Infectious diseases

Clinical recordA 24-year-old woman presented to hospital in May 2009 after two generalised seizures with focal motor onset involving the right arm and leg. She had a 2-month history of intermittent frontal headaches and twitching of the right hand that did not interfere with usual activities. Her family had noticed she had lost weight. The patient was originally from the Eastern Equatoria province in southern Sudan and spent 12 years in a Ugandan refugee camp before migrating to Australia in 2007 with her family. Her only significant past medical history was malaria. Her family were in good health. On admission, the patient was hypothermic (temperature, 35.7°C), with a Glasgow Coma Scale score of 6, and gaze deviation to the left. Initial investigations showed hypochromic, microcytic anaemia (haemoglobin concentration, 100 g/L, reference range [RR], 115–160 g/L; mean cell volume, 65 fL, RR, 78–101 fL; and mean cell haemoglobin, 20 pg/cell, RR, 25–35 pg/cell), hyponatraemia (132 mmol/L; RR, 135–147 mmol/L), and raised serum protein level (109 g/L; RR, 60–84 g/L). Results of computed axial tomography of the brain with contrast and chest x-ray were unremarkable. Cerebrospinal fluid (CSF) contained polymorphonuclear leukocytes (45 × 106/L), mononuclear cells (168 × 106/L), red blood cells (23 × 106/L), protein (0.88 g/L) and glucose (2.5 mmol/L). No organisms were seen on Gram stain. Persistent status epilepticus necessitated treatment with loading doses of phenytoin, sedation and intubation. Magnetic resonance imaging (MRI) of the brain showed extensive areas of uniform high signal intensity within the supratentorial white matter and mild meningeal enhancement (Box 1). Meningoencephalitis was diagnosed, and the patient was treated with ceftriaxone and aciclovir. Based on history, presentation and cerebrospinal fluid findings, she was also given isoniazid, rifampicin, ethambutol, pyrazinamide, pyridoxine and dexamethasone for suspected tuberculous meningoencephalitis. Multiple investigations for bacterial, viral and fungal pathogens, including serological tests for HIV, and polymerase chain reaction (PCR) tests and culture for Mycobacterium tuberculosis, gave negative results (Box 2). The patient was extubated on Day 4, and her condition improved, with no further seizures, although periods of fluctuating drowsiness and confusion were noted. Electroencephalography showed generalised slowing consistent with diffuse cerebral dysfunction. To clarify the diagnosis, lumbar puncture was repeated; CSF showed polymorphonuclear leukocytes, 0 × 106/L; mononuclear cells, 141 × 106/L; protein, 0.52 g/L; and glucose, 2.0 mmol/L; but was again Gram stain-negative. Investigations for autoimmune and malignant disease, as well as mitochondrial disorders and metabolic leukodystrophies gave negative results (Box 2). Cervical lymphadenopathy was identified in the posterior cervical triangle, and examination of a fine needle aspirate suggested reactive lymphadenitis. A subsequent biopsy showed relatively preserved nodal architecture with reactive follicles, and no evidence of granulomas or malignancy. PCR testing of the biopsy specimen for M. tuberculosis and culture gave negative results. In view of the apparent clinical response to treatment, tuberculous meningoencephalitis was considered the most likely diagnosis, despite the negative results on investigation and brain MRI. The patient was discharged on Day 36, with continuing treatment with the anticonvulsant levetiracetam, antituberculous therapy and dexamethasone (4 mg tapering by 1 mg weekly). The patient re-presented 2 weeks later with increasing confusion, somnolence, gait unsteadiness and worsening bilateral tremor, and was re-admitted. Repeat MRI of the brain with gadolinium contrast showed progression of the diffuse subcortical and deep white matter abnormalities observed on previous MRI, with extension into the midbrain and pons. Treatment was begun with methylprednisolone (4 mg daily), and antituberculous therapy was discontinued. A diagnosis of West African trypanosomiasis was considered, but peripheral blood and lymph node tissue were negative for trypanosomes; lumbar puncture was not performed because of concern about increased intracranial pressure. Because of a rapid deterioration in the patient’s condition and the continuing uncertainty over the diagnosis, a stereotactic brain biopsy was performed. Histological examination of the biopsy specimen showed meningoencephalitis with Mott (morula) cells (Box 3A), suggesting human African trypanosomiasis (HAT). Review of the previous CSF cytology specimens also revealed Mott cells (Box 3B), which had not been recognised initially. Indirect haemagglutination tests of serum for HAT-specific antibodies gave positive results, with a titre of 1:4096. Treatment with intravenous pentamidine (200 mg daily) was begun 2 months after the patient’s first presentation and was continued for 4 days pending the arrival of eflornithine provided by the World Health Organization. The patient regained consciousness after pentamidine treatment began, and her condition improved dramatically with a 14-day course of intravenous eflornithine (5 g four times daily). Corticosteroid therapy was tapered and ceased. She was discharged to a rehabilitation unit, able to walk independently and undertake basic activities of daily living, but requiring ongoing help with executive functioning. After discharge, she returned to her family and community life. She had a residual hand tremor but continued to show steady improvement in level of functioning, mentation and social interactions. At 3-month follow-up, she remained well, but repeat lumbar puncture revealed persisting CSF lymphocytosis. 1 Magnetic resonance image of the brain 17 days after presentation An axial T2-weighted magnetic resonance image at the level of the basal ganglia showed symmetrical high signal intensity in the white matter, particularly in the centrum semi-ovale (subcortical white matter) (arrowed). 2 Summary of investigations undertaken with negative results* Infectious diseases screen Viruses. Cytomegalovirus (IgM, IgG); Epstein–Barr virus (IgM, IgG, PCR), herpes simplex virus and human herpes virus 6 (PCR), adenovirus, influenza A and B viruses, parainfluenza virus, and respiratory syncytial virus (DIF), and hepatitis A, B and C and HIV (serology). Bacteria. Brucella abortus (serum agglutination titre), meningococcus (PCR), mycobacterium (PCR, culture), mycoplasma (PCR), syphilis (serology), streptococcal antigen, rapid screen for bacterial antigens, and blood, urine, cerebrospinal fluid, sputum and stool cultures. Parasites. Blood parasite screen (including malaria), cryptococcal antigen, schistosomiasis (IgG) and toxoplasma (IgM, IgG). Toxicology screen: Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ethanol, methadone, opiates. Metabolic screen: Cerebrospinal fluid pyruvate, lysosomal enzymes and very long chain fatty acids. Immune screen: Anticardiolipin antibody, anti-double stranded DNA, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antigen antibodies, anti-Purkinje cell antibody, antineuronal antibody, anti-neuromyelitis optica antibody, complement levels, cryoglobulins, lupus anticoagulant, ß2-glycoprotein, ß2-microglobulin, thyroglobulin antibody, thyroperoxidase antibody and oligoclonal bands. Oncology screen: a-Fetoprotein, tumour markers Ca 125 and Ca 19-9, flow cytometry for cell markers, and serum electrophoretogram/immunoelectrophoretogram. Other tests: Serum cortisol, ß-human choriogonadotropin, iron studies, thyroid function, vitamin D level and vitamin B12 and folate studies. PCR = polymerase chain reaction. DIF = direct immunofluorescence. * Tests are categorised for easy reference but were not necessarily performed in the order shown, rather on different occasions as clinically indicated. For example, investigations for toxoplasma and cryptococcus were performed shortly after the patient was first admitted, but those for schistosomiasis not until her second admission, almost concurrently with trypanosomiasis testing. 3 Mott cells in the patient’s brain and cerebrospinal fluid A. White matter from a brain biopsy specimen taken during the patient’s second admission showed perivascular inflammatory infiltrates composed of lymphocytes and plasma cells, including Mott (morula) cells (arrows). The cytoplasm of Mott cells contained brightly staining eosinophilic immunoglobulins (high-power magnification, haematoxylin and eosin stain). B. Review of the CSF specimens taken at presentation showed Mott (morula) cells with large Russell body inclusions (blue-staining globules), representing immunoglobulins (original magnification, × 400; Papanicalou stain). Human African trypanosomiasis (HAT or sleeping sickness) is a significant cause of morbidity and mortality in parts of Africa but is rarely seen in Australia. Lack of awareness of this disease among Australian physicians means it may be easily misdiagnosed, delaying timely treatment and resulting in inadvertent adverse outcomes. HAT is caused by the flagellated protozoan Trypanosoma brucei. Two subspecies cause human disease: T. brucei rhodesiense, which is found only in east Africa and causes an acute, fulminant illness lasting weeks to months (East African HAT); and T. brucei gambiense, which is found in western, central and parts of east Africa, and causes an indolent, chronic infection that may last many months to years (West African HAT).1 The fulminant course of T. b. rhodesiense illness means it is the form more frequently diagnosed outside Africa, in returned travellers. Infection occurs through injection of saliva containing trypanosomes from the bite of the tsetse fly, and a local skin reaction or chancre may follow. The infection follows two stages. The early (haemolymphatic) stage results from proliferation of parasites in the blood and lymph and presents with headache, fever, malaise, anorexia, anaemia and lymphadenopathy. The late (meningoencephalitis) stage occurs when trypanosomes invade the central nervous system (CNS), causing a range of neurological manifestations including psychiatric changes. Inversion of the sleep–wake cycle is common, resulting in daytime somnolence and nocturnal insomnia. Without treatment, CNS disease eventually results in coma and death. Our patient probably became infected in Uganda, where both subspecies of trypanosome are known to circulate.2 In retrospect, the initial improvement in her condition was most likely a response to corticosteroid treatment, and the subsequent regression coincided with a reduction in the corticosteroid dose. Cervical lymphadenopathy in the posterior triangle was noted at initial presentation but was recognised only during her second admission as a classic feature of T. b. gambiense disease (the Winterbottom sign3). Detection of trypanosomes in the CSF, blood or lymph tissue remains the diagnostic “gold standard”. However, methods of parasite detection vary in sensitivity, and the cyclical nature of parasitaemia means parasites are seldom detected in blood, especially in T. b. gambiense disease,4 although detected more often in CSF.5 We were not able to demonstrate trypanosomes in whole blood, lymph node tissue or CSF. In the absence of demonstrable parasites, and where there is clinical suspicion, serological testing is crucial in diagnosis of T. b. gambiense disease. The sensitivity and specificity of currently available serological tests vary from 71% to 100% and 95% to 99%, respectively. In our patient, the high antibody titre supported a diagnosis of active trypanosomal infestation, although titres are known to remain high several years after treatment.6 MRI findings in trypanosomiasis are non-specific, ranging from meningeal enhancement in earlier CNS disease to bilateral confluent hyperintense T2 signals in the subcortical white matter in late disease, as seen in our patient.7 Although not diagnostic, MRI is a useful adjunct in supporting the diagnosis as relatively few conditions cause this distinct MRI appearance, including acute disseminated encephalomyelitis, cerebral gliomatosis, the leukodystrophies and lymphoma, all of which were considered in our patient. Non-specific CNS findings are meningoencephalitis, comprising leptomeningitis and encephalitis with diffuse perivascular white matter infiltration, microglial nodules and reactive astrocytosis.8 The presence of Mott cells in the CNS and CSF is characteristic of HAT, but these cells are easily overlooked.9 They are morula forms of plasma cells containing prominent eosinophilic cytoplasmic inclusions (Russell bodies) that stain positively with periodic acid-Schiff stain and are composed of immunoglobulin M. Although Mott cells can be found in myeloproliferative disorders, they are considered virtually pathognomonic of HAT in patients with appropriate clinical findings and exposure history.10 Early stage T. b. gambiense disease is treated with pentamidine. Eflornithine, an ornithine decarboxylase inhibitor that interferes with cell division, is the recommended first-line treatment for CNS disease.11 Side effects include seizures, gastrointestinal upset and reversible myelosuppression. As it requires intravenous infusions four times daily over 2 weeks, it is not ideal in resource-constrained settings; recent studies suggest a combination of eflornithine and oral nifurtimox to be as effective but superior in ease of administration and duration of treatment (requiring eflornithine to be given only twice daily for 7 days).12 From May 2009, the WHO has included combination therapy in its essential list of medicines for treatment of West African trypanosomiasis, but was unable to provide nifurtimox for our patient, as its use was approved at that time only for Chagas disease. To our knowledge, our patient represents the fourth case of HAT identified in Australia. A case of meningoencephalitis thought to be due to T. b. gambiense was diagnosed in Perth in 2008 in an immigrant from Sudan and is also reported in this issue of the Journal13 (page 417). A case due to T. b. rhodesiense was diagnosed at our institution in 1998 in a returned traveller with acute illness after visiting a Tanzanian game park.14 The first case in Australia is said to have occurred after World War II.15 Our patient illustrates the need for clinicians to be aware of HAT as a potential cause of meningoencephalitis, particularly in African immigrants, for months or years after they move to Australia.16 Had this possibility been recognised at presentation and specifically investigated, prompt treatment could have been given, and brain biopsy avoided. Lessons from practice Human African trypanosomiasis (HAT) or sleeping sickness is rarely encountered in Australia; physicians should be aware of its possibility in individuals who present with meningoencephalitis and have lived in or visited endemic areas. Definitive diagnosis relies on parasite detection; in its absence, serological testing is the next most appropriate investigation, particularly for disease cased by Trypanosoma brucei gambiense. Corticosteroid therapy can mask symptoms of disease and falsely suggest an improvement, confounding the diagnosis. We recommend that individuals from endemic areas with clinically suspected HAT be screened serologically. This would prevent a potentially fatal delay in diagnosis and permit further monitoring and investigation to confirm and treat disease earlier.

Adam P Liu MB BS, BMedSc(Hons) · Shaun Chou MB BS, BSc(Med) · Lavier Gomes BDS, BSc(Hons), FRANZCR · Thomas Ng FRCPA, FRCPATH · Elizabeth L Salisbury FRCPA, FIAC, FFOP · Grant L Walker MB BS(Hons), FRACP · Donald R Packham FRACP

A 19-year-old Sudanese woman, who had lived for about a decade in Ugandan refugee camps, was referred for investigation of a 12-month history of a generalised rash. Two months later, her condition had deteriorated to include cachexia and drowsiness. Despite initial negative findings on investigation, human African trypanosomiasis (HAT) was suspected, and parasites were found in a double-centrifuged sample of cerebrospinal fluid. Eflornithine, the appropriate drug for treatment of late-stage disease, was obtained through the World Health Organization. This case highlights the diagnostic and therapeutic difficulties in managing late-stage HAT in a non-endemic country. Clinical recordIn January 2008, a 19-year-old Sudanese woman was referred from the community to a tertiary hospital for investigation of a 12-month history of generalised pruritus. There were no obvious precipitants or triggers for the itch. She was born in southern Sudan, but had lived in refugee camps in north-western Uganda for about a decade before migrating to Australia in November 2006. Her past medical history was non-contributory. Initial examination showed generalised hyperpigmented papules and nodules with excoriations. Prurigo was diagnosed, and treatment with topical corticosteroids was trialled. By March 2008, her condition had deteriorated, and she experienced lethargy, apathy, fevers, night sweats, weight loss, reduced rousability, abulia (impairment or loss of willpower) and seizures. The pruritus was pervasive and the scratching automatic. A past family history of human African trypanosomiasis (HAT) in her mother, which was diagnosed and treated in Uganda, was elicited. On examination, she had cachexia, and was drowsy, but rousable, and oriented to person, but not place or time. She had generalised itch with hyperpigmented, lichenified papules and excoriated nodules (Figure 1). Neurological examination showed symmetrical brisk reflexes, bilateral upper-limb cogwheeling, and myoclonic jerks involving her limbs, mouth and periocular muscles. She had palpable posterior cervical lymph nodes of less than 1 cm in diameter. Late-stage HAT was suspected, and she was admitted to hospital for further investigation. Differential diagnoses included other infective encephalitides (tuberculous and viral), vascular events and malignancies (lymphoma). Investigations showed that the patient had microcytic anaemia (haemoglobin concentration, 96 g/L; reference range [RR], 115–145 g/L), which was attributed to a known α-thalassemia trait: her renal function and hepatic function were normal. Her erythrocyte sedimentation rate was 42 mm/h (RR, < 20 mm/h). Elevated concentrations of total serum protein (104 g/L; RR, 60–80 g/L), gammaglobulin (32 g/L; RR, 8–16 g/L), IgG (24.3 g/L; RR, 5.8–13.7 g/L) and IgM (7.8 g/L; RR, 0.3–1.7 g/L) were detected. A skin biopsy suggested lichen simplex chronicus. Initial peripheral blood smears, lymph node and bone marrow aspirates all tested negative for parasites. Examination of the cerebrospinal fluid (CSF) revealed a mononuclear pleocytosis of 100 × 106 cells/L (RR, < 5 × 106 cells/L), an elevated protein level (0.9 g/L; RR, 0.15–0.45 g/L), markedly elevated level of IgM (0.36 g/L; RR, undetectable) and a low level of glucose (2.1 mmol/L; RR, 2.4–4.6 mmol/L); micro-organisms were not seen on examination of the centrifuged deposit. Gadolinium-enhanced magnetic resonance imaging (MRI) showed bilateral, symmetrical, widespread high-signal white matter change on T2-weighted imaging (Figure 2). Simultaneous T2-weighted images demonstrated high signal changes in the splenium, the brainstem and the cerebellar white matter (images not shown), and post-gadolinium images showed minimal leptomeningeal enhancement (images not shown). An electroencephalogram (EEG) showed diffuse delta-wave slowing consistent with a metabolic encephalopathy, with no evidence of ictal activity. Despite initial negative results on CSF testing, HAT was suspected on clinical grounds. Thus, repeat large-volume CSF examination was performed. Direct examination of CSF was again negative, but double-centrifuged CSF microscopy showed trypanomastigotes (Figure 3), confirming the diagnosis of late-stage HAT. Both subspecies of Trypanosoma brucei can be acquired in Uganda.1 We considered Trypanosoma brucei gambiense infection to be more likely in this patient as it is hyper-endemic in north-western Uganda and because of the subacute clinical presentation. However, as Trypanosoma brucei rhodesiense infection remained plausible, given the patient’s past travel to southern Uganda, subspecies testing was indicated. Lacking an Australian medical reference laboratory for this, we referred specimens to the Institute of Tropical Medicine (Antwerp, Belgium) for serological testing, and to a local reference laboratory for nucleic acid amplification testing.2 While awaiting results, the patient became uncommunicative, bed-bound and increasingly cachectic, making empiric trypanocidal therapy imperative. Treatment for late stage T. b. gambiense infection was commenced 19 days after admission, with intravenous eflornithine (obtained through the World Health Organization [WHO]) at a dose of 100 mg/kg every 6 hours for 2 weeks. This was tolerated without significant toxicity. At discharge on Day 39, the patient was orientated, communicative and walking independently despite persistence of slight limb hypertonia. Subsequently, subspecies serology showed elevated titres to T. b. gambiense on a serum immunofluorescent antibody test (IFAT; titre, 1:1600; RR, negative) and a card agglutination antibody test (CAAT; titre, 1:32; RR, negative). The CSF IFAT titre to T. b. gambiense was 1: 8 (RR, negative). The local nucleic acid amplification test suggested T. b. rhodesiense (data not shown), but this was felt to be clinically discordant. Three months after discharge, the patient was lucid, conversant in both English and her native tongue, neurologically intact and free from itch. Examination of her CSF showed improving pleocytosis with normal biochemical findings. MRI verified improvement; the post-contrast enhancement had resolved, but mild, diffuse cerebral atrophy was evident. She has resumed her studies and normal social activities and was relapse free at 16-month follow-up. DiscussionHuman African trypanosomiasis or sleeping sickness is caused by two subspecies of the haemoflagellate parasite Trypanosoma brucei — T. b. rhodesiense (east-African HAT) and T. b. gambiense (west-African HAT).1,3 The parasite is transmitted by the bite of tsetse flies (Glossina spp.).1 HAT is endemic only in sub-Saharan Africa, where the WHO estimates that between 300 000–500 000 people are currently infected, with 100 000 deaths directly attributed to this disease annually.3 Uganda is currently the only country where infection with both subspecies occurs. While the two foci of trypanosomiasis within Uganda appear separate, as a result of civil unrest, population displacement and the northward spread of wild and domestic animals from central and south-east Uganda, it is likely that these foci will soon converge.4-6 HAT is rarely diagnosed outside Africa. When T. b. gambiense infection is diagnosed, it is usually in the late (secondary) stage.1,7 To our knowledge, this is the first case of T. b. gambiense infection diagnosed in Australia. HAT is a biphasic disease. Early-stage disease (Stage I) denotes the post-inoculation period followed by haemo-lymphatic spread.1 An inflammatory nodule or ulcer (chancriform) may be seen at the site of inoculation, more commonly with T. b. rhodesiense infection.1 Lymphatic spread results in lymphadenopathy, with posterior cervical lymphadenopathy (Winterbottom’s sign) typical in T. b. gambiense disease.1,3 Haematogenous spread produces fluctuating fevers, hepatosplenomegaly, serositis and myocarditis, which occur in both forms of the infection, but are more common in T. b. rhodesiense disease.1 In late-stage disease (Stage II), the parasite passes through the blood–brain barrier into the central nervous system, resulting in meningoencephalitis, which is invariably fatal if not treated.1,3 Headache, ataxia, itching, speech disturbance, behavioural change, extrapyramidal signs and mental state changes may manifest.1,3 Pineal and thalamic invasion leads to hypersomnolence and circadian rhythm disruption.3 The natural history of the diseases caused by the two subspecies varies significantly; T. b. gambiense infection is insidious (over months to years), whereas T. b. rhodesiense infection usually progresses over days to weeks.1 Dermatological manifestations of HAT are non-specific. Pruritus is a pervasive symptom, present in over 50% of cases, and is a feature of disease chronicity.8 Pruritus generally correlates with greater CSF pleocytosis.8 Parasternal and generalised pruritus are common, as is peripheral oedema. Transient urticarial and macular eruptions have also been described.1,9 In very chronic disease (of more than 24 months’ duration), pruritus may decrease, heralding a pre-terminal phase of illness.8 Definitive diagnosis of HAT requires direct visualisation of the parasites in blood, CSF or tissue. Detection of trypanosomes in the CSF confirms late-stage disease. False negative results are common because of the low number of parasites in T. b. gambiense infection.1 As in the case we present here, concentration techniques such as double-centrifugation of CSF increase the sensitivity of microscopy.10 Non-diagnostic CSF changes include: lymphocyte counts of > 5/μL, increased CSF protein and IgM concentrations, and morula (Mott) cells.9,11 Identifying the subspecies of trypanosomes is difficult because both subspecies are morphologically identical. The serological tests CAAT and IFAT are available for the detection of T. b. gambiense antibodies, and this is useful in screening high-prevalence populations.9 The use of nucleic acid tests for the subspeciation of T. b. rhodesiense and T. b. gambiense is an emerging technique, and has been used successfully in the research setting.5,6,9 However, these assays are not widely available.9 Obtaining a detailed travel history from patients and recording the timing of symptoms and signs over the course of the illness remain important for differentiating the two forms of the disease. Treatment of HAT depends on the subspecies of infecting trypanosome and disease stage. Patients with early-stage disease should have CSF examination to exclude subclinical neurological involvement.9 In Australia, treatment is challenging because we have limited access to targeted therapies for HAT. The necessary drugs are accessible through the WHO. Treatments for early-stage HAT infections are parenteral pentamidine for T. b. gambiense disease and suramin for T. b. rhodesiense disease.1,6 For late-stage HAT, melarsoprol was formerly the treatment of choice.1 However, 3%–10% of patients treated with melarsoprol develop encephalopathy, which is fatal in 10%–70% of cases. Survivors of encephalopathy frequently have residual brain damage.12,13 Eflornithine is equally efficacious and less toxic than melarsoprol12,13 for late-stage T. b. gambiense infection, with lower treatment-related mortality (about 0.8%).13 Adverse effects of eflornithine include seizures, gastrointestinal upset and neutropenia, but treatment interruption is generally not required.1 Recently, one week of combination therapy with nifurtimox and eflornithine was shown to be equally effective, less toxic and easier to administer than eflornithine monotherapy for late-stage T. b. gambiense infection,14 and is now considered the treatment of choice for this infection.15 Recommended follow-up after treatment for late-stage HAT includes 3–6-monthly CSF examinations for 2 years.4 This case highlights the diagnostic and therapeutic difficulties in managing late-stage HAT in a non-endemic country. Clinicians need to be aware of infections that are non-endemic to Australia that can occur in recently arrived travellers and migrants. Appropriate treatment of HAT is life-saving and associated with good clinical outcomes. Figure 1 The patient’s rash on presentation in March 2008, showing hyperpigmented, lichenified papules and nodules with excoriation involving the trunk. Figure 2 Axial T2-weighted magnetic resonance image showing high signal in both basal ganglia (white arrow) and symmetrical high signal in the white matter, including the internal and external capsules (black arrows). Figure 3 Double centrifuged sample of the patient’s cerebrospinal fluid shown on direct microscopy showing a trypanomastigote typical of Trypanosoma brucei, the pathogen of human African trypanosomiasis (Giemsa stain; original magnification, × 800).

Paul Cherian MB BS · Ralph K Junckerstorff MB BS · David Rosen MB BS, FRACP, PhD · Prasad Kumarasinghe MD, FACD · Alan Morling BSc · Philip Tuch MB ChB, FRACP · Sonja Raven MB ChB, FRANCR · Ronan J Murray MB BS, FRACP, FRCPA · Christopher H Heath MB BS, FRACP, FRCPA

Haemophilus ducreyi is a well recognised causative agent of genital ulcers and chancroid. We report two unusual cases of non-sexually transmitted H. ducreyi infection leading to chronic lower limb ulcers. Both patients were Australian expatriates visiting Australia from the Pacific Islands — one from Papua New Guinea and the other from Vanuatu. Clinical recordsPatient 1A 51-year-old Australian man presented with a 2-month history of non-healing ulcers on the lateral aspect of his lower left leg. The ulcer developed subsequent to a dog bite received in Papua New Guinea. The wound was treated initially in Papua New Guinea with debridement and oral doxycycline and the wound resolved. Subsequently, the patient developed another ulcer adjacent to the original dog bite wound. The ulcer became increasingly painful and erythematous, and was associated with a purulent discharge. On return to Australia, he was referred to a plastic surgery unit. The patient underwent debridement of the ulcer and split skin grafting to cover the defect. He was prescribed flucloxacillin (500 mg orally every 6 hours) after surgery, but had further ulceration of the skin graft. Tissue samples were cultured and examined histologically. Subsequently, a gram-negative coccobacillus was isolated on chocolate horse blood agar incubated at 35°C in CO2. The cultured organism was sent to a reference laboratory for further identification, and a presumptive diagnosis of Haemophilus ducreyi infection was made from the characteristic “schools of fish” morphology on staining (Box 1); this was confirmed with 16S rDNA (ribosomal DNA) sequencing. The patient was referred to an infectious diseases service. On review, the wound was 2 × 1.5 cm, with a sloughy base, rolling edges and surrounding erythema (Box 2). He had no risk factors for sexually transmissible infections and had no evidence of genital lesions or inguinal lymphadenopathy. He did not undergo testing for sexually transmitted infections. He was prescribed oral azithromycin 1000 mg, with significant improvement in the ulcer appearance. The patient returned to Papua New Guinea and was subsequently lost to follow-up. Patient 2A 60-year-old Australian man who resided in Vanuatu presented to an infectious diseases unit with a 6-week history of a painful ulcer on the back of his lower leg. The ulcer developed following a visit to a jungle area of Vanuatu; he did not recall any prior injury. Before presentation, he had received dicloxacillin and metronidazole and had undergone regular iodine dressings for several weeks without clinical improvement. At review at the infectious diseases unit, the most striking feature was the severe degree of pain associated with the lesion. On clinical examination, the ulcer was 3–4 cm in diameter, with heaped-up necrotic edges and a sloughy base. The patient was not systemically unwell and had no risk factors for sexually transmissible infections. A Gram stain of tissue obtained from biopsy and swabs of the ulcer showed numerous neutrophils and a large number of gram-negative coccobacilli; an organism was isolated from the swab and from the biopsy specimen on chocolate agar incubated at 35°C in CO2. The reference laboratory identified the organism as H. ducreyi using 16S rDNA sequencing. The patient was treated with intravenous ceftriaxone 1 g daily for 1 week, followed by amoxycillin 1 g orally thrice daily for 2 weeks, and the size and associated pain of the ulcer decreased rapidly. He did not report any genital lesions and was not tested for sexually transmissible infections. The patient returned to Vanuatu but reported complete resolution of the ulcer to the treating physician. DiscussionChronic skin ulcers secondary to H. ducreyi infection in the absence of genital lesions, as in our two cases, have not been reported until recently. H. ducreyi is a fastidious gram-negative coccobacillus. The association between this organism and chancroid, a sexually transmissible genital ulcer disease, is well established.1,2 Extragenital skin ulcers have been described resulting from autoinoculation among patients with genital ulcers.3,4 Human volunteers have developed mildly painful skin lesions following inoculation with H. ducreyi.5 Humans are the only known host for H. ducreyi; there is no recognised environmental or zoonotic reservoir.1,6 Apart from our two reported cases, to our knowledge, only two other publications have described chronic skin ulcers secondary to H. ducreyi infection.6,7 Box 3 summarises these cases and the cases we have described here. In all cases, the patients had chronic skin ulcers on lower limbs without evidence of genital ulcers or inguinal lymphadenopathy. All of these patients acquired the infection in the Pacific Islands.6,7 In most cases, the organism was cultured on selective media (eg, chocolate agar) and identified using 16S rDNA sequencing techniques.6,7 H. ducreyi is difficult to isolate from culture owing to several factors. H. ducreyi grows best between 33°C and 35°C in 5% CO2 and a humid atmosphere, and will not grow at 37°C. Enriched media, such as chocolate horse blood agar, are required for the organism’s growth. Microbiological specimens must be inoculated as quickly as possible to ensure organism survival.1 Upon Gram staining, H. ducreyi aligns in a “railroad”, “chaining” or “schools of fish” (Box 1) arrangement. Definitive identification of H. ducreyi requires specific molecular tests, such as 16S rDNA sequencing.1 Recommended treatment for H. ducreyi infection includes oral or intravenous azithromycin, ceftriaxone or ciprofloxacin.8 Plasmid-mediated β-lactamase production by this organism is well recognised; in a Californian report, 88% of H. ducreyi isolates produced plasmid-mediated β-lactamase.9 However, antimicrobial susceptibilities vary geographically. This may account for the response to penicillin or amoxicillin in three of the six cases reported thus far. In summary, H. ducreyi may be an emerging aetiological agent in chronic skin ulcers in patients from the Pacific Island region. Given its fastidious nature, a high degree of suspicion is required to enable specific diagnosis. This organism should be considered in patients from this region who have non-healing ulcers without a causative organism isolated by normal culture methods. Consideration should be given to culture swabs and tissue on enriched media, such as chocolate agar, and for the use of other diagnostic tools, such as 16S rDNA sequencing. 1 Gram stain appearance of ulcer showing characteristic “schools of fish” appearance 2 Appearance of lower limb ulcer showing wound ulceration at edge of split skin graft 3 Six cases of chronic skin lesions due to Haemophilus ducreyi infection Report Patient age (years), sex Country of acquisition Presentation Culture results Confirmatory diagnosis Treatment Outcome Ussher et al6 9, female Samoa Three chronic skin ulcers on lower legs Gram-negative coccobacilli on chocolate agar 16S rDNA Penicillin Not reported 6, female Samoa Single painful ulcer on lower leg Gram-negative coccobacilli on supplemented GC agar base 16S rDNA Oral azithromycin Complete resolution 5, female Samoa Three painful ulcers on lower leg Gram-negative coccobacilli on chocolate agar 16S rDNA Oral azithromycin Complete resolution McBride et al7 23, female Vanuatu Single non-healing ulcer on lower leg No organism cultured 16S rDNA Intramuscular benzathine penicillin Complete resolution Current report 51, male Papua New Guinea Single non-healing ulcer on lower leg Gram-negative coccobacilli on chocolate horse blood agar 16S rDNA Oral azithromycin Clinical improvement 60, male Vanuatu Single painful non-healing ulcer on lower leg Gram-negative coccobacilli on chocolate agar 16S rDNA Intravenous ceftriaxone then oral amoxycillin Clinical improvement GC = gonococcal. rDNA = ribosomal DNA.

Trisha N Peel MB BS, FRACP · Deepak Bhatti MB BS · Jim C De Boer BSc, MPH, FAIMS · Ivan Stratov MB BS, FRACP, PhD · Denis W Spelman FRACP, FRCPA

To the Editor: Influenza causes around 8% of community-acquired pneumonia (CAP) episodes,1 and during the (H1N1) 2009 influenza pandemic, concurrent bacterial infections were detected in up to 29% of fatal infections.2 Determining microbial aetiology of CAP can guide antibiotic and antiviral therapy. To investigate the usefulness of microbiological diagnostic testing for CAP, we undertook a retrospective review of our pathology department’s electronic database of patients admitted with CAP to a tertiary referral centre (365 beds) and two suburban teaching hospitals (314 and 280 beds) between 1 May 2007 and 30 April 2008. Inclusion criteria were: International Classification of Diseases, 10th revision codes J09–J22 (respiratory tract infections); age ≥ 18 years; and consolidation on a chest radiograph performed within 48 hours of admission. Exclusion criteria were: hospitalisation within the previous 14 days; admission to a unit managing predominantly immunosuppressed patients; HIV infection; active tuberculosis; chest injuries; and previous inclusion in the study. Basic demographic data and microbiological investigation results were collected. We adopted the Australian CAP Study’s criteria for aetiology and classification of good-quality sputum.1 Change in management was indicated for patients with bacteria not covered by empiric regimens recommended in Therapeutic guidelines: antibiotic, version 13, or organisms with public health and infection control implications.3 Continuous variables were analysed using either Student’s t test or the Wilcoxon rank-sum test, and categorical variables with the Fisher exact test. Statistical significance was set at P < 0.05. From 2436 admissions, 341 patients met inclusion criteria. Mean age was 71.1 (SD, 17.1) years, and 72 patients (21.1%) were in residential care. Most patients (251; 73.6%) had investigations to determine aetiology (Box). Ninety-three organisms were identified from 83 patients (33.1%), most commonly Streptococcus pneumoniae (33; 13.1%), Haemophilus influenzae (14; 5.6%), influenza (11; 4.4%) and Legionella spp (9; 3.6%). Good-quality sputum taken within 8 hours of presentation had the highest diagnostic yield (47.1%). Changes to management were indicated for 37 patients (14.7%). Aetiology was identified more often in the suburban hospitals, where S. pneumoniae and Legionella spp were more common than in the tertiary centre (27.7% v 8.1% and 9.2% v 1.6%, respectively; P = 0.001). Patients in the suburban hospitals were younger and less likely to be in residential care than those in the tertiary centre (mean, 67.6 v 72.6 years and 13.7% v 24.3%, respectively; P ≤ 0.03). The Australian antibiotic guidelines recommend appropriate investigations to determine aetiology of CAP.3 Our analysis suggests that usefulness of microbiological investigations varies between different patient populations, and their value may be maximised by using algorithms similar to the recommendations for CAP investigations in United States guidelines.4 Contrary to widespread belief that microbiological diagnostic tests for CAP are low-yield and not helpful, we found that aetiology could be established in up to 55% of patients and a change in management made in 15% by using a combination of diagnostic tests. Our findings should be generalisable to other parts of Australia, as the aetiologies we observed mirror those seen in the Australian CAP Study.1 Diagnostic yield of investigations used to determine microbial aetiology for patients hospitalised with community-acquired pneumonia No. positive/no. tested (% positive) Investigation Suburban hospitals Tertiary centre Total Sputum microscopy, culture and sensitivities 14/40 (35.0%) 23/103 (22.3%) 37/143 (25.9%) Blood culture 5/42 (11.9%) 7/131 (5.3%) 12/173 (6.9%) Urinary antigen test Streptococcus pneumoniae* 14/40 (35.0%) 11/105 (10.5%) 25/145 (17.2%) Legionella pneumophila serogroup 1* 4/39 (10.3%) 1/104 (1.0%) 5/143 (3.5%) Respiratory multiplex PCR† 1/6 (16.7%) 6/17 (35.3%) 7/23 (30.4%) Bronchoscopy‡ 0/2 3/12 (25.0%) 3/14 (21.4%) Serology§ 4/27 (14.8%) 7/66 (10.6%) 11/93 (11.8%) Total patients investigated 36/65 (55.4%) 47/186 (25.3%) 83/251 (33.1%) PCR = polymerase chain reaction. * P = 0.02 for comparison of % positive between hospitals. † Nasopharyngeal swabs tested for influenza A and B, picornavirus, parainfluenza, adenovirus and respiratory syncytial virus. ‡ All bronchoscopy specimens cultured for Legionella spp, bacterial and fungal pathogens, and other investigations as requested by clinicians. § Serological tests for influenza A and B, Legionella spp, Mycoplasma pneumoniae, Chlamydophila spp and Coxiella burnetii.

Adrian R Tramontana · Vincent Sinickas

To the Editor: We present this case to highlight the differential diagnosis of afebrile seizures in patients from many asset-poor nations. A 3-year-old Congolese girl presented with sustained loss of consciousness after a prolonged generalised seizure. She had migrated, with her family, 12 months previously after a long period in a Zambian refugee camp. She was intubated briefly and given intravenous benzodiazepines. She made an uneventful recovery; she was discharged from hospital after 2 days. This was her first seizure and there was no history of fever, trauma or poisoning. The parents declined long-term anticonvulsants. Apart from mild malaria, she had been previously well and showed normal development. HIV serology and results of blood films for malarial parasites were negative; other blood tests, including an eosinophil count, were normal. Cerebral magnetic resonance imaging (MRI), performed because the diagnosis was unclear and the patient had had a prolonged seizure, revealed a single 8 mm cyst, with an enhancing wall and surrounding oedema, in the left frontal lobe. The cyst contained a scolex, pathognomonic of neurocysticercosis (Box). There were multiple foci throughout the brain, indicating active and resolving cysts. Serology results for Taenia solium were negative at presentation and 3 months later. The child was treated with 8 days of albendazole and 3 days of dexamethasone. Repeat MRI 2 months after presentation showed significant improvement, with a residual 3 mm calcified focus. The child has remained seizure-free for 18 months. Neurocysticercosis is caused by larvae of the pork tapeworm T. solium, which may encyst in the brain, eye or spinal cord, after ingestion of ova-contaminated food or water.1 In contrast, ingestion of encysted larvae (cysticerci) in undercooked meat results in intestinal infection with the adult tapeworm.1 Neurocysticercosis is common in many asset-poor countries, including those in Asia and sub-Saharan Africa from where many people in humanitarian refugee programs originate.2 In areas where it is endemic, T. solium is a leading cause of epilepsy in children and adults.3 The diagnosis of neurocysticercosis is difficult and the diagnostic differential is broad. Cerebral imaging showing typical lesions containing a scolex is diagnostic. T. solium serology is insensitive, especially in children with few cysts. Anticercal antibodies or cysticercal antigens in the cerebral spinal fluid are helpful, but these investigations are not widely available (they are available from the Centers for Disease Control and Prevention, Atlanta, United States). Treatment with anthelmintics is controversial; parasites may die spontaneously and treatment may cause local inflammation (reduced by steroids), which potentially exacerbates seizures or causes local tissue damage.4 Ocular cysticercosis should be excluded before anthelmintic treatment as the resultant inflammation may compromise sight; surgical excision should be considered if ocular cysticercosis is present.4 Empirical anthelmintics, often given before departure or following resettlement to people at risk, may potentially precipitate seizures.5 We treated this child with albendazole as there were multiple lesions likely to contain live parasites, and because anticonvulsants were declined. This case highlights that neurocysticercosis is a possible treatable cause of afebrile seizures in patients migrating from, or with a history of visiting, endemic areas, including resettled refugees. Clinicians in affluent countries are often unfamiliar with the disease, yet are managing increasing numbers of people at risk. Misdiagnosis is of particular concern because brain imaging is not routinely performed in children presenting with their first afebrile seizure. Magnetic resonance image of brain of 3-year-old girl showing cysticercus Encysted scolex of Taenia solium, surrounded by enhancing wall and significant oedema, in left frontal cerebral lobe.

Juliette M Lucey · James McCarthy · David P Burgner

The latest evidence for the essential elements of surgical prophylaxis protocols There is no question that antibiotic prophylaxis for cardiac surgery reduces surgical site infections.1 The successful implementation of prophylactic regimens, however, is often inconsistent or inadequate. The use of prophylaxis protocols or decision-support systems as either a single measure2 or as part of a patient care pathway3 has been demonstrated to improve adherence to prophylaxis, with a reduction in surgical site infections. In this issue of the Journal (page 141), a study by Haydon and colleagues4 shows that antibiotic prophylaxis protocol use in 45 Australian cardiac surgery units increased significantly between 2004 and 2008 (from 58% to 80%), but concordance with version 13 of the Australian Therapeutic guidelines: antibiotic5 was poor when both choice of agent and duration of administration were considered. In particular, there was an increased use of multidrug regimens, an increased use of vancomycin for routine prophylaxis, and a prolonged duration. The study did not examine surgical site infection rates. As prophylaxis protocols improve patient outcomes, and adherence to protocols in Australian cardiac surgery units seems to be high, it is timely to consider the optimum elements of such protocols in terms of timing of prophylaxis, duration of prophylaxis, and choice of agent. There have been a number of studies that show the relationship between timing of antibiotic administration and surgical site infections. An observational cohort study in a consecutive series of 3836 surgical procedures (vascular, trauma and abdominal) showed the optimal time for administration of β lactams was 30–60 minutes before incision.6 The risk-adjusted odds ratio of surgical site infections was 3.16 (95% CI, 1.4–7.0) if given 75–120 minutes before, 2.82 (95% CI, 1.5–5.3) for administration 15–29 minutes before, and 1.75 (95% CI, 0.9–3.4) if given in the last 14 minutes before incision. In a prospective study of 2048 patients given vancomycin prophylaxis for cardiac surgery (coronary artery bypass graft [CABG] or valve replacement), the optimum time for the start of a vancomycin infusion was shown to be 16–60 minutes before incision.7 The relative risk of infection was 7.8 (95% CI, 2.5–24.7) if started 0–15 minutes before incision and 2.2 (95% CI, 0.99–5.09) if started 61–120 minutes before. Duration of prophylaxis has been a controversial issue. The Society of Thoracic Surgeons practice guidelines8 recommend that prophylactic antibiotics be given for 48 hours or less, citing some evidence for effectiveness of single-dose or 24-hour regimens, but comment that additional studies are required to confirm the effectiveness of shorter courses. This has been addressed in a study on 838 patients undergoing CABG or valve replacement.9 Patients received cephazolin as either a single dose before incision or a prolonged regimen, with a dose before incision, then 8-hourly for 24 hours. There was a statistically significant difference in surgical site infections between the two groups (8.3% v 3.6%; P = 0.004). The choice of agent is mainly between a β lactam and vancomycin, although alternative choices are possible (eg, flucloxacillin plus gentamicin). The Society of Thoracic Surgeons practice guidelines10 recommend cephazolin for standard practice in populations that do not have a high incidence of methicillin-resistant Staphylococcus aureus (MRSA). Haydon et al’s study showed that routine vancomycin use for CABG surgical prophylaxis increased from 13% in 2004 to 44% in 2008, with similar increases seen for valve surgery — from 31% to 62% over the same period.4 Vancomycin prophylaxis for cardiac surgery is recommended in the current Therapeutic guidelines: antibiotic for institutions with a high prevalence of MRSA, for β lactam-allergic patients, or for procedures where there is a higher risk of infection with a coagulase-negative staphylococcus (eg, valve surgery, reoperations).5 Excessive vancomycin use is to be discouraged, as its activity is inferior to β lactam antibiotics for susceptible organisms and it will add selective pressure for hVISA (heteroresistant vancomycin-intermediate S. aureus), particularly if the duration of administration is prolonged. With the advent of rapid MRSA molecular detection tests, it is now possible to screen patients before surgery and use vancomycin selectively in those found to carry MRSA. An alternative is to use intranasal mupirocin routinely in the absence of a documented negative test for MRSA (and methicillin-sensitive S. aureus [MSSA]), as this agent has been shown to reduce both MSSA and MRSA surgical site infections.11 How do these recommendations relate to the Therapeutic guidelines: antibiotic? The current guidelines, version 13 (published in 2006),5 are concordant, except for the duration of therapy. It is very likely that this is the major issue that has resulted in the lack of adoption of the guidelines’ cardiac surgery prophylaxis regimens found by Haydon and colleagues. Version 14 of Therapeutic guidelines: antibiotic is currently in preparation and due to be published in 2010, and the recent studies described here have been noted by the writing committee. It is very likely that version 14 will recommend a 24-hour prophylaxis regimen and that the recommended antibiotic agents will remain unchanged. The purpose of any surgical prophylaxis protocol is to ensure adherence to the optimum choice of agent, timing of administration and duration of prophylaxis. With such adherence, surgical site infections will be minimised, thereby reducing morbidity and mortality for patients undergoing cardiac surgery.

Keryn J Christiansen MB BS, FRCPA

Objective: To examine the performance in tropical northern Australia of SMART-COP, a simple scoring system developed in temperate Australia to predict the need for intensive respiratory or vasopressor support (IRVS) in pneumonia patients.Design, setting and patients: A prospective observational study of patients admitted to Royal Darwin Hospital in the Northern Territory with sepsis between August 2007 and May 2008. Chest x-rays were reviewed to confirm pneumonia, and each patient’s SMART-COP score was assessed against the need for IRVS.Results: Of 206 patients presenting with radiologically confirmed pneumonia, 184 were eligible for inclusion. The mean age of patients was 50.1 years, 65% were Indigenous and 56% were men. Overall, 38 patients (21%) required IRVS, and 18 patients (10%) died by Day 30. A SMART-COP score of ≥ 3 had a sensitivity of only 71% for predicting the need for IRVS and 67% for 30-day mortality. As the variables most strongly associated with IRVS were serum albumin level < 35 g/L (odds ratio, 6.8) and Indigenous status (odds ratio, 2.3), we tested a modified scoring system (SMARTACOP) that used a higher weighting for albumin and included Indigenous status. A SMARTACOP score of ≥ 3 had a sensitivity of 97% for IRVS and 100% for 30-day mortality.Conclusions: The SMART-COP score underestimates the severity of pneumonia in tropical northern Australia, but can be improved by using locally relevant additions.

Joshua S Davis MB BS, DTM · Gail B Cross BSc, MB BS · Patrick G P Charles MB BS, FRACP, PhD · Bart J Currie MB BS, FAFPHM, FRACP · Nicholas M Anstey MB BS, FRACP, PhD · Allen C Cheng MB BS, FRACP, PhD

Objective: To evaluate national practice for antibiotic prophylaxis in cardiac surgery with respect to the use of protocols, agent selection and duration of administration.Design, setting and participants: Two point-prevalence surveys of intensive care units in 24 public and 27 private hospitals performing cardiac surgery in Australia, conducted in 2004 and 2008, using a structured telephone questionnaire of the attending senior intensive care clinician in each unit.Main outcome measures: Existence of a protocol in the unit for antibiotic prophylaxis, specific antibiotic agents used and their duration of administration.Results: Between 2004 and 2008, reported protocol use increased from 58% to 80% (P = 0.02), while concordance with version 13 of the Australian Therapeutic guidelines: antibiotic for both choice of agent and timing (duration of administration) remained around 10%. Use of multiple agents was common, as was continued antibiotic administration after completion of surgery. Over 4 years, the proportion of cardiac surgical units reporting vancomycin administration for routine valve surgery prophylaxis doubled to 62% (P < 0.001).Conclusion: Despite an increase in reported protocol use for antibiotic prophylaxis in cardiac surgery, concordance with national antibiotic guidelines remained low, with duration of antibiotic administration deviating most from recommendations. Prophylactic vancomycin use appears to have increased substantially in recent years. Clinical implementation of recommended perioperative cardiac surgical antibiotic prophylaxis may not occur until supported by evidence from either a large prospective randomised study or standardised national surveillance of cardiac surgical site infection rates.

Timothy P Haydon FRACP, FJFICM, FANZCA · Jeffrey J Presneill MB BS, MBiostat, PhD · Megan S Robertson FRACP, FJFICM, FANZCA

Clinical record On 1 June 2009, a 79-year-old man presented to the emergency department of a tertiary hospital in Melbourne with a 1-week history of dyspnoea and a productive cough. He had underlying chronic obstructive airways disease (COAD) and type 2 diabetes mellitus. He reported no history of fever and no recent travel or contact with people with influenza-like illness (ILI). On examination, his temperature was 37.0°C, oxygen saturation was 97% in room air, and he had an expiratory wheeze. No abnormalities were seen on chest x-ray. Full blood examination showed a peripheral white cell count within the reference range (RR), and a raised C-reactive protein level (27 mg/L; RR, < 5 mg/L). The patient was admitted to a four-bed hospital ward and treated with oral doxycycline, corticosteroids and nebulised salbutamol. A nasal swab was sent to the state reference laboratory for polymerase chain reaction (PCR) testing for respiratory viruses to identify any potential viral precipitant for the apparent exacerbation of COAD. Results received 2 days later were positive for influenza A virus, which was confirmed to be the pandemic (H1N1) 2009 strain. Treatment was then begun with oseltamivir, and the patient was placed in a single room with droplet precautions. The patient’s contacts within the hospital were traced through review of his bed movements and all staff rosters (medical, nursing, allied health, patient support services and clerical staff of the emergency department and wards). All health care workers who had come into contact with the patient were telephoned, and the extent of their contact and individual risk factors were assessed. High-risk contact was defined as having spent more than 15 minutes within 1 m of the patient without wearing appropriate personal protective equipment. Twenty-one people with high-risk contact were identified, comprising nine medical staff, six nurses, three allied health staff and three patients. All were given oseltamivir prophylaxis. By this time (2 days after the patient’s admission), three of the medical staff who had high-risk contact with the patient (eg, taking a history or examining the patient while he was receiving nebulised therapy) reported the new onset of an ILI. They were therefore given treatment doses of oseltamivir. Furthermore, one of these medical staff reported having had significant contact, while symptomatic, with nine medical registrars during a 1-hour radiology tutorial in a confined space. At that stage of the pandemic, the reference laboratory was testing a high volume of specimens for H1N1 2009 influenza, and the average time for results of specific tests to be returned was, in our experience, 2 working days. Consequently, we decided to assume that the three medical staff with ILI had pandemic 2009 influenza and to initiate a second round of contact tracing. This included contacting all patients and health care workers who had come into contact with any of these staff. We identified a further 17 medical staff and seven patients and offered them oseltamivir prophylaxis. All accepted this prophylaxis. Symptomatic staff were asked to stay home from work, but it was considered impractical to redeploy asymptomatic health care workers receiving prophylaxis to areas with less patient contact. The evaluation of exposed health care workers and dispensing of medication were conducted by infection control practitioners, infectious diseases staff and microbiology staff, in addition to their normal duties. The extra workload was estimated to be almost 2 full days for at least two staff members. Four days later, the swab results from the three symptomatic medical staff showed they were negative for influenza A, and prophylaxis for their contacts was ceased. None of the other 18 people who had significant contact with the index patient developed ILI. This case illustrates some of the practical challenges of infection control during the recent influenza (H1N1) 2009 pandemic. The patient’s presentation was atypical for pandemic influenza, and a number of health care workers and patients had significant exposures before the illness was diagnosed. Each exposed person required follow-up, counselling and management, which created a significant workload for infection control staff. This case illustrates the need for additional infection control resources — “surge capacity” — to protect staff and their contacts both inside and outside hospitals. Influenza A has been associated with exacerbations of COAD.1 However, at the time our patient was admitted to hospital, he did not meet the case definition for pandemic (H1N1) 2009 influenza proposed by the Victorian Department of Health: “acute onset of illness with a measured temperature of greater than or equal to 38°Celsius or significant history of fever (rigors, sweating, chills) plus two or more of cough, sore throat, body aches, fatigue/tiredness or shortness of breath”.2 As the pandemic progressed, clinicians began to recognise atypical presentations of influenza (H1N1) 2009. Soon after our patient’s presentation, our hospital began isolating all patients who presented with any respiratory symptoms and testing them for influenza (H1N1) 2009 as part of a more proactive strategy. However, this strategy became practical for us only when our hospital had access to “in-house” PCR testing with a reliable turnaround time of less than 24 hours. Before this, despite the extraordinary efforts of the state reference laboratory in the face of huge numbers of specimens, the logistic problems and consequent delays in obtaining results3 led to practical concerns about “bed block”. This patient was admitted early in the pandemic, and thus the management of exposed health care workers had not been well tested. Transmission of the virus to staff members had been reported elsewhere,4 and, as observed during the pandemic of severe acute respiratory syndrome, the risk of occupational exposure to respiratory pathogens is real and can be fatal.5 It was therefore essential that staff members who had significant exposure to the patient were promptly contacted, counselled and appropriately managed. Management had to be tailored to confounding factors, such as pregnancy and immunosuppressive states. This process was time-consuming and required extra staff. Novel communication methods, such as group emails and intranet updates, were used to ensure consistency and accuracy of advice to staff. New links were forged between hospital administration and infection control services to ensure appropriate information was circulated. New channels of communication between infectious diseases physicians across several hospitals, and with representatives of the state Department of Health, also allowed for discussion of management strategies. This case illustrates some of the practical problems for infection control services that were probably mirrored in hospitals across the country as the influenza (H1N1) 2009 pandemic evolved. Management of staff exposure is difficult, and a single missed case can affect many staff members. Given our experience, we believe it is crucial that additional infection control resources be provided during such an outbreak to deal with staff exposure. The Australian Health Management Plan for Pandemic Influenza6 is a useful resource, but needs to be tailored to the context. Reflection is now needed on how we might improve our response. Lessons from practice In the early stages of a pandemic, the case definition should be broad to capture atypical presentations. Diagnostic test results need to be rapidly available to allow early diagnosis and appropriate treatment, and to assist bed management in hospitals for appropriate infection control. It is important that infection control departments have extra staff available to facilitate contact tracing across the hospital and thus prevent transmission to high-risk patients and health care workers.

Uma Devi MB BS · Kirsty L Buising FRACP, MPH, MD

After a 10-day course of oral oseltamivir for pandemic (H1N1) 2009 influenza infection, a renal transplant recipient developed rapid-onset severe primary viral pneumonia due to oseltamivir-resistant virus. Respiratory failure progressed despite high-dose oral oseltamivir, nebulised zanamivir and cessation of immunosuppressive medications, but his condition improved with intravenous zanamivir. He subsequently died of non-respiratory complications. This is the first case of oseltamivir-resistant pandemic (H1N1) 2009 in Australia and the first report of resistance in a solid organ transplant recipient. (MJA 2010; 192: 166-168) Clinical recordA 38-year-old cadaveric renal transplant recipient had remained well on a standard immunosuppressive regimen until he presented 7 weeks after transplantation with coryzal symptoms and fever. Nose and throat swabs were collected for influenza testing, and he was empirically commenced on oral oseltamivir at the recommended dose of 75 mg twice a day,1,2 to be taken at home. The swabs were subsequently confirmed as positive for pandemic (H1N1) 2009 influenza (Box), and he continued taking oseltamivir for 10 days, with clinical improvement. Three days after ceasing treatment, the patient was admitted with high fever, myalgia and a cough productive of clear sputum. A chest x-ray showed pulmonary infiltrates in both upper–mid zones and the right lower zone. He was commenced on antibiotics for presumptive community-acquired pneumonia, but over the next 5 days he became hypoxic and tachypnoeic with increasing lung infiltrates and required intubation for ventilatory support. His nose and throat swabs taken on admission were negative for influenza, but 2 days after admission, a sputum sample was positive for pandemic (H1N1) 2009, as was a bronchoalveolar lavage performed 7 days after admission. His antimicrobial therapy was broadened and oral oseltamivir reintroduced at 75 mg twice daily, despite renal dysfunction, as higher oral doses have been shown to achieve therapeutic blood levels in severely ill patients.3 On Day 11, oseltamivir was reduced to 75 mg daily due to anuria, but the patient’s absorption of oral fluids subsequently ceased and pandemic (H1N1) 2009 was again detected by polymerase chain reaction (PCR) testing of samples taken on Days 17 and 19. Nebulised zanamivir 15 mg four times a day was added on Day 23, and from this point on, influenza was not detected from respiratory specimens. His immunosuppressive therapy was reduced and subsequently ceased on Day 25, but his condition continued to deteriorate, with worsening lung infiltrates and a partial pressure of oxygen/fraction of inspired oxygen (Pao2/Fio2) ratio of 55 (Pao2/Fio2 ratio < 300 indicates acute lung injury) by Day 29. On Day 30, we identified an oseltamivir resistance mutation in the neuraminidase (NA) gene — a point mutation resulting in a histidine-to-tyrosine substitution at position 275 (H275Y) — in the virus from the patient’s Day 3 sample, though it was not present in virus from his first illness preceding admission. As his clinical progress with nebulised zanamivir was still poor, intravenous zanamivir was obtained through an emergency investigational drug application for compassionate use and commenced at a modified dose of 60 mg twice a day, based on a predicted ultrafiltration rate of 10 mL/min. Two days later, this was increased to 150 mg twice a day; however, due to a sudden deterioration in his liver function tests (alanine aminotransferase, 825 U/L [normal, < 40 U/L]), the dose was reduced 3 days later to 60 mg twice daily, with prompt improvement in liver function. Oral oseltamivir and nebulised zanamivir were also continued because of uncertainty about the correct intravenous zanamivir dose for a patient on continuous venovenous haemofiltration. After 7 days of treatment with intravenous zanamivir, the patient’s condition slowly improved and he eventually became ventilator-independent, but he subsequently died on Day 78 from intraperitoneal sepsis. At that time he had ceased all antiviral therapy, and repeated tests of upper and lower respiratory tract samples were negative for influenza. Surveillance of close contacts for respiratory illness found no evidence of acquisition of pandemic (H1N1) 2009. During his admission, he was isolated in a single room under full respiratory precautions. For virological testing of respiratory specimens, dry swabs were tested by PCR only, while swabs in viral transport medium and other fluid specimens were also cultured for influenza virus using a centrifuge-enhanced shell vial culture in Madin–Darby canine kidney cells. Real-time reverse transcription PCR (rRT-PCR) assays were directed at the matrix genes of influenza A and B and the haemagglutinin genes of seasonal A/H1, A/H3 and pandemic (H1N1) 2009 viruses. Cycle threshold (CT) values ≤ 40 were regarded as positive. Samples and cultures testing positive for pandemic (H1N1) 2009 were then tested for oseltamivir resistance (Box) using an NA gene rRT-PCR with separate probes specific for the wild-type sequence and the H275Y mutation, by sequencing of the NA gene product (ABI Prism 3130xl Genetic Analyzer, Applied Biosystems Inc, Foster City, Calif, USA) for the presence of the H275Y mutation, and by testing phenotypic susceptibility to oseltamivir on isolated viruses using a fluorometric assay to determine the oseltamivir 50% inhibitory concentration (IC50).4 Samples collected during the patient’s first illness contained only wild-type pandemic (H1N1) 2009, and the isolate collected prior to antiviral therapy was phenotypically susceptible to oseltamivir, with a low IC50 of 0.43 nM (Box). In contrast, all samples testing positive to influenza during his admission contained the mutant strain, with a markedly elevated IC50 of 382.5 nM for the Day 7 isolate, compared with 649.9 nM for the reference oseltamivir-resistant pandemic (H1N1) 2009 virus strain A/Osaka/180/2009. Interestingly, the Day 7 sputum sample appeared to contain a mixture of wild-type and mutant virus on the rRT-PCR test, and sequencing of the Day 19 sample also indicated a possible mixed infection. DiscussionTo our knowledge, this is the first report of infection with oseltamivir-resistant pandemic (H1N1) 2009 virus in Australia, and the first such report in a solid organ transplant recipient with an ultimately fatal outcome. Oseltamivir and zanamivir act by specifically inhibiting the NA of influenza viruses. The H275Y mutation — the major mechanism for oseltamivir resistance in influenza A/H1N1 — was rare until it emerged in seasonal influenza A/H1N1 in 2007, but it soon became the dominant type throughout the world,5 including Australia.6 Importantly, these oseltamivir-resistant viruses remain susceptible to zanamivir. As of 9 October 2009, there had been only 31 reports of oseltamivir resistance in pandemic (H1N1) 2009 influenza virus,7 despite the large amounts of oseltamivir used internationally. All of these resistant viruses have contained the H275Y NA mutation. Most cases have occurred in patients taking oseltamivir as post-exposure prophylaxis, with few in immunosuppressed patients on long-term oseltamivir treatment.8 One immunosuppressed patient was treated with intravenous zanamivir after inhaled zanamivir was not tolerated.9 All reported cases due to resistant virus have been sporadic, with no evidence for onward transmission, and no fatal cases have been reported previously. Our patient was initially infected with wild-type virus, but his first positive sample following relapse, collected 5 days after ceasing his initial course of oseltamivir and 3 days before its reintroduction, detected only oseltamivir-resistant virus. This suggests that the resistant virus emerged in the few days after ceasing his first course of oseltamivir, possibly due to declining blood and tissue levels of the antiviral drug. During his subsequent admission, the oseltamivir-resistant strain predominated, but there was evidence of a persistent mixed infection, based on the detection of both wild-type and resistant virus by rRT-PCR on Day 7 of admission, and supported by the intermediate elevation of IC50 of that isolate. Interestingly, despite the emergence of the resistant virus, there were declining levels of both resistant and susceptible virus, in spite of the patient’s clinical deterioration and even before commencing zanamivir on Day 23, as indicated by a progressive increase in the rRT-PCR CT values (Box). In accordance with our policy for patients with proven or suspected lower respiratory tract involvement, we used twice the standard dose of oseltamivir, adjusted for the patient’s renal function. It is possible the oseltamivir therapy had continued to provide some useful antiviral activity, but we were unable to test blood levels of oseltamivir carboxylate to investigate this further. Despite the negative virological results from respiratory specimens taken while he was receiving nebulised zanamivir and oral oseltamivir, our patient’s condition continued to deteriorate, with dense pulmonary consolidation. There was concern that he was not getting adequate levels of antiviral drug in the lung tissue, so intravenous zanamivir was introduced. As there was no suitable established treatment regimen for patients on continuous venovenous haemofiltration, dosing was based on the ultrafiltration rate. This was calculated as 10 mL/min, correlating to an intravenous zanamivir dose of 60 mg twice daily, but was subsequently increased to 150 mg twice daily due to the patient’s continued respiratory deterioration. Liver function rapidly deteriorated following the dose increase but promptly recovered when the dose was reduced, suggesting that the deterioration had been drug-related hepatic dysfunction. After 7 days of intravenous zanamivir, the patient’s respiratory function had stabilised. This may have been an effect of the intravenous zanamivir and/or his improving immune function following the earlier cessation of immunosuppressive therapy. After cessation of his antiviral therapy, there was no evidence of reappearance of the virus, and his death 38 days later was due to non-respiratory complications. The management of this patient was complicated by the uncertainty surrounding correct dosing of oseltamivir and zanamivir in a severely unwell patient, with the inability to perform therapeutic drug monitoring, and the difficulties in interpreting non-invasive respiratory specimen virological results in the setting of dense pulmonary consolidation. Where absorption is suspected to be unreliable, intravenous zanamivir may prove to be a useful antiviral therapy for severely unwell influenza patients, including those with oseltamivir-resistant pandemic (H1N1) 2009 infection. Clinicians caring for immunosuppressed patients with pandemic (H1N1) 2009 should be aware of the potential for development of oseltamivir resistance during therapy and for prolonged viral shedding. Strict adherence to infection control measures is recommended until immunosuppressed patients have clinically improved and respiratory specimens test negative by both PCR and viral culture. Laboratory testing results for detection of influenza Cycle threshold value (> 40 considered negative) Day of admission Sample Influenza A matrix gene Pandemic (H1N1) 2009 H gene NA gene wild-type NA gene H275Y mutant NA gene sequence Oseltamivir IC50 of cultured virus − 13 Nose/throat swabs 29 29 32 Negative Wild-type* 0.43 nM − 9 Nose/throat swabs Negative 40 Negative Negative Wild-type* — 1 Nose/throat swabs Negative Negative — — — — 3 Sputum 17 22 Negative 28 H275Y mutant* — 7 Sputum 17 22 35 27 H275Y mutant† 382.5 nM 7 Bronchoalveolar lavage 19 23 Negative 24 H275Y mutant‡ — 8 Nose/throat swabs 23 25 Negative 27 H275Y mutant‡ — 17 Nose/throat swabs 32 40 Negative 38 H275Y mutant* — 19 Sputum 35 34 37 Negative Mixed* — 24 Nose/throat swabs Negative Negative — — — — 24 Sputum Negative Negative — — — — 28 Endotracheal aspirate Negative Negative — — — — 28 Nose/throat swabs Negative Negative — — — — 33 Nose/throat swabs Negative Negative — — — — 33 Endotracheal aspirate Negative Negative — — — — NA = neuraminidase. IC50 = 50% inhibitory concentration. — = test not done. * Sequence from patient sample only. † Sequence from cell culture isolate only. Wild-type virus was detected in this sample by polymerase chain reaction, but sequencing detected only the mutant strain. ‡ Sequence from patient sample and cell culture isolate.

David J Speers MB BS, FRACP, FRCPA · Simon H Williams BSc · Mary Pinder MB BS, FRANZCA · Harry R Moody MB BS, FRACP · Aeron C Hurt BSc(Hons) · David W Smith BMedSc(Hons), MB BS, FRCPA

From the recognition of the swine flu pandemic in late April 2009, health professionals, politicians and the public needed to know how serious pandemic (H1N1) 2009 influenza (swine flu) was in relation to other seasonal strains of influenza. The Victorian experience suggests that the circulation of pandemic (H1N1) 2009 influenza in the community was at most like influenza circulation in a season of moderate seasonal activity. We have no estimate of the total case count, but we know most infections have been mild. However, while disease in the community appears mild, and the risk of hospitalisation is low, a high proportion of patients hospitalised with swine flu required intensive care. Deaths from swine flu have not been as numerous as the modelled deaths from seasonal influenza, although people dying from swine flu are younger. Because we do not understand the laboratory-confirmed burden of disease due to seasonal influenza (as opposed to the modelled burden of disease), we could not base our response to the pandemic on an informed comparison of seasonal and pandemic influenza. We may not have needed a pandemic response to a disease that, although it has a different footprint, has been predominantly of seasonal intensity. It is critical to accumulate quality evidence about laboratory-confirmed influenza to guide our intervention policies for both seasonal and pandemic influenza.

Heath A Kelly BSc, MB BS, MPH

Objective: To describe the case characteristics and outcomes of patients hospitalised with pandemic (H1N1) 2009 influenza infection during the first 2 months of the epidemic.Design, participants and setting: Prospective case series of 112 patients admitted to seven hospitals in Melbourne with laboratory-confirmed pandemic (H1N1) 2009 influenza between 1 May and 17 July 2009.Main outcome measures: Details of case characteristics, risk factors for severe disease, treatment and clinical course.Results: Of 112 hospitalised patients, most presented with cough (88%) and/or fever (82%), but several (4%) had neither symptom. A quarter of female patients (15) were pregnant or in the post-partum period. Patients presenting with multifocal changes on chest x-ray had significantly longer hospital lengths of stay, and were more likely to require intensive care unit admission. Thirty patients required admission to an intensive care unit, and three died during their acute illness. The median length of intensive care admission was 10.5 days (interquartile range, 5–16 days).Conclusions: This study highlights risk factors for severe disease, particularly pregnancy. Clinical and public health planning for upcoming influenza seasons should take into account the spectrum and severity of clinical infection demonstrated in this report, and the need to concentrate resources effectively in high-risk patient groups.

Justin T Denholm BMed, MBioethics · Claire L Gordon MB BS, BMedSci · Paul D Johnson MB BS, PhD, FRACP · Saliya S Hewagama MB BS · Rhonda L Stuart MB BS, FRACP, PhD · Craig Aboltins MB BS, FRACP · Cameron Jeremiah MB BS · James Knox BSc(Med), MB BS, DTM · Garry P Lane MMed(ClinEpi), MQIHC, FRACP · Adrian R Tramontana MB BS · Monica A Slavin MB BS, FRACP · Thomas R Schulz BSc, MB BS · Michael Richards MBBS, FRACP, MD · Chris J Birch PhD · Allen C Cheng FRACP, MPH, PhD

Pandemic (H1N1) 2009 influenza has generated many controversies in Australia around case definitions, laboratory diagnosis, case management, medical logistics and travel restrictions. Our experience as clinical advisers in the Victorian Department of Human Services Emergency Operations Centre suggests the following: Case definitions may change frequently, and will tend to become more clinically specific over time. Early in a pandemic, laboratory diagnosis plays a critical role in case finding and pathogen identification. Later in the pandemic, standardised case management applied to well crafted case definitions should reduce reliance on the diagnostic laboratory in clinical management. The diagnostic laboratory will remain critical to monitoring disease surveillance, pathogen virulence, and drug susceptibility. Medical logistics will continue to challenge pandemic managers as the health sector struggles to do the most good for the greatest number of people. Travel restrictions remain scientifically controversial public health recommendations. Issues of scalability (escalation and de-escalation of the response) relating to virus lethality need to be resolved in current pandemic planning.

David A Bradt MD, FACEM, FAFPHM · Joseph Epstein FRACS, BA(Hons), FACEM

Objective: To compare the patient characteristics, clinical features and outcomes of adult patients hospitalised with pandemic (H1N1) 2009 influenza and seasonal influenza.Design and setting: Retrospective medical record review of all patients admitted to Liverpool Hospital, Sydney, with laboratory-confirmed influenza from the initiation of the “PROTECT” phase of the pandemic response on 17 June until the end of our study period on 31 July 2009.Main outcome measures: Severity of illness; requirement for admission to the intensive care unit (ICU) and/or invasive ventilation; mortality.Results: Sixty-four adults were admitted to Liverpool Hospital with influenza, 48 with pandemic (H1N1) 2009 influenza and 16 with seasonal influenza. Thirteen patients were admitted to the ICU. Seven required invasive ventilation, with 2 patients requiring ongoing extracorporeal membrane oxygenation (ECMO). Five patients died (mortality rate, 8%) with two deaths occurring after the study period. Patients with pandemic (H1N1) 2009 influenza were younger and less likely to be immunocompromised than patients with seasonal influenza. However, the clinical features of pandemic (H1N1) 2009 influenza and seasonal influenza were similar.Conclusions: Our findings show that the clinical course and outcomes of pandemic (H1N1) 2009 influenza virus are comparable to those of the current circulating seasonal influenza in Sydney. The high number of hospital admissions reflects a high incidence of disease in the community rather than an enhanced virulence of the novel pandemic influenza virus.

Ya-Shu Chang MB ChB · Sebastiaan J van Hal MB ChB, FRACP, FRCPA · Peter M Spencer MB BS · Iain B Gosbell MD, FRACP, FRCPA · Peter W Collett MB BS, PhD, FRACP

Australian federal and state governments were advised several years ago that an influenza pandemic would overwhelm Australian public reference laboratories. It was proposed at the time that currently underused capacity in the private sector be used to enhance pandemic responses. The current outbreak of pandemic influenza has confirmed the predictions of advisors from the private sector. Future official pandemic plans should be adjusted to take into account these observations.

Miles H Beaman FRACP, FRCPA, FACTM · Michael J Leung MB BS, FRCPA

To the Editor: Norovirus, previously known as the Norwalk agent, is a recognised cause of acute diarrhoeal illness in all age groups, but its significance in hospitalised children is poorly described. Noroviruses cause infection worldwide and year-round, with a distinct increase in disease occurrence in colder months.1 Rotavirus has long been recognised as the most important viral cause of gastroenteritis in young children, causing significant morbidity, as well as cost to the community of hospital admission and lost parental productivity.2 In July 2007, two new rotavirus vaccines were licensed for use in Australian infants; their use has reduced severe rotavirus disease requiring hospital admission.3 One difficulty in accurately documenting the role of norovirus in childhood acute diarrhoeal illness has been the limited availability of routine diagnostic testing. Enzyme-linked immunosorbent assay (ELISA) for noroviruses is now available commercially; it has limited sensitivity of 55%–93% but good specificity of 73%–97%. We retrospectively reviewed the frequency of detection of norovirus in the faecal samples taken from inpatients and outpatients with acute gastroenteritis at a tertiary paediatric hospital. We tested stool samples of 3962 children with episodes of acute diarrhoeal illness in a 12-month period (2007) and detected norovirus in 122 (3.1%). Ninety-one of the children infected with norovirus were admitted to hospital; 63 patients had a stay of less than 7 days with a median of 1 day, while 28 patients where in hospital for more than 7 days. The norovirus infection in 30 of the inpatients (33%) was hospital-acquired. Most hospital-acquired infections occurred in patients hospitalised for more than 7 days (19 of 28; 68%), and most of these patients had predisposing medical conditions, predominantly immunosuppression due to treatment for malignancy or other causes. Norovirus is a significant cause of viral gastroenteritis in infants and children. Our findings are comparable with those of other studies, which indicate that norovirus infection causes 20%–88% of viral gastroenteritis in children and is responsible for a significant proportion of hospital admissions of children with gastroenteritis.4,5 With the introduction of universal rotavirus vaccination for Australian infants, the importance of norovirus as a cause of gastroenteritis in infants and children is likely to increase. We recommend that hospitals which admit children consider using norovirus testing to establish the incidence and prevalence of disease, and to inform public health authorities responsible for infection control policy and practices.

Alison M Kesson · Nicola Benwell · Elizabeth J Elliott

Objective: To investigate the Australian public’s expectations, concerns and willingness to accept vaccination with the pandemic (H1N1) 2009 influenza vaccine.Design, setting and participants: A computer-assisted telephone interview survey was conducted between 20 August and 11 September 2009 by trained professional interviewers to study issues relating to vaccine uptake and perceived safety. The sample comprised 1155 randomly selected representative adults who had participated in a 2007 national study exploring knowledge and perceptions of pandemic influenza.Main outcome measures: Likely acceptance of pandemic (H1N1) 2009 vaccination, factors associated with acceptance, and respondents’ willingness to share Australian vaccine with neighbouring developing countries.Results: Of 1155 possible participants, 830 (72%) were successfully interviewed. Twenty per cent of the study group (169/830) reported that they had developed influenza-like symptoms during the 2009 pandemic period. Most respondents (645/830, 78%) considered pandemic (H1N1) 2009 to be a mild disease, and 211/830 (25%) regarded themselves as being at increased risk of infection. Willingness to accept pandemic (H1N1) 2009 vaccination was high (556/830, 67%) but was significantly lower than when pandemic vaccination uptake was investigated in 2007 (88%; P < 0.0001). Respondents who had already been vaccinated against seasonal influenza and those who perceived pandemic (H1N1) 2009 to be severe were significantly more willing to accept vaccination. Most respondents (793/822, 96%) were willing to share surplus vaccine with developing countries in our region.Conclusion: Although two-thirds of Australian adults surveyed were willing to accept pandemic (H1N1) 2009 vaccination, and most supported sharing vaccine with developing countries, there is a need for accessible information on vaccine safety for those who are undecided about vaccination.

Keith Eastwood MApplEpid · David N Durrheim MBChB, DrPH, FAFPHM · Alison Jones MD, FRCP · Michelle Butler MSc

Clinical record A 66-year-old woman was brought to the emergency department at the Alfred Hospital in Melbourne with severe headache and confusion after 2 days of a “flu-like illness”. Her medical history was significant only for rheumatoid arthritis, for which she was prescribed low-dose methotrexate. On initial assessment, she was found to be febrile (38°C) and agitated, and quickly required intubation for decreased consciousness. Full peripheral blood examination showed a total white blood cell count of 35.4 × 109/L (reference range, 4.5–11.5 × 109/L) and acute renal impairment (creatinine concentration, 169 μmol/L, reference range, 45–80 μmol/L). Lumbar puncture performed after intubation showed turbid cerebrospinal fluid (CSF), with 198 × 106/L polymorphs and no lymphocytes seen on microscopy. A Gram stain of her CSF showed gram-positive cocci, which were subsequently confirmed to be Streptococcus pneumoniae. S. pneumoniae was also cultured from blood taken at presentation. Intravenous therapy with vancomycin, benzylpenicillin, ceftriaxone, and dexamethasone was commenced initially, and the patient was transferred to the intensive care unit for ongoing management, including inotropic support. After antibiotic susceptibility testing, benzylpenicillin therapy alone was continued. The patient became afebrile and haemodynamically stable after 48 hours, but her neurological recovery was prolonged. She remained intubated for 10 days after admission, and required a tracheostomy for respiratory weaning. Films from blood taken shortly after admission showed target cells, acanthocytes and Howell–Jolly bodies, raising the possibility of anatomical or functional asplenia. Her family and general practitioner were questioned, but they were unaware of previous splenic surgery, or surgical scars or abdominal trauma, and did not believe that the patient had ever received pneumococcal vaccination or prophylactic antibiotics. After extubation, the patient revealed that an absent spleen was noted many years previously when she had a laparoscopic cholecystectomy, but that she was unaware of any implications or required management of asplenia. After the discovery of her (presumed congenital) asplenia, she was referred to the Victorian Spleen Registry for vaccination, commencement of antibiotic prophylaxis, and ongoing education. During her subsequent hospital stay, it became apparent that the patient had persistent neurological deficits, in particular, unilateral sensorineural hearing loss and difficulty with cognitive tasks and concentration. She spent a total of 19 days in an acute-care hospital and a further 50 days in a rehabilitation centre, and has since returned home with ongoing support from allied health professionals and carers. Overwhelming postsplenectomy infection (OPSI) is a well recognised long-term risk in patients who have undergone splenectomy. In addition, there are patients who are asplenic for other reasons, including congenital asplenia or medical conditions such as coeliac or sickle cell diseases.1 The incidence of OPSI can be reduced by instituting a suite of preventive measures,2 although auditing has shown that adherence to recommendations is poor, both in Australia and elsewhere.3-5 Partly in response to these studies, a number of national and international guidelines have been published, including recent guidelines produced by the Australasian Society for Infectious Diseases.6 In Victoria and elsewhere, there have been more systematic efforts, including the establishment of registries for people who are asplenic. Our case illustrates the risk of OPSI, and, below, we describe how this risk can be minimised. Although an individual’s risk for OPSI is only in the order of one in 500 patients per year, this carries a 50% chance of mortality for those affected,6 and a risk of significant morbidity. The cost to the health system of an individual case of OPSI can be significant, and systematic approaches to prevention are cost-effective.7 Guidelines based on the limited evidence available usually recommend a combination of vaccination and long-term antibiotic prophylaxis, plus the supply of emergency antibiotics and, possibly most importantly, patient and family education about health after, and the possible consequences of, splenectomy.1,6,8 In retrospective studies, adherence to these guidelines appeared to reduce the rate of OPSI by about 50%.2 As was the case in our patient, most cases of OPSI are due to S. pneumoniae.6 Vaccination against this organism is important, as is vaccination against Neisseria meningitidis and Haemophilus influenzae type b, and vaccination with the influenza vaccine (Box 1). Prophylactic long-term antibiotic therapy is also recommended (Box 1), on the basis of a similar level of evidence. Lack of antibiotic prophylaxis is associated with increased risk.2,3 If patients cannot tolerate long-term prophylaxis, an emergency supply of antibiotics and information on when to take these may be an appropriate alternative.6,8 Education is also important in recognising signs of infection and the need for early presentation to medical care. Insufficient medical advice to patients and their treating medical practitioners, and forgetting this advice, have been purported to be responsible for cases of OPSI occurring decades after the original splenectomy.3 Education also includes the need for travel advice, especially to areas where malaria exists, and consideration of antibiotic therapy after animal bites or other trauma. Poor adherence to guidelines has given rise to the suggestion that an active spleen registry may be the best option to ensure adherence to best-practice recommendations.9 There are few previous reports of spleen registries, and those that exist show that registries vary in their methods of operation.10 Lessons from practice Overwhelming postsplenectomy infection occurs in one in 500 patients per year, but the associated mortality rate is 50%. This risk can be reduced by about half with education, vaccination and antibiotics. Systematic approaches to postsplenectomy care are likely to be more efficient than ad-hoc approaches. The Victorian Spleen Registry was established in 2003 with funding from the Victorian Government Department of Human Services for an initial 18-month period. The registry team includes the registry coordinator, infectious disease physicians, clinical haematologists and a clinical immunologist, with additional advice received from surgeons, pharmacists and anatomical pathologists. The registry actively enrols asplenic patients; referral and patient consent are required for inclusion. Patients enrolled on the registry are provided with written information about the management of asplenia, and provided with memory aids such as refrigerator magnets and wallet-sized cards. More than 1000 patients are now enrolled. However, continuing funding for the registry is an ongoing problem. This case and others, like the one illustrated in Box 2, show the severity of even non-fatal OPSI when it occurs, and the real need to minimise the risk to patients by ensuring that they receive regular vaccination, appropriate antibiotic advice and education, as provided in a registry setting. 1 Summary of current recommendations for adult patients who are asplenic Recommendation Frequency Vaccination Pneumococcal conjugate Consider at baseline Meningococcal conjugate C Baseline Haemophilus influenzae type b Baseline Pneumococcal polysaccharide (23 valent) Baseline + 5 year Quadrivalent polysaccharide meningococcal vaccine Baseline + 5 year Influenza Annual Antibiotic prophylaxis Amoxycillin 250 mg orally or Daily, lifelong penicillin 250 mg orally Twice daily, lifelong Roxithromycin 150 mg (if allergic to penicillin) Daily, lifelong Amoxycillin 3 g (if prophylaxis not tolerated) In emergency (eg, febrile illness when unable to access medical care) Enrolment in a spleen registry where one is available 2 Middle-aged woman after overwhelming postsplenectomy infection This patient had not had all the necessary vaccinations; she survived, but required amputation of all four limbs.

Justin T Denholm BMed, MBioethics · Penelope A Jones RN, GradDipEpi · Denis W Spelman MPH, FRACP · Paul U Cameron PhD, FRACP · Ian J Woolley MB BS, FRACP

Incorrect author name: In the letter “Invasive pneumococcal disease in Western Australia: emergence of serotype 19A” in the 2 February 2009 issue of the Journal (Med J Aust 2009; 190: 166), there was an error in one of the author's names. The name “Keil D Anthony” should have been “Anthony D Keil’.

Carolien M Giele · Anthony D Keil · Deborah Lehmann · Paul G Van Buynder

Conference delegates workshopped a realistically staged disaster scenario in which they were completely isolated from outside resources If you have to have a disaster, Broome, on the remote Kimberley coast of Western Australia, seems a good place to be; that is, until you take a closer look at what it would be like at the centre of the action. And this is exactly what delegates did during the inaugural conference on Tropical, Emergency and Disaster Medicine (TED-MED), held in Broome on 22–24 May 2009. The conference was attended by 81 delegates, including 28 general practitioners, eight tropical medicine specialists, six emergency medicine specialists and five disaster medicine specialists, plus representatives of government agencies, rural and remote nurse paramedics, clinical laboratory scientists and environmental health and industry participants. In this conference, we used the scenario of a tropical cyclone to move conference attendees outside their comfort zones and draw them into the reality of health crisis management in regional Australia. As it happened, Broome turned out to be an excellent location for the TED-MED conference because of a series of recent events, including the explosion of a refugee boat off the north-west coast of Australia and a tourist vehicle rollover on the Mitchell Plateau to the north-east. To add further realism to the program, there was severe wind damage caused by storms hitting Perth the day before visiting speakers flew into Broome, and the nation was on the verge of moving from the “Delay” phase to the “Contain” phase of the response to pandemic (H1N1) 2009 influenza. There were two triggers for a broad-based conference such as this. One was a renewed emphasis on regional development, particularly in WA’s north-west, where the expansion of the Ord River Irrigation Scheme, mining and petrochemical industries, and tourism are expected to drive a threefold to fourfold expansion of the regional population over the next decade. The second trigger was the Government of WA’s Royalties for Regions policy, under which some of the revenue generated by the mining and resources industry is returned to regional WA in the form of infrastructure funding, and is expected to add impetus to the population growth in the north of the state. In his opening address, WA Director General of Health Peter Flett emphasised the challenges of providing health care to such a thinly spread population in a tropical environment. He said that there was an urgent need to tackle the declining professional population as the baby boomer generation goes into retirement. David Atkinson, from the Kimberley Aboriginal Medical Service Council, compared his extensive experience in remote Aboriginal communities with indigenous communities in remote Canada. The extremes of hot and cold were explored further by retired remote and rural general surgeon Val Lishman AM, who spoke on his work in northern Australia and as an Australasian Antarctic Expedition doctor. Val’s moving snapshot of wilderness medicine in extreme environments was a profound reminder of the importance of resourcefulness and unquenchable optimism in the face of adversity. At the centre of the conference program was a carefully researched disaster scenario (Cyclone TED). Delegates prepared for an extended problem-solving activity through a series of lectures. Major-General Paul Alexander (Australian Defence Force [ADF] Surgeon General) gave the initial plenary session on ADF health capability, reflecting on the role Defence personnel often play in disaster response. He usefully clarified what the Defence Force can do and under what circumstances they would be tasked to assist. Highlights of subsequent parallel sessions were a vivid description by plastic surgeon Fiona Wood of the management of patients with burns who were injured in the Bali bombing, the challenges to medical evacuation from a combat zone by David Werda (former ADF paramedic during United Nations deployment to Somalia), and tag-team presentations on snakebite and emergency resuscitation by George Jelinek and Steve Dunjey (both from the Emergency Department at Sir Charles Gairdner Hospital). Steve’s recent high-profile resuscitation success in outback WA led him to comment that medicine is full of surprises. “You can see unexpected survival in patients under 50 after over 20 minutes’ resuscitation.” The closing straight was led by a relay team of experts. Juliet Hubbard, speaking for Indigenous communities, advocated much wider training of health professionals in cultural safety, particularly in managing major community crises. Alison McMillan (Department of Human Services, Victoria), speaking on the Victorian bushfire disaster, reminded us how quickly local emergency services can be overwhelmed. She gave delegates a sense of the confusion that arises as responding agencies piece together a picture of a disaster. Finally, Brad Santos, a severe-weather expert from the Bureau of Meteorology, left the storm damage in Perth behind him and showed how cyclones behave, with specific reference to their severity and time course. Having given us a taste of what to expect, he introduced the disaster scenario with a scene-setting severe-weather warning. Unlike in many tabletop exercises that aim to advertise the capabilities of host agencies, the details of the scenario were not disclosed to participating agencies. Michael Watson (Clinical Microbiologist, Perth), who led the team of scenario writers, said that he wanted a realistic challenge. As it happened, the date of the conference coincided with peak high tides, enabling Michael and his team to design a realistic scenario in which cyclonic winds caused a storm surge and significant flooding. They envisaged power, telecommunications, the airport, and road links being out of action for 48 hours. To the frustration of health administrators, there was no phone-a-friend-in-Perth option. Police, fire and emergency services, ambulance services, the Royal Flying Doctor Service, the Water Corporation, the Department of Housing and the Department for Child Protection (which is responsible for resettling displaced people) had to rely on what was available locally. There was a lot of tension in the room in the early stages of the disaster scenario as participants grappled with conflicting priorities. In the wrap-up session, table after table recounted tales of resources they discovered when they started to reach out to other groups. Some discovered leadership skills they didn’t know they had. Others showed a natural talent for critical thinking under pressure. One of the conference highlights was a vivid description by Phil Kuhne (Department for Child Protection) of what it would be like in an overcrowded cyclone shelter, and why there wouldn’t be any cyclone parties on his watch. Adding a little realism to the scenario, television crews from two competing channels arrived to interview organisers and speakers just after the scenario started, diverting critical expertise when it was most needed. Cyclone TED was full-on; a draining experience for all those involved. However, there was little rest for the delegates. While the lessons of the disaster scenario were still fresh in their minds, participants split into three parallel skills-development workshops on practical aspects of disaster response, life support with particular emphasis on failed intubation drills, and deployable molecular diagnostic laboratories. Ronan Murray brought the more esoteric aspects of laboratory diagnostic support down to earth by reminding participants of the potential role of the molecular diagnostics laboratory in assisting with front-line clinical decision making in remote or rural regions. The Australasian College of Tropical Medicine took the opportunity to consult on the practical needs of health practitioners in tropical Australia, convening a small group to write up the lessons learned and condense them into a regional development framework — as one delegate put it, the “where we are, where we need to be and how we’re going to get there” of health care in tropical Australia. This process generated the action statement that was presented at the conclusion of the conference. The document, known as the Broome Declaration (Box), captured the spirit of the meeting and provided a sense of direction. In the final discussion of the conference, converting the Declaration into action was debated. There was uncertainty over where resources could be found for infrastructure development, and some scepticism over anything resembling a centrally driven capital project, but there was considerable enthusiasm for local ownership of the process from local delegates. The TED-MED Conference demonstrated that there are people who work at the hot and dusty end of health care who are willing to provide professional leadership. The Broome Declaration represents a benchmark for health development in tropical and regional Australia. It remains to be seen whether there is a substantive political commitment to support front-line health care professionals in developing health capability for regional Australia. The Broome Declaration 1. On this day, 24th May 2009, in Broome, Western Australia, we, the participants in the first consultative tropical medicine summit convened under the auspices of the Australasian College of Tropical Medicine, hereby recognise that the following 10 themes are essential to the development of tropical health: holistic, one health;* collaborative intersectoral partnership; primacy of prevention, early intervention; cultural safety;† subsidiarity;‡ leadership development; proximity of services; immediate availability; effective communication; and strategic urgency. 2. Recognising the current shortfall in health capability in this region as typical of many parts of the tropics, we commit to: establishing tropical health development priorities based on the above themes; informing health authorities of our conclusions; and working toward practical development outcomes within our immediate areas of professional influence. 3. We therefore propose the following specific priorities for north-west Australia: developing a remote access tropical medicine training program; establishing a regional development centre for all stakeholder groups in the Kimberley and the rest of the north-west; and forming a steering group to identify governance and resource support for these outcomes. * A reference to the concept of health as a state of physical, mental and social wellbeing, rather than an absence of disease, first articulated in the Declaration of Alma-Ata.1 † Achieved in a health care setting when carers and providers are attuned to the cultural context of the individuals and communities, and are sensitive to culture-specific vulnerability. ‡ The principle of devolving responsibility for decision making to as close as possible to the level of community at which action is taken.

Timothy J J Inglis DM, FRCPA, FACTM · Ronan J Murray FRCPA, FRACP, FACTM · Michael Watson FRCPA, FRACP, FACTM

In October 1918, an Allied army (Egyptian Expeditionary Force) in Palestine experienced simultaneous epidemics of falciparum malaria and influenza during the cavalry campaign that defeated the Turkish Army. Malaria infection occurred 2 weeks after the advance of cavalry units into areas without environmental mosquito control. Pandemic influenza, now thought to be an A/H1N1 strain, struck at the same time. In the Egyptian Expeditionary Force of 315 000 soldiers, 773 died from malaria and 934 from influenza–pneumonia. Disease casualties outnumbered those due to combat by more than 37 to 1. Simultaneous infectious disease epidemics can cause mass casualties, capable of overwhelming any health service.

G Dennis Shanks MD, MPH

Contagious: cultures, carriers and the outbreak narrative. Priscilla Wald. Durham: Duke University Press, 2008 (xi + 373 pp). ISBN 978 0 8223 4153 6. Although the medical aspects of communicable diseases are no doubt fascinating, the impact of infections on our local and global community is no less enthralling. Richard Preston’s The hot zone and Ken Alibek’s autobiography, Biohazard, are two examples of such intriguing narratives, the former a spine-tingling tale of the discovery of Marburg and Ebola infections and the latter exploring the Soviet bioweapons program and Alibek’s defection to the United States. Priscilla Wald’s book, Contagious, is not just another narrative about various outbreaks. It is primarily about the historical and social views in times past and present and how they paralleled, influenced and were themselves influenced by the emergence of infectious diseases. Contagion literally means to “touch together”, and originally referred to the circulation of seditious or dangerous ideas. It eventually came to be adopted as a term for communicability of infections, retaining the negative connotations of its origins. Highlights included the stigmatisation of “superspreaders”, those people who deliberately or unwittingly infect large numbers of people. Wald gives examples: a flight attendant during the SARS outbreak in 2003; Patient Zero during the early AIDS epidemic; and probably the most famous superspreader of them all — Mary Mallon, also known as Typhoid Mary, who was a healthy carrier of typhoid fever in New York in the early 1900s. Wald describes how at least one contemporary author cast Typhoid Mary as a “fallen woman” sexually. It was as if her supposed sexual transgressions, her mobility and independence — so different from that of the stereotypical virtuous woman of the time — allowed her to take on the role of a superspreader. Similarly, the ghettos in Manhattan of the early 20th century were not just seen as a home to new arrivals to the United States. They were simultaneously regarded as concentrated areas of foul infections and unfamiliar cultural beliefs emanating from immigrants waiting to be “Americanised”. Wald describes this as “medical nativism”, where one justifies the stigmatisation of immigrants through their association with communicable diseases. Wald also draws an interesting parallel between communicable diseases, the communist threat of the Cold War and popular fiction of that time (such as The body snatchers), where normal people have been infiltrated or “infected” by malicious influences, transforming them into “human-looking monsters”. The author herself is not a medical doctor but a Professor of English at Duke University in the US. The book is extremely well written, although it isn’t a light read by any means. It is a good book that has given me a new perspective on the outbreak narrative.

Sanjaya N Senanayake

Incorrect order of authors: In “ASID (HICSIG) position statement: infection control guidelines for patients with influenza-like illnesses, including pandemic (H1N1) influenza 2009, in Australian health care facilities” published online on 21 September 2009 and in the 19 October 2009 issue of the Journal (Med J Aust 2009; 191: 454-458), John K Ferguson was incorrectly listed as the first author of the article. The correct order of authors is: Rhonda L Stuart, Allen C Cheng, Caroline L Marshall and John K Ferguson.

Rhonda L Stuart FRACP, PhD · Allen C Cheng FRACP, MPH, PhD · Caroline L Marshall FRACP, PhD, GradDipClinEpi · John K Ferguson FRACP, FRCPA, DTMH

The first rat I met in South Vietnam in 1967 was a hairless pup, jiggled by the tail in front of a bawling infant in a clinic we were holding in a refugee camp in sand dunes on the central coast, south of the city of Tuy Hoa. His mother had produced it from inside her shirt for tranquilising purposes, and it did the trick. As his eyes focused, the infant’s larynx relaxed, and everyone began to feel better until stubby hands groped for the rodent. With a twist of the wrist, however, the mother avoided a spectacle that might have lingered in our minds. I met my second rat later that day. He was a hairy thing, bolting across the sandy road between the barracks, and I wondered what he was doing out in the sun. I was surprised when he came to a sudden stop, and incredulous when he began to move backwards in a limb-whirling shower of sand. I blinked to clear my eyes of perspiration and found the reason for the rat’s reverse: fishing line connecting a rear leg to the hand of a small boy squatting with friends in the shade beside one of the huts. The rat was being reeled in to be released again, and yet again, by serious captors. I met more rats when I went into one of the barracks on a “home visit”. The huts were all the same, erected on the sand from corrugated iron and jammed with 30–40 people and their belongings. The inmates had been relocated from war zones for their own “good” and passed their days in idle misery, eating grain delivered by the government and throwing their refuse into open pits. It was very hot in the barracks — literally like being in an oven because each family cooked its meals over open fires, inside the tin sheds, in the sand dunes, under the blazing sun. The huts were stifling with smoke and humanity. I made my way to one fire to see what was on for lunch and found a frying pan filled with rats. Denuded, disembowelled and beheaded, they sizzled flank by flank under the care of an older woman in black pyjamas. Nearby lay the first of my patients: a man who was sick, febrile and immobilised by a large, painful lump in his groin, which was covered by oedematous, bluish skin. An abscess, I thought, and injected the only antibiotic I had, streptomycin, before moving to the next patient, who also had an abscess. And then, another. This seemed odd, but I remembered the holiday I had once endured as a small boy on a waterless farm in Queensland and the crops of boils that had erupted in the nether regions of several of us children after sharing an inch or two of black bath water. I suspected poor hygiene. It never crossed my mind the abscesses might have had something to do with the rats. But these “boils” were so large, and the people so sick, I aspirated one and sent pus to a nearby United States Air Force laboratory. Returning in a few days for the results, I had barely begun to savour the delicious air conditioning when a door was flung open and the technician announced with great excitement: “It is P. pestis! P. pestis! [Pasteurella pestis; now known as Yersinia pestis]” So what? I wondered, trying to recall any mention of that organism in my recent undergraduate experience at the University of Sydney. The technician informed me that we had discovered an outbreak of plague. Plague in Vietnam did not begin or end in our refugee camp. It was first recorded in 1898 in Nha Trang, south of Tuy Hoa, and the absence of any local name seemed to confirm its novelty.1 It was assumed it had been transported by ship from Hong Kong, where the Chinese epidemic had reached in 1894.1 In 1906, it was reported in Saigon (now Ho Chi Minh City), where it became endemic and caused about 1000 cases a year until the strict French administration managed to restrict it to about 25 cases a year in the 1930s. It increased again in the 1940s, during World War II. From 1962, however, the incidence in South Vietnam soared —5000–10 000 cases were reported annually until 1973,1,2 after which it fell. What caused this apparent outbreak? Where did it come from? Why did it stop? Marshall and colleagues denied an outbreak, stating it had been endemic since importation, and this notable increase merely reflected better identification by the increased numbers of doctors and laboratories associated with the Vietnam War.3 As confirmation of endemicity, they cited outbreaks in refugees and Viet Cong prisoners from regions beyond the reach of allied hospitals.3 Most rejected these denials but, if endemic, where was the fertile reservoir? Rural or town rats? It was argued “if there is no evidence that plague has come from outside sources” it must be based in “local wild rodents”,4 who transmit it either directly to humans, or indirectly, via urban rodents they have infected. Historically, plague has occasionally been associated with rural disruption. In India in 19945,6 and Algeria in 2003,7 outbreaks were preceded by rural earthquakes. Did burrows of rodents in rural areas collapse, forcing their residents to join — and infect — human refugees? Did broken buildings provide access to more food and permit proliferation? In South Vietnam, during the Vietnam War there were two massive disruptions in rural ecology: the bombing campaign and defoliation. Coincident with the outbreak of plague, 7.5 million tons of bombs (plus other ordnance) were dropped on rural South Vietnam: three times the weight dropped in World War II and with 100 times the combined impact of the atomic bombs dropped on Japan.8 Did these artificially made earthquakes drive rural rodents to the towns? Did they rupture grain stores, allowing access to food sources? Was there a limit to how much even a rat could take? Did defoliation alter their eating habits, with the same result? In 1962, Operation Ranch Hand was launched to deprive the Viet Cong of food and cover. It peaked in 1968–1969 and ended in 1971, after the spraying of over 6 million acres of rural land.9 Deforestation increases contact between humans and sylvatic sources,5 and Akiev noted that 86% of cases of plague in South Vietnam between 1966 and 1970 occurred in the most defoliated provinces.10 In many of these provinces, plague appeared for the first time. Although plausible, the theory that rural mammals were the source of plague was contradicted by field studies that found the disease to be surprisingly restricted to town mammals. Although trapping in the countryside was a dangerous pastime in those days, restricting research, Marshall and colleagues found that 99% of infected animals were the town rats, Rattus norvegicus, R. rattus, R. exulans, and the house shrew, Suncus murinus.11 After the war, researchers found that zoonotic foci were restricted to human settlement. Moreover, the flea vector, Xenopsylla cheopis, “exist[ed] only on indoor, commensal rodents”.12 Later, Suntsov and colleagues found only one rare flea to be common to rural and urban rodents, making it unlikely plague would be transferred from one to the other.13 If the rural mammals were not abandoning their homes, humans were. Around 3 million people (10% of the population) were relocated to camps such as ours in Tuy Hoa, and plague has long been recognised as a disease of the poor, crowded in slums where rats proliferate on rubbish.14 Certainly, there was inadequate disposal of rubbish in our camp, but proliferation of the urban rodents may have been even more encouraged by the practice of feeding refugees with grain shipped from central deposits and stored imperfectly in the camps in the provinces.3 This promoted transportation of rats from sites of endemicity and ensured they were well fed for reproduction. Perhaps eating habits further contributed to disease. Human skinners of infected camels15 and marmots have contracted plague through breaks in the skin, and consumers of undercooked meat have become infected.16 The former are likely to present with axillary buboes and the latter cervical, but our cases were predominantly inguinal, suggesting flea bites on the legs. Also, the rats I saw being cooked were more in danger of being over- than underdone. Fleas quickly abandon the cooling bodies of their dead hosts. I suspect the refugees in our camp were infected as they prepared the corpses for dinner. The weather affects the incidence of plague and our outbreak occurred in the drier months, as observed elsewhere. It is argued that eggs and larvae of fleas perish in the wet season.17 However, the onset of the wet can hardly explain the pattern of illness, restricted infectivity and low mortality in the outbreaks in Vietnam compared with historical accounts of other epidemics. In South Vietnam generally, the classic signs of the disease were observed: the bubonic form (after the Greek bubo, for groin), in which lymph nodes draining the infecting bite of the flea are severely affected in association with the usual systemic poisoning by gram-negative bacteria; the septicaemic form, in which the lymph nodes are not prominent; and the pneumonic form, in which bacteria invade the lungs and can be very infectious.3,18 In our outbreak, however, we only recognised the bubonic form, which also seems to have predominated in other regions. Despite the crowding in the barracks, we recognised no pneumonic forms or transference. Less common features of plague were also observed in Vietnam: asymptomatic pharyngeal carriage;19 pharyngitis and cervical adenopathy;20 and meningitis, particularly if undertreated21 — but we recognised none of these forms. Vietnam, however, did not conform to the historical concepts of expanding disaster. Many outbreaks were described, but they remained contained in numbers and sites. For example, we only recognised 15–20 patients with plague, and the disease did not spread to nearby camps or the city of Tuy Hoa; nor, mercifully, did any of our team become infected, despite the lack of any preventive measures. Early diagnosis and treatment was considered “the single most outstanding facet of plague control” in Vietnam, reducing the overall mortality to 1%–5%.3 Our practice of widespread injections of streptomycin, therefore, must have been blindly successful. We did not observe any deaths. Mass vaccination with live attenuated strains of some 10 million South Vietnamese would have contributed to control, but we did not even know this existed. Our public health management bore no responsibility for the containment of plague in our camp. There was none. Did the high ambient temperature inhibit spread? Infectivity in the flea is promoted by a “blockage” in the gut, which allows the bacteria to multiply before being regurgitated into the next host, but Cavanaugh and colleagues showed that blockage was reduced when the temperature of the flea exceeds 27.5°C, and I doubt our camp ever got below that temperature.1 Hinnebusch and colleagues found all fleas fail to block at temperatures greater than 30°C and, moreover, that their lifespan at that temperature is severely reduced, arguably due to dehydration.22 Perhaps the hot, dry environment in the camp, especially in the huts where rats were killed and prepared for food, restricted the passage of the disease by its effect on fleas. The outbreak from 1962 to 1973 was probably due to proliferation of rats and refugees and catalysed by recipes (that involved cooking rodents to prevent starvation), with the bombing and defoliation more a cause of human than rodent displacement. After the war, the reported incidence fell to several hundred cases annually until 1997, and to 22 in 2000.23 No cases have been reported since 2002.24 This progress may reflect better living conditions and patient care in Vietnam, but the natural history of plague has always been episodic, with the disease emerging and disappearing for reasons not understood.7 Pham and colleagues report a reduction in the number of rodents and fleas trapped in central Vietnam from 2000 to 2007, and absence of Y. pestis in both rats and fleas in recent years, and suggest that Vietnam may have entered one of the “silent period[s]” that have historically preceded “sudden explosions of rodent or human plague”.24 Although we did not observe any plague-related deaths in the epidemic in our camp, it might have been close. One night, feeling the need to give a sick child an extra injection (and, it must be confessed, to pursue adventure), three of us set out to visit the camp, which lay on the other side of a wide river, the Song Ba, beyond the security of the town. The road bridge had been destroyed and cars had to traverse the kilometre-long railway bridge on planks of wood that covered the sleepers, about 60 feet above the fast-flowing water. To add to the challenge, no one dared use headlights. We travelled in our old Land Rover whose gears were as disinclined to engage as the brakes, and whose muffler was as loud and steering as loose as the ladies in the “entertainment” area between the camp and the Air Force base. But when we arrived at the camp, and shut down the roaring engine, we were astonished by the silence and emptiness of the streets. It was a moonless night and we had difficulty in finding the right barrack, searching along the road with increasing dismay. The people were slow to open the door, and stood silently while we gave our needle. Firelight flickered on unsmiling faces. Just how “pacified” were these people? Let’s go! We held our breath until the car started and hurried back to the bridge to begin the slow, lurching crossing to safety. Then, about a quarter of the way across, a shape loomed from the darkness in front of us and a huge truck ground to a halt, followed by some others. We had run into an American convoy on its way to war. I was driving and, looking up, against the stars I could see the shape of a machine gunner hunched down upon us. There was a pause, with engines growling like dogs gearing for savagery; then Bruce Hansen, my team leader and good friend, swung open his door, bounded across the sleepers and pounded on the door of the truck, demanding they “back up” because “we were on the bridge first” and we were “Australians”. The driver of the truck did not take long to respond. A head appeared from above me with a simple message delivered with a southern drawl. Stripped of embellishments it was, “You back up right now, or I will push you off”, and it was confirmed by a roar of his engine and a lurch of his mighty truck. There were two practical problems with our gears: finding the right one and holding it in place. Crashing through several, I found reverse and, holding it in place, began the long, backward retreat. My leader maintained criticism of my cowardice — but from the safety of the sleepers. The machine gunner maintained his downward menace. I could have drowned like a rat. Would they have counted me a victim of plague? At least I would have been spared the injections. Boys in South Vietnam play with a lizard and rats, 1967. Reproduced from the Bruce Hansen Collection with permission of his widow, Miranda Hansen. The interior of one of the barracks in the refugee camp near Tuy Hoa, South Vietnam, 1967. Reproduced from the Bruce Hansen Collection with permission of his widow, Miranda Hansen.

John S Whitehall FRACP, MRCP(UK), DCH

Vaccinia vaccine is used to immunise against smallpox, which is caused by the orthopoxvirus, variola. A 26-year-old laboratory worker was inoculating mice with vaccinia vaccine as part of research into cross-reactivity among poxviruses. This particular vaccine contained a live attenuated strain of vaccinia (Western Reserve). The laboratory worker had himself received vaccinia vaccine in 2004 because of the nature of his work. On this occasion, after inoculating two mice, he suffered a needlestick injury to the left index finger. Two days later, a cloudy vesicle, typical of vaccinia virus,1 appeared at the inoculation site (Figure, arrow). After 3 more days, the finger became acutely inflamed, with secondary lymphangitis and axillary lymphadenitis. After antibacterial therapy, the lymphangitis and lymphadenitis rapidly resolved and the vesicle disappeared within 10 days. The man remains well. Infection with vaccinia usually follows vaccination or needlestick injuries. Although this is usually mild and self-limiting, certain conditions (eg, immunocompromise, pregnancy, eczema) predispose to more severe and even fatal illness. Prior immunisation with the vaccinia vaccine is thought to prevent or reduce the severity of such infections, and it is recommended that people working with vaccinia or related orthopoxviruses be vaccinated every 10 years.1 Vaccinia immunoglobulin and certain antiviral agents have been used to treat severe infections.2 Given the potential dangers from accidental exposure and the fact that the last documented case of smallpox (in 1978) was related to a laboratory incident,3 strict infection control measures are paramount, including disinfection after injury, prompt reporting, urgent medical review, and measures to minimise secondary spread to contacts.1

Sanjaya N Senanayake