Infectious diseases

David Ogilvie White was born in Canberra on 30 August 1931 and died on 7 November 2004 after an 11-year battle with primary biliary cirrhosis. David was Professor of Microbiology at the University of Melbourne from 1967 to 1994. He held various high-level appointments at the university, including Head of the Department of Microbiology, Dean of Research and Graduate Studies, Chairman of the Academic Board, and Pro-Vice-Chancellor. David graduated in medicine from the University of Sydney in 1954 and completed a PhD on influenza virus at the Australian National University in 1958. He was an outstanding teacher of undergraduate students, and was recognised by the University of Melbourne and the Australian Society for Microbiology, each of which has named an annual excellence-in-teaching award in his honour. David’s ability as a mentor for research students and staff was exemplary. He supervised numerous BSc Honours and PhD students and a series of outstanding postdoctoral fellows, with whom he coauthored more than 100 original research papers. In 1992, he was made an Officer of the Order of Australia for “service to education, particularly in the field of microbiology”. David authored six major books on virology, including coauthorship with Frank Fenner of Medical virology, a classic text that is used in medical schools throughout the world. He was an editor of the journal Archives of Virology from 1985 to 1994, and served on the editorial boards of several other international journals. David also held positions on many national and international committees, including Foundation President of the Cell Biology Society of Australia, President of the Australian Society for Microbiology, and Foundation Member of the Commonwealth AIDS Research Grants Committee. David had lifelong interests in ornithology, exploration and wilderness, and was a life member of the Australian Conservation Foundation and the Bird Observers Club of Australia. He was Grand Master of the Australian Bridge Federation, several times Victorian bridge champion, and an Australian pairs champion. Despite his remarkable achievements, David was an extraordinarily humble and self-effacing person. Throughout his life, he voluntarily took on an enormous workload, not for self-aggrandisement or personal gain, but in the firm belief that he could make a difference. Those who were privileged to know him will remember his warm, constant and lively friendship. David is survived by his wife, Marjorie, and their three daughters, Alison, Merran and Rosalind.

Roy M Robins-Browne · Michael J Studdert

Vaccination programs can act as a paradigm for effective health programs in Indigenous people The inferior health status of Indigenous Australians has been extensively reported1 and is linked inextricably to their ongoing social and economic disadvantage.1,2 Measures to decrease this health inequity are best focused on prevention and primary care as early in life as possible.2 Infectious diseases, although accounting for only a minority of the excess disease burden in Indigenous Australians,1,3 are particularly promoted by features of their disadvantage, such as overcrowding, poor infrastructure for health and hygiene, and poor nutrition. They are also more readily and rapidly targeted for intervention than chronic diseases.3 Vaccine-preventable diseases are particularly amenable to rapid and cost-effective prevention,4 and targeted vaccination programs have been shown to reduce health disparities.5 However, delivery of these programs, like other healthcare interventions, depends on culturally appropriate health services.2 The achievements and opportunities for vaccination programs to reduce morbidity and mortality among Indigenous Australians were highlighted in a recent report from the National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases (NCIRS). This provided the first national assessment of the burden of vaccine-preventable diseases and vaccine coverage in Indigenous Australians.6 It showed that universal vaccination programs with highly effective vaccines (eg, measles, mumps, rubella, poliomyelitis, diphtheria and tetanus vaccines) have achieved excellent disease control in Indigenous people, similar to that in non-Indigenous people. Findings are similar in other countries with comparable Indigenous populations.4 In contrast, when vaccination programs are more limited (eg, hepatitis A, hepatitis B, influenza and pneumococcal disease), hospitalisation and death rates continue to be higher for Indigenous Australians than for non-Indigenous Australians.6 The report also showed gaps in vaccination coverage for both children and adults. Children identified as Indigenous had comparable coverage to other children at age 2 years, but lower coverage at age 12 months, suggesting greater delay in receipt of vaccines. Among adults aged 50–64 years (for whom influenza and pneumococcal polysaccharide vaccine have been funded since 1999 for Indigenous people alone), vaccination coverage was higher for Indigenous people than for non-Indigenous people (47% v 26% for influenza vaccine and 20% v 3% for pneumococcal vaccine), but still suboptimal. For both vaccines, Indigenous adults had higher coverage in remote areas than in non-remote areas (75% v 45% and 48% v 19% for influenza and pneumococcal vaccines, respectively). These findings highlight two key issues: the potential for expanded vaccination programs; and the need to improve delivery of current programs, especially in non-remote areas. The value of expanded vaccination programs is compellingly demonstrated by data on hepatitis A and influenza. The recognition of high infection rates and three deaths from hepatitis A in far north Queensland in the 1990s7 led to a regional vaccination program targeting Indigenous children aged under 5 years from 1999. This virtually eradicated hepatitis A in both the Indigenous and non-Indigenous population.8 Similar results after vaccination of high-incidence populations have been documented in the United States and Israel.9 Yet, the NCIRS report documented hepatitis A as an issue for Indigenous Australians outside north Queensland, with national hospitalisation rates 57 times higher in Indigenous children aged under 5 years than in non-Indigenous children the same age.6 This highlights the potential of broader national application of the strategy, which is currently being examined by the Australian Technical Advisory Group on Immunisation. In addition, deaths attributed to influenza and pneumonia are significantly higher in Indigenous Australians.6 Among age groups either not targeted for influenza vaccination (0–4 years), or where only those with risk factors such as chronic cardiac or pulmonary disease are targeted (25–49 years), the respective mortality rates are 17 times and 28 times higher for Indigenous Australians than for non-Indigenous Australians.6 In contrast, among Indigenous adults aged 50 years and over, in whom universal influenza and pneumococcal vaccination is funded, the differential mortality rate is much less (three times higher). This suggests that the vaccination program has had an impact and justifies examining more closely the expansion of universal vaccination of Indigenous people to younger age groups. As to the delivery of current programs, several presentations at the Public Health Association of Australia’s national immunisation conference in 200410 were pertinent. The conjugate pneumococcal vaccine program (introduced in 2001) provided another example of the success of appropriately targeted vaccination programs, reducing for the first time, in 2003, the national incidence of invasive pneumococcal disease in Indigenous children under 2 years of age to the levels in non-Indigenous children.11 This is similar to the impact of such a program in the United States.4 Other conference presentations highlighted the problems of vaccination delivery to Indigenous Australians in general practice. Although general practice is crucial for vaccine delivery in non-remote areas, only 27% of respondents to a national survey of GPs had a routine system for ascertaining whether their patients are Indigenous.12 Yet, Aboriginal and Torres Strait Islander people are happy to be asked about Indigenous status, provided it is done respectfully, and the reasons are explained.13 Improving GPs’ identification of Indigenous status could help increase vaccination rates of Indigenous Australians in general practice, which are lower than those of non-Indigenous Australians,14 and is vital for targeted vaccination. Improving identification is particularly important in non-remote areas, where vaccination coverage of Indigenous people is consistently lower than in remote areas,6 and where the characteristics of successful programs — accurate data on vaccination status, active promotion and outreach services, and effective collaboration across community, health authorities and providers15 — are less likely to be found. Vaccination is a safe, well accepted intervention which offers an opportunity to develop solutions in healthcare delivery that can be applied more generally. Although vaccination programs targeted only to Indigenous Australians will have less impact than universal programs, particularly in urban areas where Indigenous status may not be identified, the higher burden of disease in Indigenous people will continue to make targeting attractive. However, to translate the success shown by regional targeted programs8 to the national level requires substantial investment to improve both data collection (eg, ascertainment of Indigenous status in general practice and completeness of the Australian Childhood Immunisation Register) and service delivery (through culturally appropriate and accessible services). Provision of resources for active program monitoring and coordination equivalent to that found in successful programs in more remote areas is needed.

Peter B McIntyre PhD, FRACP · Robert I Menzies MPH

We recently diagnosed rickettsial spotted fever in four patients from the south-eastern coastal region of South Australia near Adelaide, an area not known to be endemic for this infection. All infections were acquired within the geographic range of Aponomma hydrosauri, the tick vector of Rickettsia honei. Infection by R. honei was confirmed in two patients. This extension of the known geographic range of R. honei infection may be explained, in part, by alterations in host–parasite ecology. Two spotted fever group (SFG) rickettsia species endemic to Australia are known human pathogens — Rickettsia australis and Rickettsia honei.1 R. australis, the agent of Queensland tick typhus (QTT), is transmitted by ticks of the genus Ixodes, principally I. holocyclus,2,3 and has been associated with infections along the eastern seaboard from tropical north Queensland to Wilsons Promontory, in Victoria. The hosts for these tick vectors are mammals, including native rats and bandicoots.2 Confirmed cases of R. honei infection, or Flinders Island spotted fever, have previously been described only on Flinders Island, in Bass Strait,4 although a rickettsial spotted fever illness, possibly caused by R. honei, has also recently been reported from the east coast of Tasmania.5 Recently published findings indicate that the parasitic tick Aponomma hydrosauri, which has a variety of reptile species as its hosts, may be the principal vector of R. honei.6 We describe four patients from coastal South Australia (SA) near Adelaide who presented with an illness characterised by fever, severe malaise, diffuse maculopapular rash, and laboratory findings indicating acute SFG rickettsial infection. Clinical recordsPatient 1In October 2001, a 65-year-old woman from the south coast of SA (Box 1) was referred after 5 days of high fever, rigors, prostration, headache and generalised muscle pain. On Day 5, a non-pruritic rash appeared on the trunk and subsequently spread to the extremities, including the palms and soles. Two days before the onset of fever, while working in her garden, she had experienced sudden pain in her right groin, which she attributed to an ant bite; no tick or other arthropod was seen. She developed a mild purple skin discoloration in her right groin, but no eschar. She had not travelled recently or been bushwalking and had had no contact with animals, but her house bordered on bushland. On admission she appeared unwell, with tachycardia and temperature over 39°C. There was a diffuse maculopapular rash (Box 2), but no eschar, and crackles were audible in the left lung base. Chest x-ray showed bilateral reticular infiltrates that were most pronounced in the left mid and lower zones. Results of laboratory tests, including rickettsial serological testing, culture and polymerase chain reaction (PCR), are shown in Box 3. There was no initial response to empiric therapy with flucloxacillin, gentamicin and azithromycin. Three days after admission, she was reviewed by an infectious diseases physician and her antibiotic therapy was changed to 100 mg doxycycline twice daily, which resulted in rapid improvement of her condition, with resolution of fever and near-complete disappearance of rash within 48 hours. Doxycycline therapy was continued for 7 days. A week after discharge, she was well and there were no clinical or laboratory abnormalities. Patient 2In December 2002, a 74-year-old man from the south coast of SA (Box 1) was referred after 5 days of high fever, rigors, malaise, and severe prostration with mild confusion. He had a generalised, non-pruritic maculopapular rash, predominantly on the trunk but also on the extremities, including the palms and soles (Box 2). There was no history of recent travel or animal or arthropod exposure, but his house was on the edge of bushland. He had noticed numerous lizards in the vicinity of his house, but had not had any direct contact. On examination, he appeared unwell, with a temperature of 40°C and diffuse rash, but no other abnormal physical findings. Empiric therapy with flucloxacillin, ceftriaxone and gentamicin was started, but doxycycline (100 mg twice daily) was substituted 24 hours later after review by an infectious diseases physician. Within 48 hours, the fever resolved and he was discharged home. On review 6 weeks later, he was well, with no abnormal clinical or laboratory findings. Patient 3In March 2003, a 44-year-old woman from a southern Adelaide suburb (Box 1) presented after 8 days of lethargy, fever, rigors, headache, arthralgia and muscle pains; 4 days after the initial symptoms appeared, a maculopapular rash appeared over her trunk and limbs. She gave a history of probable insect bite 4 or 5 days before symptom onset. She had a temperature of 39°C and a widespread macular, blanching eruption over her trunk and limbs, including the palms and soles. A number of blood cultures, as well as serological tests for cytomegalovirus, Epstein–Barr virus, parvovirus B19, Ross River and Barmah Forest viruses, and also leptospirosis, were negative. On Day 4 of admission (12 days after onset of symptoms), she started a 7-day course of doxycycline (100 mg twice daily), and the fever resolved within 24 hours. At follow-up 3 weeks later, there was complete resolution of rash and normalisation of all haematological and biochemical parameters. Patient 4In May 2003, a 58-year-old man from a southern Adelaide suburb (Box 1) presented with 7 days of high fever, followed 2 days later by a macular rash on the trunk and limbs, which resolved within 72 hours. On the night of admission he awoke with dyspnoea, but there was no cough or sputum. There was no history of tick bite or recent direct animal exposure. On examination, his temperature was 38.4°C and there were bilateral basal chest crackles. There was no rash or eschar. Chest x-ray showed bilateral basal interstitial shadowing. After initial treatment with intravenous benzylpenicillin and erythromycin, his antibiotic therapy was changed to 100 mg oral doxycycline twice daily as treatment for presumed atypical pneumonia. Acute and 2-week convalescent serological tests showed no evidence of recent infection with Chlamydophila species, legionella, Mycoplasma pneumoniae, Q fever, parvovirus B19, Epstein–Barr virus, cytomegalovirus or Rickettsia spp. PCR testing of a throat swab for M. pneumoniae and Chlamydophila spp. was negative. The fever resolved within 48 hours of starting doxycycline therapy, and he was discharged home. The patient subsequently moved interstate and was lost to follow-up. Laboratory methodsMethods used for rickettsial serological testing, culture and PCR were all established and optimised at the Australian Rickettsial Reference Laboratory, Geelong Hospital, Victoria, and are described in detail elsewhere (N Unsworth, Postgraduate Student, Australian Rickettsial Reference Laboratory, Geelong Hospital, Geelong, VIC, personal communication). Serological tests were performed using antigen from SFG species R. honei, R. australis, R. akari, R. conorii, R. sibirica and R. rickettsii in an indirect microimmunofluorescence assay (IFA). IFA against the typhus-group rickettsiae R. typhi and R. prowazekii was also performed and was negative in each case. Rickettsial culture of buffy coat cells from peripheral blood and homogenised skin biopsy tissue was performed in Vero (African green monkey kidney)-cell monolayers. PCR with primers designed to amplify conserved sequences of the SFG rickettsial 17 kDa gene was performed on DNA extracted from buffy coat cells and skin tissue, and from any culture isolate. Rickettsial species was assigned on the basis of DNA sequence of the amplified portion of the 17 kDa gene. DiscussionWe describe four cases of rickettsial spotted fever in the south-eastern coastal region of South Australia, where this infection has not previously been recognised. In Patients 1 and 2, there was clearcut serological evidence of acute SFG rickettsial infection, with at least a fourfold rise in antibody titre. The causal pathogen was identified in Patient 2 as R. honei. Patient 3 had a compatible illness and history of antecedent arthropod bite, and developed low level SFG rickettsial antibodies 33 days after symptom onset. Patient 4 had positive rickettsial blood culture, from which R. honei DNA was identified. In this patient there were no detectable rickettsial SFG antibodies in serum taken during the acute phase of the illness or in Week 2 of convalescence. The serological response to some SFG rickettsial infections may be delayed or even absent, especially in patients treated with tetracyclines.7 After inoculation and dissemination through the bloodstream, SFG rickettsiae proliferate within vascular endothelial cells, resulting in vasculitis and (usually) a characteristic rash. The four patients described presented with fever, maculopapular rash, severe malaise, muscle pains, and, in two cases, respiratory symptoms and signs, together with pulmonary infiltrates. In the original case series of Flinders Island spotted fever, common symptoms included fever, headache, myalgia, arthralgia, cough, and maculopapular rash.4 All our patients required hospital admission, but it is likely that mild or asymptomatic infection occurs in others and remains undiagnosed.8 In all cases, there were significant abnormal laboratory findings, including deranged liver function, activated neutrophils on blood film, and markedly elevated C-reactive protein levels (Box 3). White blood cell counts were either low or normal, and one patient had significant thrombocytopenia. Antibiotic therapy with tetracyclines reduces the duration and severity of illness in most reported series of SFG rickettsial infection, including Flinders Island spotted fever.4,9 Symptoms and abnormalities in laboratory findings resolved rapidly for all our patients after doxycycline therapy was initiated; three of the four had had no discernible response to previous antimicrobial regimens, including, in 2 cases, macrolide drugs, which have been proposed elsewhere as a suitable alternative treatment for rickettsial SFG infections if tetracyclines are contraindicated.10 Of the four rickettsial species implicated in human infections in Australia, R. australis and R. honei cause spotted fever, which, until now, has been reported only along the eastern seaboard. Uniquely for arthropod-transmitted infections of humans, the vector of Flinders Island spotted fever has recently been shown to be Aponomma hydrosauri, a parasitic tick found on reptiles.6 This tick is found in the coastal geographic range of its host species in Tasmania, Flinders Island in Bass Strait, as well as much of southern mainland Australia, including south-eastern South Australia,11 where the cases we describe occurred. Although two of our patients gave histories suggesting arthropod bites a few days before onset of symptoms, there was no unequivocal tick exposure in any patient. This accords with the original case series of Flinders Island spotted fever, in which only four of 26 patients gave a history of tick bite, and reinforces the importance of not discounting possible tick-borne infection based on apparent lack of exposure. The interval of 2–5 days between possible tick exposure and onset of fever in two of our patients is consistent with reported incubation periods in individual cases of Flinders Island spotted fever where a tick has been isolated,4 whereas the incubation period of R. australis infection is probably somewhat longer.1 That most of our cases occurred in warmer months is also consistent with the observed seasonality of Flinders Island spotted fever,4 and with the predicted activity of A. hydrosauri. These cases define a previously unknown focus of rickettsial spotted fever in regions of recent population growth near Adelaide, South Australia. Environmental changes bringing humans into unusual propinquity with native fauna and their arthropod ectoparasites could increase both the geographic range and number of rickettsial species causing disease. Other ecological disturbances, including climate change and complex alterations in predator–prey relationships that increase populations of biting arthropods, may also lead to increases in the incidence of arthropod-borne infection.12,13 On the other hand, our recognition of Patient 1 as a case of SFG rickettsial infection clearly resulted in heightened local awareness of this diagnosis and increased active case finding. It is possible that locally acquired cases of rickettsial infection have been presenting to clinicians for many years without being recognised. Increased awareness and improved diagnostic capability, particularly molecular-amplification and DNA-sequencing technologies, are also likely to increase the number and species range of human rickettsial diagnoses.14 The microbiology, ecology and epidemiology of SFG rickettsial infections in South Australia require further study. Meanwhile, clinicians should be aware that rickettsial infections, particularly Flinders Island spotted fever, may occur outside previously described geographic ranges in Australia. Clinically compatible cases should be further investigated with appropriate serological and microbiological tests, and empiric doxycycline therapy should be considered to shorten the duration of illness. 1 Map of the South Australian coast, showing the locations south of Adelaide where the four patients with rickettsial spotted fever lived 2 Diffuse maculopapular rash associated with spotted fever group rickettsial infection Patient 1 Patient 2 3 Laboratory test results for four patients with rickettsial spotted fever Laboratory test (reference range) Patient 1 Patient 2 Patient 3 Patient 4 White cell count (4.0–11.0 × 109/L) 3.3 × 109/L 8.6 × 109/L 8.5 × 109/L 7.8 × 109/L Blood film Left shift and toxic changes in neutrophils Left shift and toxic changes in neutrophils Left shift and toxic changes in neutrophils Mild reactive lymphocytosis Platelet count (150–450 × 109/L) 74 × 109/L 189 × 109/L Normal 194 × 109/L Alanine aminotransferase (< 50 U/L) 311 54 305 120 C-reactive protein (< 6 mg/L) 262 149 243 148 Acute SFG antibody titre < 128 (Day 6)* < 128 (Day 6)* < 128 (Day 9)* < 128 (Day 7)* Convalescent SFG antibody titre 512 (Day 19)* > 1024 (Day 17)* 128 (Day 33)* < 128 (Day 18)* Rickettsia SFG culture of buffy coat cells and skin Buffy coat and skin negative (Day 9)† Buffy coat and skin negative (Day 8)† Buffy coat and skin negative (Day 12)† Buffy coat positive (Day 12);†no skin biopsy taken Rickettsia SFG 17 kDa gene PCR of DNA extract from tissue Buffy coat and skin negative Buffy coat negative; skin positive Buffy coat negative Buffy coat and skin negative 17 kDa gene sequence analysis nd Ricksettia honei (100% homology) nd Ricksettia honei (100% homology) All test samples were obtained on the day of admission to hospital unless otherwise specified: * day after symptom onset; †day of collection after symptom onset. All skin biopsies were obtained from the anterior abdominal wall. SFG = Spotted fever group. PCR = Polymerase chain reaction. nd = Not determined.

John R Dyer MB BS, FRACP · Lloyd Einsiedel BM BS, PhD, FRACP · Patricia E Ferguson BMed (Hons) · Andie S Lee MB BS · David L Gordon PhD, FRACP, FRCPA · Nathan B Unsworth BBiomedSc, BSc (Hons) · Stephen R Graves PhD, FRCPA

Bradley T Martin,* Pamela Palasanthiran,† Iain B Gosbell,‡ Thelma Barbagiannakos,§ Emma J Best,¶ Richard L Henry** * Respiratory Fellow (currently, Department of Respiratory Medicine, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145), † Infectious Diseases Specialist, ¶ Infectious Diseases Fellow, Sydney Children’s Hospital, Sydney, NSW; ‡ Director, § Hospital Scientist, SWAPS Staphylococcal Reference Facility, South Western Area Pathology Service, Sydney, NSW; ** Head of School of Women’s and Children’s Health and Senior Associate Dean, Faculty of Medicine, University of New South Wales, Sydney, NSW. bradleymATchw.edu.au To the Editor: We report a case of severe pneumonia in a previously healthy 3-year-old girl of European background. Non-multiresistant methicillin-resistant Staphylococcus aureus (MRSA) was isolated from her sputum, and she was treated with intravenous vancomycin, followed by oral rifampicin and fusidic acid. After antibiotic therapy ceased, symptoms recrudesced, and computed tomography of the chest showed bronchiectasis. Sputum again grew MRSA (now also resistant to rifampicin, fusidic acid and erythromycin), as well as Pseudomonas aeruginosa. She was treated with intravenous vancomycin, ceftazidime and tobramycin. As the MRSA persisted, vancomycin was replaced with intravenous linezolid, followed by a course of oral linezolid and trimethoprim–sulfamethoxazole. More than a year after her original illness, she continues to have a productive cough and requires nebulised tobramycin to prevent exacerbations. The patient’s only risk factor was contact with her mother, who had an MRSA buttock abscess incised several months earlier. Phage typing and pulsed-field gel electrophoresis revealed that the mother’s and daughter’s isolates were identical (Box). They were found to belong to the Queensland strain of community-acquired MRSA (CA-MRSA) and to possess Panton–Valentine leukocidin, a virulence factor which is highly associated with necrotising pneumonitis and invasive primary skin infection. 1 CA-MRSA is a growing problem in Australia, and severe pneumonia due to this organism has recently been reported in adults. 2,3 The isolation of CA-MRSA before prolonged courses of antibiotics, its characterisation as a virulent strain, the response to appropriate treatment and the recrudescence of symptoms on cessation of therapy demonstrate that it was the causative organism in this case. The case is also noteworthy for the documented intrafamilial spread and the fact that the patient did not belong to the Pacific Islander community, in which CA-MRSA infections in south-western Sydney most commonly occur.4 Most S. aureus strains in the community are sensitive to flucloxacillin and dicloxacillin, so these remain the empirical treatments of choice, unless CA-MRSA is isolated or strongly suspected. CA-MRSA strains are non-multiresistant, and oral antibiotic options include clindamycin, trimethoprim–sulfamethoxazole or rifampicin and fusidic acid. 5 Intravenous vancomycin is commonly used in severe infections, but recent evidence suggests that linezolid, an oxazolidinone antibiotic with efficacy against multiply resistant bacteria, including MRSA, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci, may be more effective.6 Issues of cost, toxicity, local availability, potential development of resistance and sensitivity of isolates in vitro need to be considered before determining appropriate treatment. In conclusion, clinicians should be aware of the growing problem of CA-MRSA and the potentially devastating consequences of infection with this organism, even in otherwise healthy children. Pulsed-field gel electrophoresis (PFGE) of Staphylococcus aureus strains 1. Low-range PFGE marker. 2. Control S. aureus strain (NCTC 8325). 3. S. aureus isolate from patient. 4. S. aureus isolate from mother. 5. Queensland strain of community-acquired methicillin-resistant S. aureus (CA-MRSA).

Bradley T Martin · Pamela Palasanthiran · Iain B Gosbell · Thelma Barbagiannakos · Emma J Best · Richard L Henry

John R Gowardman,* Catherine Kelaher,† Joy Whiting,‡ Peter J Collignon§ * Intensive Care Physician (currently Launceston General Hospital, Launceston, TAS 7250), † Medical Student, ‡ Data Manager, § Director of Infectious Diseases and Microbiology, The Canberra Hospital, Canberra, ACT, and Professor, Canberra Clinical School, Australian National University, ACT, and University of Sydney, NSW. john.gowardmanATdhhs.tas.gov.au To the Editor: Bloodstream infections are frequent in healthcare settings and cause significant mortality and morbidity. 1,2 Most of these infections are caused by intravenous catheters, particularly central venous catheters (CVCs). Over 250 000 catheter-related bloodstream infections occur annually in the United States, 1 and over 3000 in Australia.2 Many CVCs are retained when no longer essential. For example, a recent one-day audit in a US teaching hospital found that 15% of CVCs (11/74) were “unjustified” most of these had been inserted in the intensive care unit but retained unecessarily after discharge from the unit.3 The risk of bloodstream infection is much higher with CVCs than with peripheral venous catheters (4.0 versus 0.2 per 1000 line-days).2,4 Such simple facts are often overlooked or inadequately emphasised in preventive programs, and CVCs may be retained for convenience. Our intensive care unit maintained an informal clinical practice of routinely removing CVCs when patients were discharged from the unit. However, an audit found that many CVCs were retained, often inappropriately, thus exposing patients to needless increased risk.5 A formal intervention policy aimed at improving CVC removal was implemented. This included a month of staff education, culminating in introduction of a formal written policy in March 2003. CVCs were to be removed when no longer clinically required or at discharge from the intensive care unit, unless the patient met predetermined retention criteria (ie, administration of vasoactive or venotoxic drugs [eg, dopamine or vancomycin] or parenteral nutrition solutions; poor peripheral venous access [after two attempts] with ongoing need for intravenous therapy; or transfer to another intensive care or coronary care unit). We undertook a prospective observational study of all patients with CVCs in the intensive care unit of our hospital in the period March to August 2003. Patients were grouped according to whether the CVC was removed per policy before or at discharge from the intensive care unit; whether it was retained per policy at discharge from the unit; or whether it was retained in breach of policy. All patients were followed up for 7 days after CVC removal. Those who died within this time were excluded from the analysis. We studied a total of 305 CVCs in 272 patients (Box). We observed: high compliance with the written policy (91%), significantly lower CVC in-situ times when policy was followed (5.1 v 8.1 days), low CVC reinsertion rates (7%), no difference in incidence of bloodstream infections between the groups. This study demonstrates that a formal policy directed at early CVC removal is effective in lowering CVC in-situ times without incurring clinical cost to the patients (eg, excessive CVC reinsertion rates). Policy breaches were infrequent (8% of all CVCs), but, when they occurred, CVC retention appeared unnecessary, and CVC in-situ times were significantly prolonged. The risk of sepsis with CVCs may be substantially lowered by policy-driven removal of CVCs, without compromising patient care. Comparison of patient characteristics and CVC outcomes when removal policy was followed versus when it was breached Policy followed Policy breached P (policy followed v breached) CVC removed CVC retained* Total CVC retained Patient characteristics Number of patients 176 71 247 25 Age (years) (SD) 60.2 (17.9) 64.9 (15.7) 61.7 (17.5) 69.0 (15.3) 0.02 ICU length of stay (days) (SD) 4.7 (8.2) 3.3 (5.2) 4.3 (7.6) 2.1 (2.0) 0.06 APACHE II score (SD) 14.7 (6.9) 14.8 (7.0) 14.6 (17.5) 14.2 (5.1) 0.31 Ventilation time (h) (SD) 51 (89) 46 (123) 51 (103) 31 (55) 0.19 CVC outcomes No. of CVCs (% of all CVCs) 202 (66%) 77 (25%) 279 (91%) 26 (8%) nt In-situ time Hours (SD) 97 (115) 202 (186) 124 (148) 197 (136) 0.009 Days 4.0 8.4 5.1 8.1 Tips cultured (% of CVCs) 136 (67%) 51 (66%) 187 (67%) 19 (73%) nt Tips infected (% of CVCs) 20 (9%) 11 (14%) 31 (11%) 4 (15%) 0.51 Catheter-related bloodstream infections Total no. 2 (1%) 0 2 (1%) 1 (4%) nt Per 1000 CVC days 2.5 0 1.4 6.0 0.33 CVC reinsertions (% of CVCs) 15 (7%) 4 (5%) 19 (7%) 0 0.38 Mean no. of ports idle (per day) na 1.5 na 1.6 nt Peripheral catheters Total no. 260 36 296 50 nt Mean no. per patient 1.5 0.5 1.2 0.5 nt Mean in-situ time (h) 63 66 64 81 nt CVC = central venous catheter. nt = not tested. na = not applicable. * Reasons for appropriate CVC retention were drug administration (32%), poor peripheral access (34%), transfer to another high dependency unit (25%) and total parenteral nutrition (9%).

John R Gowardman · Catherine Kelaher · Joy Whiting · Peter J Collignon

Despite recent and largely undeserved adverse publicity, mefloquine remains a useful antimalarial Although malaria causes most suffering among children in the tropics, it should not be forgotten that it remains a major cause of military casualties. In September 2003, about 300 US Marines and support staff were deployed to Liberia, West Africa. Of those troops who spent at least one night ashore, 69 contracted falciparum malaria, an attack rate of 44%.1 Forty-four required evacuation for medical care to Europe or the United States. While none died, several developed cerebral malaria and required mechanical ventilation. Malaria was also common among Australian Defence Force (ADF) personnel deployed to East Timor between 1999 and 2000, with 385 cases reported, an attack rate of 5%.2 Eighty-four per cent of these cases were caused by Plasmodium vivax, which, while not life-threatening, causes significant morbidity. Relapse of P. vivax infection, caused by the re-emergence into the bloodstream of parasites lying dormant in the liver (so-called hypnozoites), was a major problem in this group, with 96 relapses reported despite 2 weeks of primaquine therapy.2 This pattern of infection is frequently observed in patients who contract malaria elsewhere in Asia and the Pacific, as reported by Charles and colleagues in this issue of the Journal.3 Nevertheless, effective chemoprophylaxis is readily available for Australian travellers. The challenge for medical practitioners is to select the most appropriate regimen and then to convince patients to use it. Malaria chemoprophylaxis for areas with chloroquine-resistant malaria* (including the Pacific Islands, South-East Asia, the Indian subcontinent, China, Africa and South America)4 Atovaquone + proguanil 250 mg + 100 mg (child > 40 kg and adult) 1 tablet orally, daily (starting 1 to 2 days before entering, and continuing until 7 days after leaving, malarious area) OR Doxycycline (child > 8 years: 2 mg/kg up to) 100 mg orally, daily (starting 2 days before entering, and continuing until 4 weeks after leaving, malarious area) OR Mefloquine (child 15 to 19 kg: tablet; 20 to 30 kg: tablet; 31 to 40 kg: tablet) 250 mg orally, weekly (starting 2 to 3 weeks before entering, and continuing until 4 weeks after leaving, malarious area). * Whatever chemoprophylaxis is prescribed, patients should be counselled that no prophylaxis is 100% effective, and the importance of mosquito avoidance should be emphasised. Mefloquine as chemoprophylaxisMuch has been written (and broadcast) about the neuropsychiatric side effects of mefloquine. While a number of class actions have been instituted, none has as yet reached resolution. Identifying malaria chemoprophylaxis with any confidence as the cause of major psychiatric illness or behavioural disturbance is problematic,5 even more so during or soon after exposure to an extremely stressful military environment. This issue is illustrated by allegations that mefloquine was responsible for fatal assaults committed by Canadian soldiers in Somalia and British soldiers in Sierra Leone, and that it contributed to the killings of spouses by US soldiers recently returned from Iraq. Similarly, it was alleged that psychiatric morbidity among ADF personnel who had been deployed to East Timor was attributable to mefloquine therapy. While it is reassuring that in this issue of the Journal, Kitchener and colleagues report no excess morbidity among ADF personnel taking mefloquine prophylaxis,6 the issue of tolerability of mefloquine is a real one. A double-blind, randomised controlled trial of malaria chemoprophylaxis comparing mefloquine and atovaquone–proguanil (Malarone [GlaxoSmithKline]) found that 139 of 483 (29%) participants taking mefloquine experienced an adverse neuro-psychiatric side effect, most commonly insomnia or strange or vivid dreams.7 Such side effects were reported in 69 of the 493 (14%) participants taking atovaquone–proguanil. The overall frequency of adverse events was similar in the two groups (71% and 67%, respectively), but the events were sufficiently severe to require discontinuation of the drug in 5% of those taking mefloquine versus 1.2% of those taking atovaquone–proguanil. Assessing tolerance to mefloquine before exposure (as undertaken by the ADF) might identify many of those intolerant of this drug, allowing an alternative agent to be selected. Alternative agents for chemoprophylaxisIn Australia, doxycycline is the most widely prescribed drug for malaria chemoprophylaxis. While its side effects are relatively benign (eg, thrush, photosensitivity and oesophagitis), the challenge is to ensure compliance. Numerous studies have demonstrated that adherence to a daily prophylactic regimen is unsatisfactory, especially among those requiring long-term protection.8 Atovaquone–proguanil is highly effective for chemoprophylaxis, but is costly and, like doxycycline, must be taken daily. There has been a resurgence of interest in primaquine as chemoprophylaxis, a drug generally used to prevent relapse of P. vivax. However, it too must be taken daily for prophylaxis and, like many other old “off-patent” orphan drugs, it is inordinately expensive. Tafenoquine, a much-anticipated drug related to primaquine, is now in phase III clinical trials. After three well-tolerated loading doses, a single monthly dose appears protective.9 However, like primaquine, it can cause severe haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Thus, it is necessary to screen for this condition before beginning the drug. New agents for treating malariaAs Davis and colleagues discuss in this issue, artesunate is a highly effective and well tolerated antimalarial agent.10 It belongs to the artemesinin class of drugs derived from the Chinese wormwood plant qinghaosu, and is taken by many expatriates as “emergency standby treatment” at the first sign of fever (unpublished observation). While this practice is effective, particularly when combined with appropriate diagnostic tests, such as the rapid antigen test used in the case reported in this issue by Howden and colleagues,11 it is not without risk. The very short half-life of the active metabolite, dihydroartemesinin, means that any parasites remaining in the blood after a short course of therapy may not be cleared, leading to recurrent parasitaemia.10 Suitable drugs to combine with artesunate include mefloquine, doxycycline (if taken for one week), or, in the few regions where these drugs remain effective, combined pyrimethamine and sulfadoxine.10 Further risks of relying on emergency standby treatment alone include failing to recognise non-classical symptoms of malaria (such as diarrhoea), and exhausting drug supplies through premature self-medication for non-malarial illnesses. Of note, counterfeit artesunate is offered for sale in several Asian countries where pharmaceuticals are unregulated; the only artemisinin derivative available in Australia is artemether in combination with lumefantrine.10 A malaria vaccineAn effective malaria vaccine suitable for non-immune soldiers, travellers and the even larger population of residents of malaria-endemic countries remains a priority. The long-standing search for a vaccine has been invigorated by the creation of the Malaria Vaccine Initiative, a public–private partnership supported by the Bill and Melinda Gates Foundation. The recently published phase II malaria vaccine trial in Mozambique involving this initiative and GlaxoSmithKline Biologicals is an example of the productivity of this partnership.12 While the vaccine produced a statistically significant level of protection (29.9% to 57.7%), it is likely that, for now, doctors will continue to advise mosquito avoidance and to reach for the prescription pad rather than the vaccine refrigerator when preparing patients for trips to malarious areas.

James S McCarthy FRACP, MD

Objective: To assess changes in and factors associated with recent malaria notifications in Western Australia (WA).Design: Retrospective analysis of the WA Notifiable Infectious Diseases Database and enhanced surveillance questionnaires completed by attending medical practitioners.Patients: Cases of malaria notified between January 1990 and December 2001.Main outcome measures: Annual notifications by demographic variables (including age, sex, occupation and place of residence), region/country of acquisition, chemoprophylaxis used, Plasmodium species and outcome.Results: 482 patients were notified (mean age, 31 years; 80% male); 57% lived in Perth, 31% in country areas and 12% in an immigration detention centre. Comparison between the 6-year periods 1990–1995 and 1996–2001 showed that Plasmodium falciparum cases increased from 29 (14%) to 108 (44%; P < 0.001), while Plasmodium vivax cases decreased from 157 (77%) to 122 (50%; P < 0.001); immigrants in detention, defence force personnel and cases from Africa were increasingly represented (P < 0.05 in each case). Only 31% of patients took regular chemoprophylaxis and, among these, the regimen was appropriate in only a quarter. There was a median period of 3 days between symptom onset and diagnosis. One patient died.Conclusions: There has been an increase in P. falciparum cases in WA since 1990. This reflects the influx of immigrants in detention, deployment of military personnel to East Timor and increasing numbers of cases from Africa. A significant number of Australian travellers who developed malaria had not taken chemoprophylaxis either regularly or at all, and, of those who had, the regimen was inadequate in most.

Donnetta M Charles MB BS · Julie Hart MB BS · Wendy A Davis MPH, PhD · Timothy M E Davis DPhil, FRACP · Eleanor Sullivan MPH · Gary K Dowse FAFPHM, MSc

Objectives: To describe the tolerability of mefloquine in Australian soldiers for malaria prophylaxis, including a comparison with doxycycline.Design: Open-label, prospective study and cross-sectional questionnaire and interview.Setting and participants: Two contingents of Australian soldiers, each deployed to East Timor for peacekeeping duties over a 6-month period (April 2001–October 2001 and October 2001–May 2002).Outcome measures: Withdrawals during the study; adverse events relating to mefloquine prophylaxis; willingness to use mefloquine again on deployment.Results: Of 1157 soldiers starting on mefloquine, 75 (6.5%) withdrew because of adverse responses to the drug. There were three serious adverse events of a neuropsychiatric nature, possibly relating to mefloquine. Fifty-seven per cent of soldiers using mefloquine prophylaxis reported at least one adverse event, compared with 56% using doxycycline. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. Of the 968 soldiers still taking mefloquine at the end of their deployments, 94% indicated they would use mefloquine again. Of 388 soldiers taking doxycycline prophylaxis who were deployed with the first mefloquine study contingent, 89% indicated they would use doxycycline again.Conclusions: Mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline.

Scott J Kitchener MB BS, DrPH, FAFPHM · Peter E Nasveld MB BS, BMedSci(Hons), FACTM · Robin M Gregory BAppSc, MBus · Michael D Edstein MSc, PhD

A 28-year-old woman from Sudan who had lived for 9 years in Victoria, Australia, was diagnosed with falciparum malaria 2 months after splenectomy for massive splenomegaly of unknown cause. Chronic falciparum malaria can occasionally present years after leaving endemic areas in partially immune patients. It should be considered in such patients with presentations possibly related to malaria, including splenomegaly, anaemia, or a long history of intermittent fevers and chills. Infection with Plasmodium falciparum is well known as a cause of acute malaria among travellers from endemic areas, such as Africa and South-East Asia. However, chronic infection persisting for months may occur in endemic areas among those with a degree of partial immunity, and cases have been reported in people who left an endemic area up to 5 years previously.1,2 We report a case of falciparum malaria recurring 9 years after the patient migrated from Sudan to Victoria, Australia. The anopheles mosquito vector does not occur in this region of Australia and, if imported, is unlikely to survive for long. The patient initially presented with fever and massive splenomegaly, and the diagnosis of malaria was made after a splenectomy had been performed. Clinical recordA 28-year-old woman from Africa who had been living in Australia for 9 years presented to the emergency department with a one-week history of fever, rigors, abdominal pain, nausea and vomiting. She had no abnormalities on physical examination, apart from mild dehydration, and was discharged with a presumptive diagnosis of viral gastroenteritis. The next day, she presented to the gastroenterology outpatient clinic. Malaria was considered in the differential diagnosis, and she was admitted for further investigation and treatment. Past history: The patient was born in Eritrea and lived there for 6 years, followed by 12 years in Sudan, before migrating to Australia. She had had multiple episodes of malaria while in Africa, but could not recall exactly the drug therapy she received. In Australia, she experienced multiple episodes of nausea, abdominal pain and fever every 3 to 6 months, almost identical to her previous episodes of malaria. Although thick and thin malaria blood films were performed during each of these episodes in Australia, a diagnosis of malaria could not be confirmed. Ten months before current presentation: The patient’s general practitioner noted hepatosplenomegaly and, given her history of probable schistosomiasis exposure through freshwater irrigation canals in East Africa, tested her for schistosomiasis. Stool samples were positive for eggs of Schistosoma mansonii, and schistosoma serological tests were also positive (indirect haemagglutination titre, 256 [positive, > 32]; enzyme immunoassay IgM ratio, 1.5 [positive, > 1.2]). Computed tomography and ultrasound examination of the abdomen demonstrated massive splenomegaly (17 cm) and hepatomegaly (15 cm), with no radiological evidence of portal hypertension. Laboratory studies demonstrated anaemia and neutropenia consistent with hypersplenism. The platelet count could not be measured because of clumping (Box 1). She was treated with praziquantel, but continued to have episodes of abdominal pain and anorexia. Two months before current presentation: Because of these continuing episodes, as well as haematological evidence of hypersplenism, splenectomy was performed after appropriate vaccinations. Repeat thick and thin films before the splenectomy were again negative for malaria, although an immunochromatography card test (ICT) for malarial antigens was not performed. Initial histological examination of the spleen revealed only congestion and some mononuclear-cell infiltration. Current presentation: The patient had not travelled to a malaria-endemic area since arriving in Australia 9 years previously, nor had she been near an airport in the preceding 6 months. Results of haematological and biochemical tests are shown in Box 1. A rapid ICT for malaria antigen was performed (NOW ICT Malaria P.f/P.v. Test, Binax Inc, Portland, USA) and was positive for falciparum malaria (Box 2). The patient was admitted to hospital, and treatment begun with intravenous quinine (600 mg three times daily), as recommended for this form of malaria. The following day, thick and thin blood films were reported as showing 0.5% malaria parasitaemia. Parasite morphology, along with the prolonged period between the last possible exposure to malaria and illness, was considered consistent with Plasmodium malariae infection. Treatment was changed to oral chloroquine (620 mg initially, followed by 310 mg 6 hours later and on Days 2 and 3). Because of the conflicting results of the blood film and ICT test, polymerase chain reaction (PCR) tests for malarial antigens were performed at the Victorian Infectious Diseases Reference Laboratory and at the Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, NSW. Results of both tests a month later confirmed P. falciparum as the causative parasite. Further expert review of the blood film showed features consistent with P. falciparum (Box 3). Progress and follow-up: The fever, vomiting and abdominal pain resolved rapidly, and the patient was discharged after 3 days in hospital. After the positive PCR result for P. falciparum, she was treated again, as an outpatient, with atovaquone plus proguanil (1000 mg and 400 mg, respectively, daily for 3 days). Two weeks after completion of therapy, thick and thin films were found to be negative for malaria parasites. Serological tests for human immunodeficiency virus, hepatitis B and hepatitis C were all negative. A stored blood sample that had been taken 7 months before the current presentation was tested and found to be positive for malaria antibodies (immunofluorescent antibody titre, 160 [positive, > 20]). Further review of the computed tomography scan performed before splenectomy showed no features of chronic liver disease, and detailed histological review of the spleen again demonstrated congestion and a lymphocytic infiltrate (compatible with hyperreactive malarial splenomegaly), but no malarial parasites or pigment. At 6-month review, the patient reported no further symptoms. Screening of her children and husband for malaria (by thick and thin blood films and ICT) and schistosomiasis (by indirect haemagglutination assay) gave negative results. DiscussionThis case is notable because of the prolonged period (9 years) between the last possible exposure to malaria and the diagnosis of falciparum malaria, which was confirmed by PCR. Although it is well recognised that P. malariae infection can persist for many years,3 to our knowledge the longest previously reported delay between exposure and subsequent diagnosis of falciparum malaria is 5 years. In that case, the patient donated blood 5 years after leaving a malarious area, and was found to have falciparum malaria on testing after the recipient of the blood transfusion developed malaria; details in the report are limited.2 Recently, mathematical modelling was used to estimate the duration of P. falciparum infection after interruption of transmission.4 The authors estimated that the maximum duration of infection was about 4 years. Chronic falciparum malaria may occur in people who have lived in endemic areas and have developed partial immunity to the malaria parasite, resulting in low-grade parasitaemia.5 Antimalarial antibodies have been detected in high titres in such patients.6 Massive splenomegaly, now termed “hyperreactive malarial splenomegaly syndrome”,7 is a manifestation of chronic malaria. The demonstration of malarial parasites after splenectomy in patients not recently exposed to malaria raises the possibility of this syndrome.8 Major diagnostic criteria include: massive splenomegaly (> 10 cm) when no other cause can be found; immunity to malaria (ie, demonstration of antimalarial antibodies); and a clinical and immunological response (fall in antibody levels) to antimalarial therapy,9 or a significant reduction in spleen size and improvement in haematological parameters with antimalarial therapy.10 Our case highlights the fact that malaria may still present a major diagnostic challenge. In hindsight, it was likely that our patient had hyperreactive malarial splenomegaly syndrome. Use of other diagnostic tests, including PCR, before splenectomy might have enabled a trial of antimalarial treatment and possibly averted the need for surgery.9 Although thick and thin blood film examination using Field or Giemsa–Wright stain is the established “gold” standard for malaria diagnosis,11 repeated appropriate blood films in our patient before splenectomy were negative. An experienced laboratory can achieve sensitivity of 50 parasites/μL blood (0.001% red blood cells infected), but a survey of UK laboratories found that most achieved sensitivity of 500 parasites/μL blood when compared with a reference laboratory.12 As this case demonstrates, the new, more sensitive ICT card tests can be valuable in difficult-to-diagnose cases of P. falciparum infection. These tests detect circulating P. falciparum histidine-rich protein 2 (HRP-2) in whole blood and provide an immediate result, with sensitivity of 77%–98% and specificity exceeding 95% for falciparum malaria, correlating with counts of 100–300 parasites/μL blood.13 Other ICT kits that detect different antigens are available and can detect all four Plasmodium species.13 Although the sensitivity of these rapid antigen tests is good, a negative result does not exclude malaria. PCR techniques are even more sensitive, detecting levels as low as 5 parasites/μL blood,14 and are available on special request at reference laboratories around Australia. PCR can detect the specific plasmodial species and is therefore useful when morphological diagnosis is difficult, or when clinical suspicion warrants further attempts at diagnosis despite negative results from blood films and ICT. A recent study in Sudan showed that P. falciparum can survive for months in human hosts during the 9-month dry season, when no transmission occurs.5 Many people had ongoing PCR positivity for falciparum malaria, despite having levels of parasitaemia below the threshold for detection on thick and thin blood films. This phenomenon was demonstrated by our patient, whose blood films were repeatedly negative over years. However, splenectomy may unmask underlying chronic P. falciparum infection sufficiently to allow detection of parasitaemia on blood films.15 Chronic falciparum malaria should be considered in the differential diagnosis in patients from endemic areas presenting with symptoms possibly related to malaria, even years after their last possible exposure. Although thick and thin blood films remain the standard laboratory investigation, the relatively inexpensive and more sensitive malaria ICT card test should be a routine adjunct to blood films to detect P. falciparum. PCR testing may be warranted before excluding chronic malaria as the diagnosis. 1 Results of laboratory investigations Test Reference range 7 months before 2 months before* Current admission Haemoglobin (g/L) 115–165 105 104 97 White cell count (× 109/L)† Total 4.0–11.0 2.7 3.1 8.2 Neutrophils 2.0–7.5 0.91 0.95 1.64 Lymphocytes 1.0–4.0 1.39 1.71 5.58 Monocytes 0.1–0.8 0.38 0.38 0.9 Eosinophils < 0.4 0.02 0.07 0.08 Mean cell volume (fL) 82–95 90 85 84 Mean cell Hb concentration (g/L) 320–360 334 331 321 Albumin (g/L) 36–48 39 40 Bilirubin (μmol/L) < 18 23 26 ALP (U/L) 35–104 45 206 ALT (U/L) < 55 16 153 GGT (U/L) < 45 9 43 Urea (mmol/L) 2.5–7.7 4.3 1.9 Creatinine (mmol/L) 0.03–0.11 0.046 0.047 Thick and thin malaria blood films Negative Negative Positive‡ Hb = haemoglobin. ALP = alkaline phosphatase. ALT = alanine aminotransferase. GGT = γ-glutamyltransferase. * Pre-splenectomy. †Platelet count was not recordable because of clumping. ‡Films showed 0.5% parasitaemia; rapid immunochromatography card test and polymerase chain reaction tests were also positive for Plasmodium falciparum. 2 Rapid immunochromatography card test (ICT) for malaria Positive result for Plasmodium falciparum on immunochromatography card test (ICT) in our patient. The card test is performed on whole blood and gives a result within 10 minutes. 3 Thin blood film from the patient The ring form of Plasmodium falciparum (arrow) is apparent in a normal-sized red blood cell.

Benjamin P Howden FRACP, FRCPA · Gautam Vaddadi MB BS · M Lindsay Grayson MD, FRACP, FAFPHM · Joseph Manitta BAppSci(MLS), AIMS, MASM

Emma J Best,* Monica M Lahra,† Pam Palasanthiran‡ * Paediatric Infectious Diseases Fellow, † Microbiology Registrar, Neonatal Medicine, Royal Prince Alfred Hospital, Sydney, NSW. ‡ Infectious Diseases Physician, Sydney Children’s Hospital, Level 4, High Street, Randwick, NSW 2031; PalasanthiranpATsesahs.nsw.gov.au To the Editor: Pasteurella multocida is an oral commensal of domestic pets known to be an opportunistic human pathogen after traumatic animal contact. The most common infections in humans are skin and pulmonary infections. This report outlines a case of P. multocida meningitis, which has not previously been reported in Australia. A 19-day-old girl presented with a 12-hour history of fever and poor feeding. Her temperature was 39.5°C, and she was irritable, with no localising signs or skin lesions. A full septic screen was performed. Cerebrospinal fluid (CSF) showed a neutrophilic pleocytosis and gram-negative coccobacilli. She was treated with intravenous cefotaxime and gentamicin. Within 24 hours both CSF and blood cultures showed growth of gram-negative bacilli. The initial Gram stain, growth on chocolate agar and positive oxidase and catalase tests were suggestive of a Haemophilus species. However, further biochemical tests revealed the organism to be P. multocida. The infant made an excellent clinical recovery, with normal neurological and growth assessments at 6 and 12 months. The family owned two cats but reported no contact between their baby and the pets. A single tonsillar swab performed on each cat by a veterinarian 10 days after the baby’s presentation failed to isolate Pasteurella species. The family elected to keep the pets. Pasteurella meningitis occurs at extremes of age, in the immunocompromised (associated with liver cirrhosis, renal disease and haematological malignancies) and after traumatic head injury.1 Infants aged under 1 year account for almost half the cases of P. multocida meningitis. On review of the literature, we found 37 reported cases of P. multocida infection in infants (Box).1-5 In more than three-quarters of these cases, there was known contact with household animals — in more than half of these contact was non-traumatic (licking or presumed handling of the pet). Molecular studies in one of the cases with no history of traumatic contact confirmed that P. multocida isolates from pet and infected child were indistinguishable.2 This infection is unusual, and, given the popularity of household pets, the risk appears low. However, this case highlights the relative immunocompromise of newborn infants, and is a reminder of the importance of hand hygiene and preventing contact between newborn infants and pets. Details of 38 case reports of invasive Pasteurella multocida infection in infants (including current case)1-5 Mean age (range) 2.6 months (1 day– 11 months) Type of infection Meningitis 30 (79%) Puerperal sepsis, chorioamnionitis 7 (18%) Bacteraemia (postnatal) 1 (3%) Nature of animal contact Traumatic (scratch, bite) 9 (24%) Non-traumatic 22 (58%) Unknown 7 (18%) Type of animal (n = 31) Cat 16 (52%) Dog 11 (35%) Both 4 (13%)

Emma J Best · Monica M Lahra · Pam Palasanthiran

To the Editor: I report a patient with splenic infarction associated with group A streptococcal sepsis that occurred post partum. Although spontaneous splenic infarcts have been associated with many types of infections, to my knowledge this is the first published report of an association with this organism. A 29-year-old woman had an unremarkable term labour and vaginal delivery of her third child. On Day 2, she felt feverish, but no abnormalities were detected on clinical examination or pelvic ultrasound examination. Over the next 24 hours, she developed abdominal pain and sweats, and appeared flushed. On Day 3, her temperature was 37.6°C, and she developed nausea and diarrhoea. Empirical treatment was begun with intravenous ampicillin and metronidazole. She developed hypotension (blood pressure, 90/60 mmHg) and an erythematous rash of the legs and diffuse erythema of the trunk, anterior thighs and face. Relevant results of laboratory investigations are summarised in Box 1. On Day 4, a vaginal swab was taken, and antibiotic therapy changed to ticarcillin–clavulanate and clindamycin on the basis of presumed toxic shock syndrome. The next day, the patient developed oedema of the hands and feet, a sore throat and sore ankles. Group A streptococcus grew from the vaginal swab. Blood cultures showed no growth, but the samples had been taken after antibiotic therapy was begun. Over the next few days, the patient’s condition improved, but on Day 9 again deteriorated, with recurrence of low-grade fever and the development of sharp, retrosternal chest pain. Computed tomography (CT) of the chest with a pulmonary angiogram revealed a small right lower-lobe opacity, suggestive of a pulmonary infarct. The CT scan also revealed multiple splenic infarcts (Box 2). Screening for thrombophilia gave normal results. She was treated initially with intravenous heparin, followed by oral warfarin for 3 months. Her clinical recovery was slow but complete. This patient had probable toxic shock syndrome caused by group A streptococcus.1 She had the non-specific features of toxic shock syndrome2 (fever, nausea, diarrhoea, rash, abnormal hepatic and renal function) and disproportionate abdominal pain as the initial symptom. The only criterion lacking for “definite” toxic shock syndrome was the isolation of group A streptococcus from a normally sterile site (it was isolated only from the vagina). Puerperal toxic shock syndrome caused by group A streptococcus is well reported,1,2 with mortality of 25%–50%.2 The patient’s clinical course was complicated by multiple splenic infarcts and a possible pulmonary infarct, thought to have developed in situ with no identifiable prothrombotic diathesis. Splenic infarction is not common and is usually associated with a haematological or rheumatological disorder.3,4 Spontaneous splenic infarcts have been associated with infections, but there is only one report of these infarcts in association with toxic shock syndrome, in that case caused by Staphylococcus aureus.5 The infarcts have been postulated to be caused by circulating endotoxin.5 1 Abnormal laboratory results Investigation Result RR White cell count (x 109/L) 11.07* 3.50–11.00 Platelet count (cells x 109/L) 63 150–450 Prothrombin time (s) 15.3 12–5 ESR (mm/h) 22 0–12 C-reactive protein (mg/L) 56 < 3 INR 1.2 0.8–1.1 Alkaline phosphatase (U/L) 298 38–126 γ-Glutamyltransferase (U/L) 95 0–30 Albumin (g/L) 18 33–48 Creatinine (μmol/L) 111 60–110 * 63% band forms. ESR = erythrocyte sedimentation rate. INR = international normalised ratio. RR = reference range. 2 Computed tomography of the abdomen Scan shows one of multiple splenic infarcts — in the lateral third of the spleen.

Adrienne Torda

A stocktake of vaccination strategies and challenges The 9th National Immunisation Conference of the Public Health Association of Australia was held in August 2004 in Cairns, Queensland, in conjunction with the 1st Asia–Pacific Vaccine Preventable Diseases Conference. The conference was attended by more than 400 delegates, predominantly from the Asia–Pacific region. A theme of the conference was the potential of vaccines to achieve greater equity in health outcomes. A session on the Australian recommended immunisation schedule generated vigorous discussion, highlighting the difficulty of dealing with a schedule that includes vaccines not funded for universal use. Meningococcal diseaseThe epidemiology of meningococcal disease differs substantially around the world, with variation in both incidence and predominant serogroups. In parts of Africa, serogroup A causes regular epidemics. New Zealand has experienced a serogroup B epidemic for more than a decade, focused on the Maori–Pacific Islander community. In Australia, serogroup C has caused about 50%–70% of cases in Victoria and Tasmania since 2000, while serogroup B has been more common elsewhere.1,2 Serogroup C has also emerged as a significant problem in the United Kingdom and parts of Europe, especially in older children and adolescents. Mary Ramsay (Communicable Diseases Surveillance Centre, UK) provided an overview of the European experience of meningococcal disease, comparing vaccine schedules and outcomes. Use of meningococcal C conjugate vaccines, which provide more predictable and long-lasting immunity than polysaccharide vaccines, was pioneered in the UK with a national campaign beginning in 1999. Following the UK success, other European Union countries have begun programs, but schedules differ. In the UK, the vaccine is given at 2, 3 and 4 months; in Spain, at 2, 4 and 6 months; while, in The Netherlands, a single dose is given at 12 months. The last schedule, identical to that in Australia, was chosen because serogroup C is uncommon under the age of 12 months, and a single dose is sufficient for protection over this age. Preliminary data suggest that immunity persists longer when the last dose is given after 5 months of age.3 As outlined by Rosemary Lester (Department of Human Services, Victoria), meningococcal C conjugate vaccine was funded in Australia for children at age 12 months from 1 January 2003, and was accompanied by a catch-up program for children and adolescents aged 1–19 years. The school-based component of the catch-up program achieved good coverage across Australia in 2003–2004. Data on disease impact will be available in subsequent years. While a polysaccharide vaccine protects against meningococcal serogroups A, C, W135 and Y, and a conjugate vaccine protects against serogroup C, there is no commercially available vaccine against serogroup B. Since 1990, New Zealand has experienced a prolonged meningococcal epidemic thought to be attributable to a specific strain of serogroup B, combined with crowding and exposure to tobacco smoke. In response to this epidemic, and in partnership with the Norwegian Institute for Public Health and Chiron Vaccines, the New Zealand government has sponsored development of a vaccine for the New Zealand strain (MeNZB). After demonstration of adequate immune responses, a national rollout of this vaccine began in July 2004. Because of the unique nature of this program, assuring vaccine safety is critical. Stewart Reid (Chair of the New Zealand vaccine advisory committee) described a national safety monitoring program which, in scope and comprehensiveness, is at the level of world’s best practice. Pneumococcal diseaseKim Mulholland (Centre for International Child Health, University of Melbourne) gave an overview of the rapid and varied developments in conjugate pneumococcal vaccine trials around the world. Use of the polysaccharide pneumococcal vaccine was shown over 20 years ago in Papua New Guinea to reduce deaths, but neither this vaccine nor the newly available conjugate vaccine is used in any country with high death rates from childhood pneumonia. Although the current conjugate pneumococcal vaccine covers only seven serotypes, this vaccine, with two additional serotypes, has been shown to prevent invasive pneumococcal disease (IPD) and non-bacteraemic pneumonia in children from Soweto, South Africa.4 Peter McIntyre (National Centre for Immunisation Research and Surveillance, Sydney) and Vicki Krause (Centre for Disease Control, Northern Territory) outlined vaccine programs to control pneumococcal disease in Australian adults and children. Since the late 1990s, the 23-valent polysaccharide pneumococcal vaccine has been funded nationally for Indigenous adults aged 50 years and over and, in Victoria, for all adults aged 65 years and over. There is now convincing evidence from north Queensland of a decrease in IPD among Indigenous adults. Among the elderly, recent data have also shown a greater reduction in IPD in Victoria than in New South Wales, where there is no funded program for this age group.5 The polysaccharide vaccine will be funded for all adults aged 65 years and over from January 2005. Since 2001, the seven-valent pneumococcal conjugate vaccine has been funded only for Indigenous children and for others with specified medical conditions. From January 2005, it will be funded for all children under 2 years of age. Data from national surveillance of IPD for 2003, presented for the first time at the conference, show a measurable decrease in IPD in Indigenous children, so that the incidence in these children is now below that in non-Indigenous children. It is clear that universal funding is timely, and that vaccination has contributed to greater equity in health outcomes between Indigenous and non-Indigenous children in Australia, as previously shown for black children and white children in the United States.6 Immunisation in the PacificViliame Sotutu (Fiji School of Medicine) and Rob Condon (Public Health Physician, Fiji) highlighted the problems in providing vaccines to children in the 22 countries and territories in the Pacific, most of which are small and separated by vast distances. Many of the countries have young, growing populations with low living standards and high unemployment rates. Health status is variable, and political instability is not uncommon. The Expanded Programme on Immunization was introduced in 1977, jointly funded by the World Health Organization and individual countries. However, immunisation schedules vary between countries, and procurement and logistic strategies are often inefficient. Recent outbreaks of measles in Papua New Guinea and the Solomon Islands, with high death rates, and outbreaks of rubella in Samoa, with cases of encephalitis, highlight the fragility of control of vaccine-preventable diseases in the Pacific. More emphasis should be placed on vaccine delivery to island communities, and Australia can make an important contribution to this effort. Haemophilus influenzae type b diseaseAgustinus Sutanto (Catholic Hospital in Ampenan, Lombok, Indonesia) presented the results of a recently completed randomised controlled trial of the Haemophilus influenzae type b (Hib) vaccine PRP-T on the Indonesian island of Lombok. The trial, which enrolled 55 000 children aged under 2 years and was randomised by hamlet, produced evidence of a substantial, unrecognised burden of Hib disease. This type of “vaccine probe” study, pioneered in Gambia, is able to measure disease burden through differential vaccine impact, where routine data on disease notification and hospitalisation are not available.7 Mary Ramsay (Communicable Diseases Surveillance Centre, UK) presented the results of a series of studies, including seroepidemiology, nasopharyngeal Hib colonisation and routine measurement of disease frequency, to explore reasons for a resurgence of Hib disease in the UK. First, herd immunity, resulting from the 1992–1993 national catch-up program for children up to 5 years of age, had waned because no booster dose had been given in the second year. Second, this effect was exacerbated by the introduction of a less immunogenic vaccine combination. This resulted in an increase in cases among children aged 1–4 years, who were consequently targeted by a national booster campaign. The UK experience emphasised the importance of maintaining high-quality surveillance in order to rapidly assess unexpected problems, which may emerge even in apparently very successful vaccination programs.8 New vaccinesGraham Barnes (Gastroenterology Department, Royal Children’s Hospital, Melbourne) is involved in developing an Australian candidate rotavirus vaccine. The first licensed vaccine was withdrawn from the US market in 1999, after identification of a small but definite increased risk of intussusception. Following this experience, trials of new vaccine candidates have needed to be large enough to exclude any significant increased risk of intussusception. Two new candidate vaccines appear to have achieved this goal, one of which was recently licensed in Mexico. Terry Nolan (School of Population Health, University of Melbourne) described progress with vaccines against human papillomavirus (HPV), the major cause of cervical cancer worldwide. It is now established that these vaccines prevent HPV infection, and long-term studies will determine their impact on cancer. The potential availability of HPV vaccines has raised new issues of timing of vaccination and communication of the rationale to parents, who may not appreciate the risk of sexually acquired infections during adolescence. Both rotavirus and HPV vaccines are likely to be available in Australia within the next 3–5 years. Conference themes and resolutionsTraditionally, the final session of the conference is devoted to developing resolutions, many of which have been implemented. On the basis of public health benefit, the Australian Technical Advisory Group on Immunisation and the National Health and Medical Research Council recommend vaccines for inclusion in the Australian Standard Vaccination Schedule. Conference resolutions were dominated by the strong feeling that the Australian government should fund all vaccines that have been recommended by these two bodies.

Peter B McIntyre PhD, FRACP, FAFPHM · Heath A Kelly MPH, FAFPHM · E Kim Mulholland MD, FRACP

We report two elderly women who presented with hypertensive crisis and acute pulmonary oedema, which responded poorly to antihypertensive therapy. The patients were later diagnosed as having hepatitis C virus-related cryoglobulinaemia. Acute pulmonary oedema is a well-known complication of severe hypertension,1 but, to our knowledge, has never been reported in association with mixed cryoglobulinaemia. We report two patients with severe hypertension who presented with pulmonary oedema which was not controlled until cryoglobulinaemia was diagnosed and treated with plasmapheresis and methylprednisolone. Clinical recordsPatient 1Presentation: A 66-year-old woman presented to our emergency department in late February (winter) with severe dyspnoea of 2 hours’ duration. She had a 10-year history of hypertension, and had had a stroke 3 months before, but had recovered. Over the previous month, her blood pressure had been over 210/120 mmHg, and she had intermittent dyspnoea, orthopnoea and leg oedema. On examination, she was orthopnoeic, with blood pressure of 218/124 mmHg, regular pulse of 126 bpm, and respiratory rate of 36 breaths per minute. She had engorged jugular veins, bilateral chest crackles, hyperpigmentation of the legs and marked bipedal pitting oedema. A chest radiograph showed diffuse haziness over both lungs. Electrocardiography (ECG) showed inverted T waves in leads V4 to V6. Oxygen saturation was 77% while breathing 100% O2 (reference range [RR], 95%–100%). Initial management: The patient was intubated and mechanically ventilated. Her central venous pressure was 13 cmH2O (RR, 3–11 cmH2O), and pulmonary wedge pressure was 19 mmHg (RR, 6–12mmHg). She was treated with intravenous glyceryl trinitrate and diuretics, but over the next 48 hours her blood pressure fluctuated between 300/130 mmHg and 200/90 mmHg, and pulmonary oedema persisted. After 2 days, the patient was extubated. Over the next 24 hours, she developed massive bilateral pleural effusions and numerous petechiae over the legs. Echocardiography revealed a normal left ventricular (LV) ejection fraction (72%) and diastolic dysfunction. Radionuclide angiography confirmed these findings. Laboratory tests showed hypoalbuminaemia, proteinuria (daily protein loss, 9.3 g), haematuria with granular casts, impaired renal function, anaemia and thrombocytopenia (Box 1). Nephrotic syndrome was diagnosed. Further tests revealed a decreased serum concentration of complement components C3 and particularly C4, and markedly raised concentration of rheumatoid factor. However, tests were negative for antinuclear (ANA), anti-double-strand-DNA (anti-ds-DNA), antiglomerulo-basement-membrane and antineutrophil-cytoplasmic antibodies. A cryoglobulin test was positive (Box 2). Immunofixation electrophoresis of the cryoprecipitates showed monoclonal IgM/kappa and polyclonal IgG. A test for hepatitis C virus antibodies (anti-HCV) was then performed and was positive. Diagnosis: On Day 27 of admission, the patient was diagnosed with type II mixed cryoglobulinaemia associated with HCV infection. At that time, her blood pressure was still fluctuating between 230/130 mmHg and 180/100 mmHg, and pulmonary oedema and massive pleural effusions persisted, despite vigorous antihypertensive therapy with frusemide, intravenous glyceryl trinitrate, an α-adrenergic blocker and angiotensin-converting enzyme inhibitors. Repeated thoracocentesis was required to release massive effusions (initially transudative, but later haemorrhagic). Renal biopsy revealed diffuse glomerulonephritis with crescent formation. Management: Plasmapheresis was started on Day 27, along with pulse therapy of intravenous methylprednisolone (500 mg daily for 3 days). After five courses of plasmapheresis in 12 days, the hypertension and pulmonary oedema were controlled. The patient was discharged from hospital on Day 57 of admission. At discharge, serum creatinine level was 141 μmol/L (reference range [RR], 53–106 μmol/L), and she was taking prednisolone (25 mg), diltiazem (180 mg), spironolactone (75 mg) and doxazosin (8 mg) per day. Patient 2Presentation: In February, 2 years after Patient 1, a 77-year-old woman presented to our emergency department with a 1-day history of severe dyspnoea and orthopnoea. She had had hypertension for 3 years. On several occasions during the previous month, her blood pressure had risen to 200/120 mmHg. On examination, she was stuporous, with blood pressure of 200/110 mmHg, regular pulse of 112 bpm, and respiratory rate of 36 breaths per minute. She had engorged jugular veins, bilateral chest crackles, hepatomegaly, ascites and bipedal oedema. A chest radiograph showed bilateral diffuse haziness, and ECG showed a generalised low QRS complex. Blood gas analysis showed pH, 7.43 (RR, 7.35–7.45); Paco2, 3.9 kPa (RR, 4.7–5.3 kPa) and Pao2, 11.2 kPa (RR, 12.7–13.3 kPa) while breathing oxygen through a mask. Initial management: The patient was intubated and mechanically ventilated. Central venous pressure was 12 cmH2O. Echocardiography revealed concentric LV hypertrophy, normal LV ejection fraction, but impaired LV diastolic function. Blood pressure fell to 170–200/90–100 mmHg in 2 days, after diuretic and nitroprusside therapy, but pulmonary oedema and respiratory failure did not decrease, even after haemodialysis. She had massive ascites, bilateral pleural effusions, hypoalbuminaemia, proteinuria (daily protein loss, 3.5 g), haematuria, poor renal function, anaemia and thrombocytopenia (Box 1). Nephrotic syndrome was diagnosed. Levels of both C3 and C4 were markedly low. ANA and anti-ds-DNA antibodies were negative, but rheumatoid-factor titre was markedly high. Cryoglobulin tests on Days 14 and 16 of admission were positive. Immunofixation electrophoresis of serum cryoprecipitates showed polyclonal IgG. HCV tests were negative for anti-HCV antibody but positive for serum HCV RNA. Diagnosis: The diagnosis of type III mixed cryoglobulinaemia associated with HCV infection was thus established on Day 16 of admission. At that time, the patient was still being mechanically ventilated and needed repeated thoracocentesis (effusions were initially yellow, but later became haemorrhagic). Computed tomography of the head showed multiple ischaemic infarcts. Management: Plasmapheresis and methylprednisolone pulse therapy (1 g intravenously daily for 3 days) were started on Day 17 of admission. The patient was extubated the next day and discharged from hospital 2 weeks later, after two courses of plasmapheresis. Serum creatinine level at discharge was 291.5 μmol/L. DiscussionHypertensive crisis with rapid-onset pulmonary oedema has been associated with coronary artery disease,2 renal artery stenosis3,4 and phaeochromocytoma,5 but a search of English-language articles in PubMed revealed no previous reports of an association with mixed cryoglobulinaemia. The latter is characterised by the presence of cold-precipitable cryoglobulins in serum. Underlying diseases include autoimmune and infectious diseases, especially hepatitis C.6-9 “Mixed” indicates that the cryoglobulins in these patients contain either monoclonal plus polyclonal immunoglobulins (type II cryoglobulinaemia), or polyclonal immunoglobulins (type III cryoglobulinaemia).7 In hepatitis C, cryoglobulins usually contain anti-HCV antibody, HCV RNA and IgM rheumatoid factor (ie, anti-IgG autoantibody).9 Cryoglobulins often trigger the formation of immune complexes, leading to immune-complex-type vasculitis, and produce cutaneous, vasomotor, renal and neurological symptoms.7-9 In our patients, factors precipitating the acute pulmonary oedema included hypertensive crisis, renal insufficiency and probably coronary insufficiency. The hypertensive crisis and pulmonary oedema had abrupt onset, progressed rapidly to respiratory failure, were accompanied by nephrotic syndrome, and responded poorly to antihypertensive and diuretic therapy. Our patients had had moderate hypertension for 3–10 years before their blood pressure suddenly rose markedly 2 to 3 months before the development of pulmonary oedema. Hypertension has been found in 37% of patients with cryoglobulinaemia.6 When the underlying disease of cryoglobulinaemia (eg, hepatitis C) flares up, levels of cryoglobulins (which contain HCV-RNA) increase, resulting in higher levels of circulating immune complexes, acute vasculitis and raised blood viscosity. These factors all precipitate the abrupt rise in blood pressure and pulmonary oedema, and explain the failure of conventional antihypertensive agents. Treating cryoglobulinaemia in our patients decreased renal vasculitis and ischaemia, fluid overload, and ultimately hypertension and pulmonary oedema. Coronary vasculitis, found at autopsy in 22% of patients with mixed cryoglobulinaemia,6 could contribute to pulmonary oedema. However, both our patients had a normal LV ejection fraction, suggesting that neither had significant coronary vasculitis. In both patients, acute pulmonary oedema developed in winter. Whether cold weather worsens hypertension by precipitating more cryoglobulins and increasing viscosity awaits further observation. In our patients, the initial features that led to the suspicion of vasculitis were petechiae, proteinuria and haematuria. Further testing revealed decreased complement levels (especially C4). These and other manifestations, including oedema, ascites, recurrent pleural effusions, cerebral infarction and glomerulonephritis, were caused by circulating cold-precipitable immune complexes and resulting vasculitis.6-9 Chronic HCV infection stimulates B-cell clones to proliferate and produce cryoprecipitable IgM antibody with rheumatoid-factor activity10 — an important laboratory index of HCV-related mixed cryoglobulinaemia. However, Patient 2 was negative for anti-HCV antibody, possibly because the sensitivity of the anti-HCV immunoassay, although high, is still suboptimal,11 or because the anti-HCV antibodies were concentrated in cryoprecipitates, and therefore not detectable by the serum assay.7 In both patients, the refractory hypertension and pulmonary oedema responded to plasmapheresis and methylprednisolone therapy. Conventional treatment of mixed cryoglobulinaemia aims to reduce circulating immune complexes through immunosuppression and plasmapheresis.8 Although immunosuppressive therapy alone could ameliorate vasculitis,12 plasmapheresis has shown hypotensive effect in immune-complex nephritis, including mixed cryoglobulinaemia.13 It also reduces plasma viscosity and improves perfusion of the affected organs,14 thus helping in patients with hypertension, encephalopathy or severe renal impairment. Neither patient had a history of blood transfusion, surgery, intravenous drug use or tattooing. They probably acquired HCV infection through non-sterile injections or acupuncture in local clinics, the most common source of HCV infection in Taiwan.15,16 With the increasing prevalence of hepatitis C,17 knowledge of its extrahepatic manifestations is important. Our two patients illustrate the association with mixed cryoglobulinaemia presenting with hypertensive crisis and acute pulmonary oedema. 1 Blood test results before diagnosis of cryoglobulinaemia Test Patient 1 Patient 2 Reference range Serum albumin (g/L) 24 24 32–45 Serum urea nitrogen (mmol/L) 13.9 36.8 2.9–8.2 Serum creatinine (μmol/L) 230 412 53–106 Haemoglobin (g/L) 59 98 120–160 Platelet count (× 109/L) 105 69 150–450 Complement 3 (g/L) 0.62 0.30 0.79–1.19 Complement 4 (g/L) 0.02 0.07 0.17–0.37 Rheumatoid factor 1:10 240 > 1:20 480 < 1:40 2 Cryoglobulin test Cryoglobulin particles float in the serum and precipitate at the bottom of the test tube at 4°C. The particles dissolve on rewarming of serum to body temperature.

Li-Na Lee MD, PhD · Shyh-Chyi Lo MD · Fu-Chi Lin BS · Hon-Ping Lau MD · Jih-Shuin Jerng MD · Pan-Chyr Yang MD, PhD

Gwendolyn L Gilbert,* Heather F Gidding,† Josephine Backhouse,‡ Peter B McIntyre§ * Director, ‡ Serology Project Officer, Centre for Infectious Diseases and Microbiology, Institute of Clinical Pathology and Medical Research, PO Box 533, Wentworthville, NSW 2145. † Epidemiologist, § Director, National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, University of Sydney, Westmead, NSW. LyngATicpmr.wsahs.nsw.gov.au To the Editor: Varicella vaccine was licensed in Australia in 2000. It is safe and efficacious and can prevent significant acute morbidity, significant out-of-pocket expenses for parents of affected children and, in Australia, prevents an estimated 450 admissions to hospital and one death per year.1 In September 2003, the National Health and Medical Research Council (NHMRC) recommended giving varicella vaccine to all children at 18 months of age.2 The net effect of childhood immunisation on varicella morbidity will depend on vaccination coverage. Modelling of Australian (unpublished National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases data) and UK3 seroprevalence data suggests that, for a range of vaccine efficacy estimates, 80% coverage is required before morbidity is reduced in adults. Accurate Australian coverage data are unavailable, as varicella vaccine is not funded under the National Immunisation Program.2 National serosurveillance can provide a practical alternative estimate of vaccine uptake. The first Australian national serosurvey of vaccine-preventable diseases, for which sera were collected between July 1996 and February 1999, established baseline seroprevalence for future assessment of the effects of changes in the vaccination schedule. It showed that the incidence of varicella was highest in 5–9-year-old children,4 indicating that infant vaccination would provide optimal protection. The second national serosurvey (with sera collected in 2002) is under way, with methods identical to those of the first.4 We compared varicella IgG levels in children aged 1–5 years, testing 459 sera in the first serosurvey and 380 in the second (see Box). The proportion with protective or equivocal antibody levels increased between the two serosurveys. The difference was statistically significant only in 3–4-year-olds, which is consistent with the greatest uptake when children enter childcare. Although there is some variation in varicella incidence over time, the changes are consistent with only modest vaccine uptake in the time that varicella vaccine has been available in Australia. The only other available estimates of varicella vaccine uptake are from GP consultations5 and reports to the Australian Childhood Immunisation Register (ACIR), which also indicate it is modest. For example, only 6.2% of children aged 4 years were reported to the ACIR to have received varicella vaccine (Brynley Hull, Epidemiologist, National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, personal communication). This is probably an underestimate, as there is no incentive for notifying varicella vaccination. However, a low vaccination uptake is consistent with use only in the private sector, and could lead to an increase in adult morbidity (despite an overall reduction in infection rates) because of a higher average age of infection (unpublished National Centre for Immunisation Research data). Unless vaccine is provided in the routine immunisation program at no cost to parents, uptake is unlikely to meet the 80% target required to reduce disease burden in all ages.3 Varicella IgG seroprevalence in preschool children in the 1st and 2nd national serosurveys 1st serosurvey, July 1996 to February 1999 2nd serosurvey, 2002 Age group No. Positive Negative Equivocal* No. Positive Negative Equivocal* Increase in positive and equivocal (95% CI) P 1 to < 3 years 138 27 (19.6%) 111 (80.4%) 0 152 34 (22.4%) 118 (77.6%) 0 2.8% (−6.6 to 12.2) 0.6 3 to < 5 years 214 72 (33.6%) 140 (65.4%) 2 (0.9%) 152 73 (48.0%) 79 (52.0%) 0 13.4% (3.3 to 23.6) 0.01 5 years 107 61 (57.0%) 46 (43.0%) 0 76 43 (56.6%) 33 (43.4%) 0 −0.4% (−15.0 to 14.1) 1.0 Total 459 160 (34.9%) 297 (64.7%) 2 (0.4%) 380 150 (39.5%) 230 (60.5%) 0 4.2% (-2.4 to 10.8) 0.2 *Sera giving equivocal results by enzyme immunoassay were retested and most were resolved by immunofluorescence (IF). These results represent the few that were still equivocal by IF and are probably low-titre positive results.

Gwendolyn L Gilbert · Heather F Gidding · Josephine Backhouse · Peter B McIntyre

Sirus Naraqi, an inspiring and warm-spirited doctor with a deep commitment to bettering the lives of the underprivileged, died in Sydney on 18 August 2004, after a two-year illness. Sirus Naraqi spent much of his free time visiting remote areas of Papua New Guinea, providing medical treatment and giving advice to Baha’i communities. (Reproduced with permission from the Baha’i World News Service.) Born in Persia on 30 September 1942, Sirus Naraqi served as a general practitioner to the Persian army before emigrating to America in 1969. There he completed postgraduate training at the University of Chicago and the University of Illinois, followed by numerous consultant physician and academic appointments. Sirus used his interest in infectious diseases to express his strong humanitarian desire to serve in areas of greatest need, such as Papua New Guinea (PNG), where he took up the Chair of Medicine at the University of PNG in 1983. During his time at the university, he led major research projects on severe forms of malaria, snakebite and meningitis. His warmth and style were important in preparing junior colleagues for positions of leadership. Because of its research and educational programs, the university’s Faculty of Medicine achieved international recognition. In 1998, after Sirus had spent 15 fruitful years in PNG, the University of Sydney appointed him Professor of Medicine and Associate Dean at Nepean Hospital, Penrith. Sirus had a lifelong commitment to community service. This included continuing participation in public debate; work with the World Health Organization on tuberculosis, malaria and HIV/AIDS; research and rural health work in PNG; and promotion of international human rights, literacy, hygiene and nutrition for the underprivileged. He also held numerous positions of leadership within the Baha’í congregation. The Queen made Professor Naraqi a Commander of the British Empire in 1998 for his service to PNG. The entirety of Sirus — his personal and professional actions — was inspired and strengthened by his Baha’i faith, an inclusive belief that expresses the oneness of humanity and the permanence of the human spirit, and that considers work in the spirit of service to others as worship of God. As a former colleague in PNG said, Sirus was the embodiment of equanimity, graciousness, clarity and generosity. Sirus was treasured by many people. Medical students respected his generosity of spirit and his dedication to teaching and to the profession. He did not seek effect or popularity. He was a world citizen who gave respect spontaneously and received it in return. His academic colleagues delighted in his integrity, commitment, firm principles and intellectual capacity. He is survived by his wife Mitra and children Ladan, Naysan, Anisa and Gulita.

Stephen R Leeder

To the Editor: We report an unusual case of Ross River virus (RRV) disease in a 7-year-old child. The patient presented to her general practitioner with fever, rash and pain in the lower limbs. Swelling of the joints of the hands and left knee was found, with a widespread rash that covered the trunk, limbs and face. The rash comprised lesions of varying types, including maculopapular, vesicular and petechial lesions (Box). Rash in a child with Ross River virus disease The general practitioner transferred the patient to the state tertiary paediatric service. No antibiotics were given before transfer. On arrival at Princess Margaret Hospital for Children, Perth, the patient was unwell, with a fever of 38°C. A provisional diagnosis was made of septicaemia (probably meningococcal), and treatment was begun with intravenous ceftriaxone. Extensive investigations were performed, but results of all initial serological, polymerase chain reaction and culture investigations were negative. Rheumatology review was requested because of the prominent arthritic component of the illness. This revealed widespread polyarthritis, and the illness was felt to be a reactive or post-infectious process. The child’s family raised the possibility of RRV disease, as her grandmother had had this disease several years previously, and the child had stayed overnight at her grandmother’s home in a coastal lake area 2 weeks before disease onset. The area had abundant mosquitoes, as well as kangaroos, which are vertebrate amplifiers for RRV.1 Serological tests for RRV were performed 3 days after admission, and were negative for IgG and positive for IgM. Repeat serological testing during convalescence showed a fourfold rise in IgG titre (from 80 to 320), confirming the diagnosis of RRV disease. The patient’s rash decreased over several days. She had persistent synovitis in the left knee at review 3 weeks after admission. At review at 8 weeks all symptoms and signs had resolved, and she had full function. This case highlights the fact that, while RRV disease with severe symptoms and arthritic manifestations is uncommon in children, it nevertheless should still be considered in the differential diagnosis of children with a febrile and arthritic disease.1,2 This child’s illness appears to have been a reactive vasculitis and polyarthritis, which, while well recognised with other infections, is not well described in association with RRV disease in children. RRV arthritis is caused by joint infection, and treatment is currently based on empirical anti-inflammatory regimens. During the recent RRV disease epidemic in Western Australia, 1174 notifications for RRV disease were received between 1 October 2003 and 31 March 2004. Of these, 21 patients were aged 15 years or younger. Thus, while RRV disease is an infrequent illness in children, it does occur, and should be considered in the differential diagnosis of a child who presents with a febrile illness, rash and joint symptoms from an area with known autochthonous transmission of RRV.

Kynan T Feeney · Kevin J Murray · Amanda J Whittle · Gary K Dowse

The emergence and spread of multidrug-resistant pathogens has increased substantially over the past 20 years. Over the same period, the development of new antibiotics has decreased alarmingly, with many pharmaceutical companies pulling out of antibiotic research in favour of developing “lifestyle” drugs. Reasons given for withdrawing from antibiotic development include poor “net present value” status of antibiotics, changes in regulations requiring larger drug trials and prolonged post-marketing surveillance, clinical preference for narrow-spectrum rather than broad-spectrum agents, and high new-drug purchase costs. Major improvements in infection control in Australia are needed to prevent further spread of resistant clones, buying some time to develop urgently needed new antibiotic agents. Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. A change in the health and research culture is needed to improve cooperation between public, academic and private sectors.

Patrick G P Charles MB BS, FRACP · M Lindsay Grayson MD, FRACP, FAFPHM

Trial: Hatakka K, Savilahti E, Pönkä A, et al. Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial. BMJ 2001; 322: 1327-1329. QuestionIn children attending daycare centres (population), does long term consumption of probiotic milk (intervention) prevent infections (outcome)? Trial detailsObjective: To examine whether long term consumption of a probiotic milk could reduce gastrointestinal and respiratory infections in children in daycare centres. Design: Randomised, double-blind, placebo-controlled study over 7 months. Setting: 18 daycare centres in Helsinki, Finland. Participants: 571 healthy children aged 1–6 years; 282 in the intervention group (mean age, 4.6 years; SD, 1.5 years) and 289 in the control group (mean age, 4.4 years; SD, 1.5 years). Intervention: Milk with or without Lactobacillus GG. Average daily consumption of milk in both groups was 260 mL. Main outcome measures: Number of days with respiratory and gastrointestinal symptoms, absences from daycare because of illness, respiratory tract infections diagnosed by a doctor, and courses of antibiotics. Results: Children in the Lactobacillus group had fewer days of absence from daycare because of illness (4.9 days [95% CI, 4.4–5.5] versus 5.8 days [95% CI, 5.3–6.4]; absolute difference, 16% [P = 0.03]). Corresponding age-adjusted findings were 5.1 days (95% CI, 4.6–5.6) for the Lactobacillus group versus 5.7 days (95% CI, 5.2–6.3) for the control group; age-adjusted difference, 11% (P = 0.09). There was also a relative reduction of 17% in the number of children having respiratory infections with complications and lower respiratory tract infections (unadjusted absolute reduction, 8.6%; 95% CI, -17.2% to -0.1%; P = 0.05; age-adjusted odds ratio, 0.75; 95% CI, 0.52–1.09; P = 0.13) and a 19% relative reduction in courses of antibiotic for respiratory infection in the Lactobacillus group (unadjusted absolute reduction, -9.6%; 95% CI, -18.2 to -1.0; P = 0.03; adjusted odds ratio, 0.72; 95% CI, 0.50–1.03; P = 0.08). Conclusions: Lactobacillus GG may reduce respiratory infections and their severity among children in daycare. The effects of the probiotic Lactobacillus GG were modest but consistently in the same direction. CommentaryRationale for the trialChildren attending daycare centres are more likely to suffer gastrointestinal and respiratory infections than children cared for at home or in small family groups.1 There are public health and economic consequences, including direct medical costs and the indirect cost of parents taking time off work to care for sick children.2 Studies support the use of probiotics to reduce the incidence of antibiotic-associated diarrhoea3,4 and to hasten recovery from rotavirus diarrhoea.5 Probiotic bacteria may have a beneficial effect on the host immune response by altering intestinal microbial balance. Trial methodsThis was a randomised, double-blind, placebo-controlled trial carried out in 18 daycare centres in children aged 1–6 years over 7 months, which included winter. Daycare staff, parents, children and investigators were blinded or unaware of treatment allocation. Randomisation was effectively concealed, as children were allocated to intervention or control groups by a computer-generated block-randomisation procedure, with stratification on the basis of age and daycare centre. The randomisation procedure was successful in equalising baseline characteristics between placebo and active groups, apart from the control group having slightly younger children and more children with more than five recent infections. There was excellent follow-up, with nearly 90% of children completing the study, although reasons for withdrawal were not stated. Groups were analysed on an intention-to-treat basis. A random selection of 100 faecal samples was assessed to confirm compliance. Outcome measures included days of respiratory or gastrointestinal symptoms, days of absence from daycare because of illness, and number of upper respiratory tract infections complicated by lower respiratory tract infections. In summary, this trial was well designed and conducted. The average compliance in both groups was 60%. Unfortunately, there was a difference in age distribution between the two groups after randomisation. The investigators decided before the study that a minimum clinically relevant beneficial effect would be a 20% difference between the groups. Thus, based on previously reported episodes of illness in children attending daycare, they used a power calculation to estimate that, to detect a 20% difference with a power (or sensitivity) of 90% with 95% confidence, they needed to enrol 250 children per group. They were able to achieve this goal. New informationThe authors claim that milk containing Lactobacillus GG slightly reduced the incidence of respiratory infections and antibiotic treatment in children. The effect of probiotics was modest when adjustments were made for age. Of the measured variables — days of any illness, days of respiratory or gastrointestinal symptoms, and absence because of illness — only for absence because of illness was there a difference between the intervention and control groups that approached statistical significance, although there was a trend towards less illness for the other variables in the Lactobacillus group. It is useful to look at the tables of results in the article in question. Table 2 presents the raw data, and it is clear from scanning both the unadjusted and age-adjusted results that the effect is modest at best. The unadjusted days of absence because of illness was 4.9 days in the probiotic group and 5.8 days in the control group (ie, an improvement of 0.9 days); when adjusted for age, the difference between the probiotic group and the control group was 0.6 days. This raises the question of whether a reduction of 0.6 days in duration of absence because of illness is actually clinically useful. When the episodes of illness were diagnosed by a doctor (Table 3 of the article), the overall episodes of illness and courses of antibiotics prescribed for infections were significantly reduced for the probiotic group. Of all antibiotic courses prescribed, there were 119 in the probiotic group versus 144 in the control group, with an absolute percentage reduction of 8.0% (95%CI, -16.6 to 1.0). The P value was 0.07, thus approaching, but not reaching, statistical significance. However, the age-adjusted results (reported as odds ratios) are less impressive and the statistical significance of these findings is further reduced, with a 95% confidence interval crossing unity, and a P value of 0.17 — not significant. The results are thus entirely consistent with a chance difference. Implications for clinical practice This is the first large, high quality study to examine this interesting research question.6 There were no reported harmful effects of the Lactobacillus GG; costs were not fully explored in the report. The author of the accompanying editorial stated that probiotics “show promise but bigger studies are needed”.7 This is not entirely correct, as the study was adequately powered to detect a 20% difference and it failed to report a convincing clinical effect. However, it is likely that further clinical research will be undertaken in this and related areas, such as the use of probiotics to hasten recovery from acute gastroenteritis in children and the prevention of antibiotic-associated diarrhoea.

Mark G Coulthard MB BS, FRACP · Craig M Mellis MD, MPH, FRACP

To the Editor: Pertussis (whooping cough) is a readily transmissible respiratory infection that may cause severe respiratory illness. The burden of severe pertussis affects infants, often resulting in hospitalisation (especially those aged under 6 months) and death (1 in every 200 patients aged under 6 months).1,2 In Australia, there were nine deaths from pertussis between 1993 and 1997, predominantly in young infants, and a further five young infant deaths during the 2001–2002 epidemic.3,4 Epidemics occur every 3 to 4 years.2 Pertussis cases and hospitalisations in children aged under 6 months continue to occur in south-east Queensland, with 19 notifications since January 2003. There has been a shift in the epidemiology of pertussis in Australia and the United States, from a disease of young children to a disease of adolescents and adults of child-bearing age.1,5 In Australia, there has been a preponderance of pertussis notifications in adult females.5 Pertussis vaccine is already provided free to children at ages 2, 4 and 6 months, 4 years and 15 years, as part of the National Immunisation Program.2 However, young infants remain incompletely protected by vaccination, as the third, completion dose of the primary course of pertussis vaccination is not given until 6 months of age. A national study of hospitalised infant pertussis cases in 2001 indicated that parents were the presumptive source of pertussis infection for their children in more than 50% of cases.6 This has led the National Health and Medical Research Council to recommend that both parents should receive a (once-only) adult booster dose of pertussis vaccine, either when planning pregnancy or as soon as possible after delivery of an infant.2 The cost of the vaccine is about $30. As yet there is no suggestion that funding will be made available to provide this vaccine to all new parents as part of the National Immunisation Program. However, the amount is not a high price to pay for the protection of a new baby and its parents, particularly now that new parents will receive additional financial support from the federal government. The potential exists to promote opportunistic maternity-ward-based administration of this vaccine to post-partum mothers and their partners. We encourage all medical practitioners, especially obstetricians and paediatricians, to discuss this important issue with parents.

Brad J McCall · Rod P Davison · Michael D Nissen · Clare B Nourse

Patrick G P Charles,* Michelle Ananda-Rajah,† Paul D R Johnson,‡ M Lindsay Grayson§ Infectious Diseases Physician, † Infectious Diseases Registrar, ‡ Deputy Director, § Director, Infectious Diseases, Austin Health, PO Box 5555, Heidelberg, VIC 3084. Patrick. CharlesATaustin.org.au To the Editor: We agree with Buising and colleagues1 that, in terms of predicting clinical outcomes, the Pneumonia Severity Index (PSI) developed by Fine and colleagues2 is heavily weighted towards age and pre-existing comorbidities. However, we disagree with both their proposed “solution” and the concept on which it appears to be based. Although the current Australian antibiotic guidelines suggest that admission to the intensive care unit should be considered mainly for patients with class V community-acquired pneumonia (CAP),3 a review of the data of Fine and colleagues suggests that patients in both class IV and class V are most likely to need this type of care. In the PSI’s validation cohort of 38 039 patients, 73% of those requiring intensive care fitted these classes.2 Thus, by simply modifying the current antibiotic guidelines to include patients with CAP in either class IV or V as being at greatest risk of needing intensive-care admission, the recommendations would be accurate. By comparison, Buising and colleagues advocate using the modified British Thoracic Society (BTS) rule, which was validated in only 244 patients.4 While this approach may have some future merit, we believe there are insufficient data to advocate its use at present. A comparison of the PSI and original BTS criteria found that PSI classes IV and V were more sensitive at predicting need for intensive-care admission.5 Secondly, we are concerned about the suggestion by Buising and colleagues that young patients with severe CAP who are not in PSI class V could have worse outcomes if they do not receive broad-spectrum antibiotics.1 This implies that severe CAP is more likely to be due to unusual or resistant pathogens. This is not supported by available evidence. Instead, early clinical consideration of the likely pathogens and the potential use of new diagnostic “point of care” tests (eg, pneumococcal and Legionella urinary antigen assays and analysis of throat swabs by polymerase chain reaction for respiratory viruses and “atypical” pathogens) are likely to be of greatest benefit in empirical antibiotic prescribing. Although CAP is a common admission diagnosis, there are very few published Australian studies defining its aetiology, optimal treatment and clinical outcomes. We are currently undertaking a large prospective study (the Australian Community-Acquired Pneumonia Study) at six major hospitals in three states to address these issues. Results should be available in late 2005.

Patrick G P Charles · Michelle Ananda-Rajah · Paul D R Johnson · M Lindsay Grayson

Kirsty L Buising,* Karin A Thursky,† James F Black,‡ Graham V Brown§ * Clinical Research Fellow, † Physician, ‡ Head of Epidemiology, § Head, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, VIC 3050. Kirsty.buisingATmh.org.au In reply: We thank Charles and colleagues for their comments. The modified British Thoracic Society (mBTS) severity score for patients with community-acquired pneumonia (CAP) has been validated in more than one study (the largest involving 1068 patients from three countries1) and is recommended by the British and American thoracic societies. It predicts requirement for intensive care with comparable sensitivity to the Pneumonia Severity Index (PSI) score (using classes IV and V)2 (unpublished data), and is easy to use, requiring four variables rather than 21. The study cited by Charles and colleagues showing that the BTS severity score was less sensitive used an older version of the tool. We believe the mBTS score represents a reasonable, simple alternative tool to identify severe pneumonia, although neither score should replace clinical judgement. Caution is needed when relying on a scoring system that may give false reassurance about patients not recognised to be at risk. Early recognition of severe illness enables early intensive-care intervention, which is associated with better outcome.3 The major guidelines for management of CAP recognise the entity of severe pneumonia and recommend broader-spectrum antibiotic therapy.4-6 Whether the spectrum of pathogens in severe pneumonia differs from that in mild pneumonia is not yet clear, as data are conflicting.7,8 However, a percentage of patients with severe pneumonia will have more resistant or unusual pathogens. Inadequate antibiotic therapy for patients with severe pneumonia is associated with higher mortality. For intensive-care patients, where there is less perceived “room for error”, a strategy of broad empirical antibiotic therapy and early narrowing to directed therapy is usually promoted.

Kirsty L Buising · Karin A Thursky · James F Black · Graham V Brown

Although cutaneous leishmaniasis is occasionally seen in Australia in overseas travellers and migrants, visceral leishmaniasis has been reported rarely and only in people who were immunocompromised. We describe an 18-year-old immunocompetent man who presented with pancytopenia and a 2-week history of fever and lethargy a year after visiting the Greek Islands. Visceral leishmaniasis was diagnosed after a bone marrow biopsy showed protozoa, and the patient responded well to treatment with liposomal amphotericin. To our knowledge, this is the first case of visceral leishmaniasis in an immunocompetent patient in Australia. The leishmaniases are a group of infections caused by protozoa belonging to the genus Leishmania. We report an immunocompetent patient with visceral leishmaniasis, probably acquired in Greece. As far as we are aware, this is the first report of visceral leishmaniasis in an immunocompetent person in Australia. Clinical recordAn 18-year-old man of Greek parentage presented with a 2-week history of dry cough, diarrhoea, lethargy, anorexia and fever. He had a past history of cutaneous vasculitis of uncertain aetiology and acne vulgaris. He was not taking any regular medication. On examination, the patient’s temperature was 37.5°C, but no other abnormalities were evident. Investigations (Box 1) showed that he had pancytopenia, raised erythrocyte sedimentation rate and hypergammaglobulinaemia. The raised rheumatoid factor and anti-dsDNA levels were thought to be most likely related to inflammation. Treatment was begun with intravenous ceftazidime and gentamicin because of the febrile neutropenia. A bone marrow biopsy performed on Day 2 to investigate the cause of the pancytopenia showed cellular bone marrow with relative erythroid hyperplasia. Multiple blood cultures gave negative results. As the fever persisted, roxithromycin was added to the regimen on Day 4, and vancomycin on Day 8. Serological testing was negative for multiple infections, including HIV infection, but positive for parvovirus B19 IgM, although negative for IgG, on Days 1 and 9. The provisional diagnosis was parvovirus-related pancytopenia. The patient was discharged without antibiotic therapy 12 days after admission, as he felt well, although he still had a fever. A month after discharge, the pancytopenia persisted. Repeated parvovirus B19 serological testing was negative for both IgM and IgG. A second bone marrow biopsy at this time revealed occasional macrophages containing amastigotes (the resting intracellular stage of leishmaniae, formerly known as Leishman–Donovan bodies; Box 2). Review of the first bone marrow biopsy specimen failed to show any protozoa. Further questioning revealed that the patient had visited Greece for a 5-week holiday a year before presentation. A diagnosis was made of visceral leishmaniasis, probably acquired through sandfly bites. The patient was treated with liposomal amphotericin B, 250 mg daily for 4 consecutive days and then weekly for 2 weeks. The diagnosis was confirmed when promastigotes (the motile form of the organism) were successfully cultured. Leishmaniasis is not notifiable in Australia. The patient’s blood count returned to normal 2 months after starting treatment with amphotericin. He remained well 2 years after ceasing treatment. DiscussionThis case illustrates an unusual cause of pancytopenia in Australia. It is important to consider leishmaniasis as a differential diagnosis when the patient has a relevant travel history, as in this case. The diagnosis was not made on the first bone marrow biopsy, as smears from bone marrow usually contain few organisms, and have a sensitivity of 80%–85%.1 The major clinical syndromes caused by the genus Leishmania are cutaneous, mucosal and visceral leishmaniasis. Leishmaniasis is transmitted by Phlebotomus or Lutzomyia sandflies and infects dogs and foxes as well as humans. Numerous cases of cutaneous leishmaniasis have been reported in Australia,2,3 but to our knowledge only three cases of visceral leishmaniasis — one in a renal transplant patient4 and two in patients with HIV infection.5 Visceral leishmaniasis occurs in the Mediterranean region, northern Africa, the Middle East and central Asia, China and parts of South America.6 The differentiation of species causing leishmaniasis is complex and is performed only in reference laboratories. Visceral leishmaniasis is caused by Leishmania donovani, L. infantum or L. chagasi. L. infantum is the common species in the Mediterranean littoral and probably the cause of our patient’s infection. The incubation period of visceral leishmaniasis is usually 2–8 months. Many infections are subclinical, but the classic presentation is with fever, weight loss, hepatosplenomegaly, pancytopenia and hypergammaglobulinaemia. The definitive diagnosis depends on demonstrating either amastigotes in tissue or promastigotes in culture. Splenic puncture is the most sensitive means of obtaining a diagnosis, but biopsy of the bone marrow and liver is almost as good. In immunosuppressed individuals, promastigotes can sometimes be cultured from the buffy layer of centrifuged blood, and amastigotes can be seen in macrophages in biopsy specimens from various tissues. Testing for antileishmanial antibodies is not generally available and may be difficult to interpret. Pentavalent antimony compounds have been used to treat leishmaniasis for decades, but often have severe side effects, and resistance is developing.7 The aminoglycoside aminosidine (also known as paromomycin) is also effective when used either alone or in combination with an antimonial compound.7 Amphotericin can achieve 98% long-term cure in both antimonial-unresponsive and previously untreated patients.7 Lipid formulations of amphotericin are the most active antileishmanial agents.8 Although leishmaniasis is rare in Australia, it needs to be considered as a possible differential diagnosis of pancytopenia, remembering that the disease can present up to several years after return from an affected area. If untreated, visceral leishmaniasis is potentially fatal. 1 Investigations in a patient with visceral leishmaniasis Investigation Result Reference range Haemoglobin level (g/L) 82 135–175 Total white cell count (cells/L) 2.2 × 109 4–11 × 109 Neutrophil count (cells/L) 0.8 × 109 2.0–7.5 × 109 Platelet count (cells/L) 106 × 109 150–400 × 109 Erythrocyte sedimentation rate (mm/h) 120 0–15 Antinuclear antibody titre 1/160 < 1/160 Anti-dsDNA level (IU/mL) 10 < 8 Rheumatoid factor level (kIU/L) 240 < 20 IgG level (g/L) 19.1 6.5–16.0 IgA level (g/L) 4.3 0.6–4.0 2 Bone marrow biopsy in visceral leishmaniasis Light micrograph of bone marrow, showing macrophages containing amastigotes characteristic of Leishmania spp. Amastigotes are the non-flagellated intracellular stage of the protozoan, formerly known as Leishman–Donovan bodies. They appear as spherical or oval organisms 2–6 μm in length that contain two darker-staining organelles — a nucleus and a kinetoplast (arrow). The latter is a distinct region of the mitochondria containing mitochondrial DNA. (Giemsa stain; scale bar = 10 μm.) Transmission electron micrograph of bone marrow, showing an amastigote with a kinetoplast characteristic of Leishmania spp. (arrow). (Scale bar = 1 μm.)

Oui Ju MB BS · David I Grove MD, FRACP, FRCPA · Wilfrid J Jaksic FRACP · Geoffrey W Dart FRACP, FRCPA

Anton Y Peleg,* Wendy J Munckhof† * Infectious Diseases Registrar, Alfred Hospital, Prahran, VIC 3181; † Specialist in Infectious Diseases and Microbiology, Infection Management Service, Princess Alexandra Hospital, Brisbane, QLD. A. PelegATalfred.org.au To the Editor: Infection with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is emerging in many countries, including Australia.1 We report the first case of fatal necrotising pneumonia caused by CA-MRSA in Australia. A previously well 21-year-old Aboriginal man presented to the emergency department with fever and a productive cough. He had no known risk factors for sepsis (such as immunosuppression, diabetes, HIV infection, alcoholism, asplenia or recent influenza) and no history of hospitalisation in the previous 12 months. Chest x-ray revealed left mid-zone consolidation. He was prescribed amoxycillin–clavulanate and discharged. Two days later, the patient re-presented, with rigors, haemoptysis and agitation. Examination revealed a respiratory rate of 38 breaths per minute, oxygen saturation of 79% breathing room air, temperature of 38.7°C, sinus tachycardia (135 beats per minute), and a systolic blood pressure of 80 mmHg. Respiratory examination revealed diffuse coarse crepitations. No other source of infection was identified. The patient required intubation, mechanical ventilation and inotropic support. Sputum and blood samples were taken for culture, and empirical treatment was begun with intravenous ceftriaxone, erythromycin and a single dose of gentamicin and rifampicin. Initial investigations showed leukopenia (2.3 × 109/L; reference range [RR], 3.9–12.7 × 109/L), acute renal failure with a serum creatinine level of 0.18 mmol/L (RR, 0.06–0.11 mmol/L), and severe metabolic and respiratory acidosis (pH, 7.19; RR, 7.38–7.43). The following day, blood and sputum cultures showed gram-positive cocci resembling staphylococci, and intravenous flucloxacillin was added to the antibiotic regimen. Repeat chest x-ray revealed bilateral necrotising pneumonia. Despite resuscitation efforts, the patient died 48 hours after admission. Susceptibility testing of blood and sputum isolates subsequently confirmed MRSA. The isolate was sensitive to erythromycin, clindamycin, gentamicin, ciprofloxacin, tetracycline, vancomycin, rifampicin and fusidic acid. Methicillin resistance was confirmed by detection of the mecA gene by polymerase chain reaction (PCR). Further PCR testing of the isolate revealed the Panton–Valentine leukocidin (pvl) gene, an important virulence factor that has been associated with necrotising pneumonia2 and death,3 and is rarely found in methicillin-susceptible S. aureus or hospital-acquired MRSA isolates.1,2,5 Typing of the isolate by pulsed-field gel electrophoresis showed that it was the recently described “R” pulsotype of CA-MRSA, or “Queensland clone”.4 This clone was first noted in the white population in south-east Queensland in 2000, and is uncommon in Aboriginal people.4 Most CA-MRSA infection in Aboriginal people is caused by WA-MRSA, which may be less virulent than the Queensland clone of CAMRSA as it lacks the Panton–Valentine leukocidin.5 This is the first reported case of fatal necrotising pneumonia caused by CA-MRSA in Australia and illustrates the invasive nature of this infection. Thus far, CA-MRSA has predominantly caused skin and soft tissue infections, but the incidence of life-threatening sepsis is increasing. The first case of severe pneumonia caused by CA-MRSA in Australia was reported in early 2003.6 Fatal cases of necrotising pneumonia caused by CA-MRSA have also been described in the United States3 and France,7 and this presentation is becoming a particular feature of this organism. Clinicians should consider the possibility of CA-MRSA in any patient presenting to hospital with severe staphylococcal sepsis or pneumonia and should consider including parenteral vancomycin in the initial empirical therapy, particularly in geographic locations where CA-MRSA has been reported and in ethnic groups at increased risk.

Anton Y Peleg · Wendy J Munckhof

Lloyd K Morgan General practitioner (retired), PO Box 150, Lorne, VIC 3232. lloydmorganATiprimus.com.au To the Editor: O’Leary et al1 are pessimistic about the value of antibiotic treatment for leptospirosis, based on an inconclusive Cochrane review2 and no proven mortality decrease. Yet we can be more optimistic, given the efficacy of prophylactic doxycycline (soldiers in Panama were 95% protected by 200 mg once-weekly3), the susceptibility of leptospira to various antibiotics in vitro (especially penicillin, but not erythromycin4), and the existence of a Herxheimer reaction with penicillin,5 which indicates in-vivo activity. The Cochrane review2 was of randomised controlled trials of confirmed cases. It included 75 patients given antibiotics and 75 given placebo. Penicillin (61 patients) and doxycycline were not compared. The time from symptom onset to starting antibiotics was stated in only two trials (9 and 2 days). Nevertheless, the review concluded that penicillin or doxycycline may do more good than harm. In the spirochetaemic phase of leptospirosis (Days 4–7), vasculitis causes multiorgan failure. Successful treatment with antibiotics seems likely if commenced within 2 days of symptom onset, before generalised vasculitis is irreversible. Unfortunately, early diagnosis and efficacy assessment is difficult because symptoms are protean and non-specific, no rapid laboratory test exists, the condition is mild and self-limited in most cases, and mortality varies from zero to 7%. A high index of suspicion is essential so that antibiotics can be commenced empirically. The consensus is that antibiotics should be commenced within 4 days. In one study, starting antibiotics within 7 days was associated with shorter illness, and if antibiotics were started within 2 days the shorter duration was highly significant (P = 0.006).6 Another trial showed penicillin commenced on Day 9 was beneficial, but antibiotics had been used before entry to the trial.2 Various penicillins and tetracyclines have seemed useful, but only oral doxycycline and intravenous benzylpenicillin are recommended. These are the first and second preferences, respectively, in Therapeutic guidelines antibiotic.7 In the case described by O’Leary et al,1 antibiotics were commenced on Day 3, but the penicillin dose was only half the recommended daily dose for leptospirosis. The vasculitis was probably terminal before the patient was transferred to Concord Hospital.

Lloyd K Morgan

A small number of Australian babies continue to acquire HIV infection unnecessarily The World Health Organization estimates that each year worldwide about 700 000 children are infected with HIV.1 Most of these infections occur through mother-to-child transmission in resource-poor settings, predominantly in Africa and Asia. Mother-to-child transmission rates of 30% continue to occur, despite the fact that this form of transmission is almost entirely preventable with antiretroviral therapy and formula feeding. The barriers to implementation of prevention strategies include restricted access to antenatal testing, cost and limited availability of antiretroviral therapy, poor workforce resources, and political obstacles, such as have occurred in South Africa.2 . . . the concerns about cost-effectiveness have largely been resolved . . . The outlook for babies born to HIV-positive mothers in high-income settings has improved dramatically. Most pregnant women with HIV infection in Western Europe or North America can expect an infection risk for their infant of less than 2%.3,4 This ability to interrupt perinatal transmission of HIV is, of course, only possible if the mother’s status is known. From 1998 to 2002, 103 pregnant Australian women were aware of their HIV-positive status. None of their infants was infected. During the same period, HIV was diagnosed in eight of the 15 infants born to mothers who became aware of their status only after giving birth.5 Overall, almost half the women in Australia with HIV infection known to have completed a pregnancy were unaware of their status before the birth of their baby.6 With this ignorance, no interventions can be offered. Despite the ready availability of prevention strategies, it appears that a small number of Australian babies continue to acquire HIV infection unnecessarily. The solution to this calamity is to prevent HIV infection in women and, when it does occur, to identify it before or during pregnancy. Unfortunately, national policies on antenatal screening are flawed. The Australian National Council on AIDS and Related Diseases recommends that “[pregnant] women found to be at higher risk of HIV . . . should be encouraged to undergo HIV antibody screening”, but does not explain the term “higher”.7 HIV antibody testing is now recommended for all pregnant women in the Northern Territory, New South Wales and Queensland, but the national guidelines continue to be followed in South Australia, Western Australia and Victoria. However, the facts show that existing practice fails to identify a number of preventable cases of mother-to-child transmission.8 The policy of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists is that HIV testing of pregnant women is the standard of care.9 Between 1995 and 1999, surveys indicated that rates of antenatal testing in Australia increased from 20%10 to 33%,11 and a recent survey suggests that the rate continues to increase slowly.12 Routine testing has been opposed on several grounds. There are quite reasonable concerns that routine testing might result in a degree of coercion and the conduct of testing without proper pre- and post-test counselling. Clearly, any recommendation to offer testing to all pregnant women would need to be accompanied by systematic strengthening of counselling and consent procedures. However, the strongest argument against routine antenatal testing has been that, given the low prevalence of diagnosed HIV infection in women, it is unlikely to be cost-effective. Our recent report challenges this position.13 We evaluated the cost-effectiveness of universal antenatal testing. We assumed that society would pay $39 000 per life-year gained, about twice the national average per-capita income. This value has been shown to result in efficient resource allocation.14 This is less than the cost per life-year gained for other screening programs currently under way in Australia, and is the valuation of a life-year gain used implicitly by the Australian Pharmaceutical Benefits Advisory Committee.15 The costs of universal testing — about $1.8 million — are offset by economic benefits for a prevalence of undiagnosed HIV of 0.0044%, or 1 in 23 000. The true prevalence is unknown, but available data suggest it is of this order. The major costs taken into account in our model were the training and time required for counselling about testing, and the pathology costs. The major benefit is that a young life might be extended by 60 or 70 healthy years. Many women in Australia with HIV infection were born overseas and are less likely to have comprehensive health insurance than those born here. Their access to antenatal care is thus limited. It is possible that women with undiagnosed HIV infection are currently over-represented among those missing the testing currently being done. If there were to be a uniform national approach to HIV testing, then education of the public, providers and clinic populations could be expected to improve the consent process. In the United States and Europe, anonymous HIV serological surveys among women giving birth in the 1980s gave way to recommendations for routine testing. Such surveillance of women giving birth has been seen as politically difficult in Australia.16 Given that concerns about cost-effectiveness have largely been resolved, the time has now come for public health and political courage to make it national policy that HIV testing be recommended for all women receiving antenatal care.

John B Ziegler FRACP, MD · Nicholas Graves PhD