home intravenous therapy with meropenem to complete a course of 6 weeks’ intravenous treatment. A 6-week course of oral ciprofloxacin 750 mg twice daily was introduced, starting in Week 6. The patient had a total of 11 weeks of antibiotic treatment. A follow-up abdominal ultrasound during Week 6 showed complete resolution of the liver abscesses. A repeat TOE during Week 11 showed resolution of the aortic valve vegetation after antimicrobial therapy. After 11 weeks, the patient’s white blood cell count and CRP level remained normal and she was clinically well, so antibiotics were ceased. Three months after ceasing antibiotics, the patient remained clinically well and had normal full blood count, CRP level and liver function test results. DiscussionC. violaceum is a gram-negative, facultative anaerobic, non-sporing coccobacillus. It is commonly found in water and soil in tropical and subtropical regions of South-East Asia, South America and northern Australia. Apart from South America, it is endemic in the same regions as B. pseudomallei.1 Human disease is rare, and is most frequent in the wet season. Trauma is often an antecedent event, with abscess formation at the site. Systemic infections can be rapidly progressive, leading to metastatic abscess formation identical to that seen in melioidosis, with past documented mortality rates of 60%.2 We believe endocardial C. violaceum infection has not been reported previously. Immunodeficiency predisposes to the infection, although most patients with C. violaceum infections have no underlying immunodeficiency. B. pseudomallei and C. violaceum are both characteristically resistant to penicillin, ampicillin and first- and second-generation cephalosporins. However, there are some significant differences between the antibiotic sensitivities of the two bacteria. Ceftazidime and meropenem have become the drugs of choice for treating B. pseudomallei infection.3 White and colleagues demonstrated a 50% reduction in mortality from melioidosis using ceftazidime compared with combined chloramphenicol, co-trimoxazole and doxycycline.4 Sookpranee et al demonstrated the benefit of ceftazidime combined with co-trimoxazole compared with combined co-trimoxazole, chloramphenicol and doxycycline.5 Currie recommends ceftazidime, meropenem or imipenem as initial intensive therapy for melioidosis.6 Cheng et al found meropenem and ceftazidime equally effective in 6 years’ experience with 214 patients, although meropenem was preferred in critically ill patients.7 Resistance of B. pseudomallei to amikacin has been documented.8 In contrast to B. pseudomallei, C. violaceum infection is uncommon, with about 150 cases reported in the world literature, compared with over 200 cases of melioidosis documented in one series alone.7 No reports of controlled therapeutic trials have been published. Susceptibility to third-generation cephalosporins and aminoglycosides varies.9 However, there are documented cases of ceftazidime resistance from Australia,10 India11 and Brazil,12 with resulting fatalities. Amikacin in combination with gatifloxacin has been found to be successful for the treatment of puerperal sepsis from C. violaceum.13 Other case reports record cures with co-trimoxazole, quinolones, tetracyclines and chloramphenicol.14 Currently, there are limited published studies confirming the success of meropenem in treating C. violaceum infection.14 In conclusion, physicians should not rely on ceftazidime alone for treating a febrile traveller with suspected melioidosis, until infection with C. violaceum has been ruled out by microbiological cultures. There is a minor role for amikacin as combination therapy for C. violaceum infections (but no role for B. pseudomallei). Co-trimoxazole in combination with other agents may be an alternative if carbapenems are contraindicated. To exclude endocarditis, transoesophageal echocardiography should be considered. A summary of antibiotic recommendations for B. pseudomallei and C. violaceum infections is provided in Box 2. 1 Chromobacterium violaceum infection A: Computed tomography scan of the abdomen showing multiple hepatic abscesses. B: Transoesophageal echocardiogram showing C. violaceum vegetation on aortic valve (cursors). 2 Summary of antibiotic recommendations Bacterium Ceftazidime Amikacin Meropenem Burkholderia pseudomallei Standard therapy Resistant Standard therapy Chromobacterium violaceum Failures and fatalities reported Success in combination Anecdotal success

Ivan W M Lim MB BCh, BAO · Peter J Stride MB BS, FRACP · Robert L Horvath MB BS, FRACP · Christian R Hamilton-Craig MB BS, FRACP · Phi P Chau MB BS

Azithromycin is recommended as the first-line antibiotic for the prophylaxis and treatment of pertussis, a common vaccine-preventable communicable disease. Azithromycin is better tolerated than other macrolide antibiotics. Access to azithromycin is limited, as the product information and the Pharmaceutical Benefits Scheme do not include azithromycin for pertussis. Issues regarding access to azithromycin are highlighted in a case report of pertussis exposure in a tertiary paediatric hospital.

Asha C Bowen BA, MB BS, DCH · Mark J Ferson MD, FRACP, FAFPHM · Linda V Graudins BPharm, DHP, FSHPA · Pamela Palasanthiran MB BS, FRACP, MD

A 56-year-old man with a history of rheumatoid arthritis presented with a 2-day history of worsening pain in his left foot. Treatment with high-dose steroids was of no benefit, hence a diagnosis of septic arthritis was considered. However, the patient’s condition deteriorated despite empirical antibiotic therapy. Following persistent investigation, the cause was identified as a fastidious Legionella longbeachae infection, and appropriate antibiotic therapy led to complete resolution of the sepsis. This emphasises the importance of considering infections with atypical organisms in patients on immunosuppressive therapy. Clinical recordIn July 2008, a 56-year-old retired man presented with a 2-day history of worsening pain in his left foot. His medical history included seropositive active rheumatoid arthritis (RA), type 2 diabetes mellitus with microvascular complications, and idiopathic dilated cardiomyopathy managed with an implantable cardioverter-defibrillator and permanent pacemaker (left ventricular ejection fraction: 12% in 2006, 42% in 2008). His RA had been difficult to control — intermittent flares, usually involving his feet, were managed with high-dose steroids. Before presentation, the patient was taking weekly oral methotrexate (20 mg) and daily prednisolone (7.5 mg). Leflunomide, hydroxychloroquine and sulfasalazine therapy had failed to control his RA in the past and were withdrawn because of adverse reactions. Treatment with rituximab, an anti-CD20 monoclonal antibody, in September 2007 (two 1000 mg infusions, administered 2 weeks apart) had also failed to control his RA, and tumour necrosis factor-α (TNF-α) inhibitors were contraindicated owing to his cardiac disease.1 On examination, the patient had diffuse swelling with tenderness over the small joints of his left foot and ankle, with minimal erythema. He was not constitutionally unwell; however, his C-reactive protein (CRP) level was 64 mg/L (reference range [RR], 0–10 mg/L), and he was anaemic (haemoglobin level, 86 g/L [RR, 130–175 g/L]) and leukopenic (white cell count, 2.0 × 109/L [RR, 4.0–11.0 × 109/L]; neutrophil count, 1.6 × 109/L [RR, 1.5–7.5 × 109/L]). A provisional diagnosis of RA flare was made, the patient was admitted to a private hospital, and high-dose oral prednisolone therapy (50 mg/day) was begun. Over the next 2 days, there was no improvement in the patient’s left foot swelling and pain, and his haemoglobin and CRP levels worsened further (haemoglobin level, 77 g/L; CRP level, 102 mg/L). However, he remained afebrile. He was transfused with three units of packed red cells. A whole body bone scan was performed to test for underlying infection, and it revealed intense tracer uptake in the region of the fourth and fifth tarsometatarsal joints of the patient’s left foot (Box). He subsequently developed fever, chills, tachycardia and painful swelling in his left wrist. In view of the worsening clinical features and the increasing CRP level, an alternative diagnosis of septic arthritis or osteomyelitis was strongly suspected, rather than a flare of RA. Blood cultures were ordered, and intravenous flucloxacillin therapy was begun; methotrexate was withdrawn, and the dose of prednisolone was reduced to 25 mg daily. A computed tomography scan of the patient’s left foot showed only soft tissue swelling, with no cortical destruction, fracture or collection. The patient was then transferred to our institution as his treating physician was to go on leave. On examination, he was febrile, had synovitis of his left wrist, and had marked swelling and erythema of his left foot, extending to the ankle. A Gram stain of an aspirate from his left wrist, collected on admission to our hospital, revealed occasional gram-negative bacilli. Further blood cultures were ordered and flucloxacillin was substituted with meropenem. The next day, meropenem was changed to cefepime for better coverage of possible Pseudomonas infection, pending blood culture results. The cellulitis of the patient’s left foot did not resolve during the next 2 days, and possible septic arthritis developed in the right fourth finger (distal interphalangeal joint). Despite ongoing antibiotic therapy, the patient’s condition deteriorated. He became neutropenic (neutrophil count, 0.3 × 109/L), and the swelling of his left foot extended to the knee. His haemoglobin level dropped to 82 g/L, and he required transfusion of two additional units of red cells. He had daily temperature spikes, but blood and synovial fluid cultures were still showing no growth at 4 days after the initial aspirate and blood samples were taken. To identify the apparently fastidious bacterium noted in the initial wrist aspirate, synovial fluid from the left wrist was plated onto various selective media. Colonies grew on buffered charcoal yeast extract medium, and a Legionella species was suspected. Azithromycin and moxifloxacin were added to the treatment regimen 5 days after the patient was transferred to our institution, and cefepime was withdrawn. The neutropenia was treated with subcutaneous injections of granulocyte colony-stimulating factor. The patient’s condition improved dramatically during the next few days; complete resolution of cellulitis and joint swellings occurred with ongoing appropriate antibiotic therapy. Polymerase chain reaction analysis confirmed that the isolated bacterium was a Legionella species, which was subsequently shown by 16S ribosomal RNA gene sequencing to be Legionella longbeachae. Extensive review of environmental risk factors did not reveal a recent source of exposure to this organism, and there had been no precedent pneumonia. He was discharged home and prescribed a 6-week course of oral azithromycin and moxifloxacin. On follow-up at 6 weeks, his CRP level and white cell count had normalised, with complete resolution of symptoms. DiscussionThis case shows how challenging it can be to differentiate between flare and infection in patients with RA who present with worsening local symptoms. Adding to the diagnostic challenge in this case was the involvement of a particularly fastidious organism. To our knowledge, this is the only reported case to date of septic arthritis with L. longbeachae without preceding pulmonary infection in a patient with RA, although two cases of septic arthritis with Legionella pneumophila in immunocompromised patients without lung involvement have been reported.2,3 Extrapulmonary infections by Legionella species are rare and are generally thought to arise from haematogenous spread after pulmonary infection. L. longbeachae is responsible for about 4% of cases of community-acquired legionellosis worldwide, and about 30% of cases in Australia and New Zealand.4 It is commonly found in soils and potting mixes, and occasionally in water.5 However, our patient was not a gardener, and we could not identify any other recent source of exposure to L. longbeachae. Patients with RA have an increased risk of infection because of the disease itself and immunosuppressive therapy.6 Therefore, a differential diagnosis of underlying infection with typical and atypical organisms should be considered when patients with RA present with disease flares that do not respond to appropriate escalation of immunosuppressive therapy. Several factors complicated the management of this patient’s condition. In particular, his RA was difficult to control; he also could not be administered TNF-α inhibitors (owing to his underlying moderate-to-severe heart failure) as per current expert consensus recommendations.1 Abatacept (a selective blocker of T-cell co-stimulation) is being considered as a future treatment option in this patient. He also had anaemia of chronic disease secondary to the active RA, for which erythropoietin therapy was begun after discharge; he did not require further blood transfusions over the 6 months after discharge. In addition, he was leukopenic; this was likely to be secondary to the sepsis because, although he had previously been treated with rituximab, his lymphocyte count was normal 1 month before presentation and at follow-up. Our patient presented with an apparently simple flare of RA that developed into life-threatening sepsis with neutropenia. This case illustrates the need for a high index of suspicion of infection with unusual organisms when symptoms suggestive of active arthritis in such patients do not respond to standard treatment. Delayed regional bone scans of a patient with persistent pain and swelling of the left foot Intense tracer uptake is visible in the left foot — in the fourth and fifth tarsometatarsal joints, with flare extending along the shaft of the fourth metatarsal. A: Posterior view of both feet. B: Anterior view of both feet. C: Left lateral view of left foot. D: Right lateral view of left foot.

Manish Dugar MB BS · Wayne A Rankin PhD · Emily Rowe MB BS · Malcolm D Smith PhD, FRACP

To the Editor: A 60-year-old Hispanic woman, who had lived in the United States for 10 years, presented with a 1-day history of altered mental status. Physical examination revealed ascites and enlarged right axillary lymph nodes. Magnetic resonance imaging (MRI) of the brain showed multiple intracranial lesions (Box, A). Computed tomography of the chest and abdomen showed massive adenopathy in the right axilla, multiple nodules in upper lung fields, ascites and retroperitoneal adenopathy. Her cancer antigen (CA) 125 level was 1469 U/mL (reference range, 0–35 U/mL); CA27.29 and CA19-9 levels were within the upper limit of the normal ranges. She was initially thought to have metastatic cancer of unknown primary site. However, a right axillary node biopsy revealed necrotising granulomas and no malignancy; an acid-fast bacteria (AFB) stain was negative. Ultrasound-guided retroperitoneal lymph node biopsy showed necrotising granulomas and no malignancy; an AFB stain was positive. We began investigations for disseminated tuberculosis (TB). A QuantiFERON-TB Gold test (Cellestis, Valencia, Calif, USA) and sputum and right axillary node cultures were positive for Mycobacterium tuberculosis; peritoneal and cerebrospinal fluid cultures were negative. Polymerase chain reaction (PCR) of samples of peritoneal fluid and from bronchoalveolar lavage was negative for M. tuberculosis DNA, but a sample from the retroperitoneal lymph node tested positive. The patient was started on four-drug therapy for TB and her condition progressively improved. Follow-up MRI of the brain 5 months later showed a decreased size of all intracranial lesions (Box, B), and her CA125 level was 84 U/mL. Peritoneal TB can mimic advanced ovarian cancer because of similarities in clinical signs and symptoms, such as ascites, abdominal pain and elevated CA125 levels.1 The association of peritoneal TB with high CA125 levels was first described in 1987.2 The positive predictive value of CA125 levels to detect malignancy is estimated at 60%, rising to 98% in postmenopausal women.3-4 In most reported cases of peritoneal TB, CA125 levels were below 500 U/mL; rarely, levels up to 1200 U/mL have been seen.1-4 Culture is of limited clinical usefulness, as results take up to 6 weeks. Although microscopy is rapid, cheap and highly specific, its sensitivity has been shown to be as low as 31% for extrapulmonary TB.5 PCR is of limited value in diagnosing peritoneal TB. Detecting M. tuberculosis DNA by PCR in ascitic fluid poses many challenges — differences in technique, contamination with other bacteria, and the variable number of acid-fast bacilli in samples have been shown to influence its reliability.4-5 Negative results from microscopy, culture and PCR should not distract from a diagnosis of TB. In the face of a growing international incidence of TB, it is important to consider this transmissible and treatable disease in the context of abdominal symptomatology, ascites and raised serum CA125 levels — especially in ethnic groups in which TB prevalence is high. Misdiagnosis or delayed diagnosis can lead to infertility, premature menopause and death. Magnetic resonance (MR) imaging of the brain before and after treatment A: B rain MR image showing multiple intracranial lesions involving the left cerebellum, left occipital lobe, left parietal lobe and corpus callosum. B: MR image of the brain 5 months post-treatment, showing a decrease in the size of all intracranial lesions.

Riad O El Fakih · Bassem M Chehab · Rami A Mortada · Maha Assi

Dengue transmission in Australia is currently restricted to Queensland, where the vector mosquito Aedes aegypti is established. Locally acquired infections have been reported only from urban areas in the north-east of the state, where the vector is most abundant. Considerable attention has been drawn to the potential impact of climate change on dengue distribution within Australia, with projections for substantial rises in incidence and distribution associated with increasing temperatures. However, historical data show that much of Australia has previously sustained both the vector mosquito and dengue viruses. Although current vector distribution is restricted to Queensland, the area inhabited by A. aegypti is larger than the disease-transmission areas, and is not restricted by temperature (or vector-control programs); thus, it is unlikely that rising temperatures alone will bring increased vector or virus distribution. Factors likely to be important to dengue and vector distribution in the future include increased dengue activity in Asian and Pacific nations that would raise rates of virus importation by travellers, importation of vectors via international ports to regions without A. aegypti, higher rates of domestic collection and storage of water that would provide habitat in urban areas, and growing human populations in northern Australia. Past and recent successful control initiatives in Australia lend support to the idea that well resourced and functioning surveillance programs, and effective public health intervention capabilities, are essential to counter threats from dengue and other mosquito-borne diseases. Models projecting future activity of dengue (or other vector-borne disease) with climate change should carefully consider the local historical and contemporary data on the ecology and distribution of the vector and local virus transmission.

Richard C Russell MSc, PhD, FACTM · Bart J Currie FRACP · Michael D Lindsay PhD · John S Mackenzie PhD · Scott A Ritchie PhD · Peter I Whelan BSc

To the Editor: We concur with Aratchige and colleagues that mumps in young adults is a “forgotten” disease,1 and believe that mumps control in Australia has suffered from both the successes and failures of our measles elimination program. Among residents of Sydney’s eastern and southern suburbs, 100 cases of mumps were notified in the second half of 2007. Sixty-three per cent of those who contracted the disease were aged 20–29 years, and 65% were male. This compares with an average of 13.6 cases (range, 4–32 cases) notified per annum from 1999 to 2006. During the second half of 2007, one institution managed three cases of severe orchitis in men aged 25–29 years whose diagnosis was confirmed by a positive mumps IgM test. In all three, initial fever and transient parotitis were followed after 7–10 days by severe testicular pain and swelling. Fever and testicular pain continued for a further 1–2 weeks, precluding their return to work. None had been vaccinated. Although mumps vaccine was introduced in Australia in 1980, mumps control has not been an explicit priority compared with measles.2 It seems that public health authorities in industrialised countries have assumed that measles control efforts based on two doses of the measles–mumps–rubella (MMR) vaccine would lead to simultaneous mumps control. While doubt has been cast over the effectiveness of this approach and raised the possibility of a three-dose schedule,3 we agree with the view of Schmid and colleagues that public health authorities should focus on adequate vaccination coverage and adherence to the recommended two-dose MMR vaccination scheme.4 The Australian birth cohort reported by Aratchige et al to have a dip in mumps immunity was the cohort born in the years 1978–1982.1 This group may have avoided natural measles (as well as mumps), missed the Measles Control Campaign in 1998 (which targeted primary-school children with MMR vaccine), and was subject to an ineffective national effort in 2001 to target young adults with MMR vaccine.2 At the time of the 2007 mumps outbreak, this cohort was aged 25–29 years and was the hardest hit. Concerted action to raise the level of two-dose coverage among young adults is urgently needed. Novel strategies exist for targeting this highly communication-aware age group through convergent Internet and mobile phone technologies. Social network sites such as MySpace and Facebook are heavily used by young people, and the proportion of mobile phones with Internet access is increasing. Sporting clubs and major entertainment events are another avenue to be considered with respect to both their physical and virtual locations (eg, posters at the clubs or events, advertisements on their websites). A comprehensive guide has recently been produced for Internet-based prevention of sexually transmitted diseases.5 It is well and truly time to adapt such methods to the promotion of MMR vaccination.

Mark J Ferson · Pam Konecny

Postnatal infection may represent a preventable risk factor for onset of psychotic disorders in adolescence and early adulthood. The mechanism of action is likely to involve site-directed triggering of the brain’s innate immune system, mediated principally through localised activation of microglial cells. This triggering may occur in response to systemic inflammatory stimuli, without direct involvement of the central nervous system. Microglial activation can represent a primary response or a secondary phenomenon at sites made vulnerable by prior injury; that is, areas containing previously activated microglia will respond more strongly to a new stimulus. The presence of activated microglia is indicative of a recent insult or active disease. It is not characteristic of long-established neurodevelopmental abnormalities. Activated microglia, acting through a variety of cytokine and other signal systems, have the capacity to significantly interfere with synaptic turnover and thus, over time, alter synaptic architecture and function. This pathophysiological path should be investigated more systematically as it may explain a novel “neuroprotective” mode of action for some existing antipsychotic compounds.

Ian B Hickie MD, FRANZCP · Richard Banati MD, PhD · Claire H Stewart PhD · Andrew R Lloyd MD, FRACP

To the Editor: We read with interest Giles and colleagues’ recent article, which examined the adoption of strategies to reduce perinatal transmission of HIV infection in Australia.1 They found that uptake of strategies to reduce perinatal HIV transmission had increased, with widespread use of antiretroviral therapy (ART) and breastfeeding avoidance. The authors also noted that caesarean birth was a strategy less commonly utilised by women with HIV infection. They made particular comment about the caesarean delivery rate for women known to have HIV infection in Western Australia. It was disappointing that the authors did not refer to our recent publication describing the low rate of perinatal HIV transmission in WA using an individualised delivery modality policy.2 In our consecutive series of 56 pregnancies between 1991 and 2005, 48 (86%) were managed by a multidisciplinary team, with 98% (47/48) of women receiving ART (one woman actively declined this intervention). Only one baby in the group who received care through the multidisciplinary team acquired perinatal HIV. This pregnancy occurred in 1991 in a woman with advanced disease who received zidovudine monotherapy, a situation not applicable today. Elective caesarean delivery was based on either obstetric indications or a high HIV RNA level; 75% of women in our series had a vaginal delivery. The findings of our study were of particular note because 39% of mothers were Aboriginal, and predominantly from rural and remote regions of WA. Although the patient numbers in our study were small, the current international evidence does not support mandatory caesarean delivery for women receiving ART with undetectable plasma HIV RNA.3 The risk of vertical transmission in this circumstance is low, and caesarean birth is associated with short- and long-term morbidity (most notably, placenta accreta). Recent series have shown a trend of increasing vaginal birth rates among women with well controlled HIV infection.4,5 When infection is well controlled, we believe that the mode of delivery should be individualised, and vaginal birth should be an option for women who desire this delivery method. It is disappointing that Giles and colleagues appear to imply that the low caesarean delivery rate in WA is a reflection of suboptimal HIV care processes, rather than evidence-based practice.

Marisa T Gilles · Martyn A French · Jan E Dickinson