William John Hannan McBride

Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of the Safety and Tolerability of IC51, an Inactivated Japanese Encephalitis Vaccine

BACKGROUND Japanese encephalitis (JE) is the most important mosquito-borne viral encephalitis and has a high case fatality rate. It is caused by Japanese encephalitis virus. Improved vaccines are urgently needed for residents in countries of endemicity, travelers, and the military. The aim of the present trial was to evaluate the safety and tolerability of IC51, Intercells Vero cell-derived, purified, inactivated JE vaccine. METHODS This was a randomized (3:1), double-blind, placebo-controlled, multicenter phase 3 trial. Healthy subjects were randomized to receive 2 doses of IC51 (n=2012) or placebo (n=663) at a 4-week interval. Adverse events following immunization (AEFI) were documented over a period of 2 months. RESULTS The rate of severe AEFI was similar in the IC51 group (0.5%) and the placebo group (0.9%). The rate of medically attended AEFI and all AEFI was also similar in the IC51 group and the placebo group. The same applied for all adverse events, including local and systemic tolerability. Importantly, there were no signs of acute allergic reactions. CONCLUSION The Intercell JE vaccine IC51 had a safety profile similar to that of placebo. These data, together with the immunogenicity data from a recent phase 3 trial, form the basis of application for licensure of this vaccine. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00605058.

Evaluation of dengue NS1 test kits for the diagnosis of dengue fever

Detection of the dengue NS1 antigen during the symptomatic phase of illness represents an important advance in the diagnosis of dengue fever. The sensitivity of 2 commercial kits was evaluated in a panel of 91 serum samples collected at defined intervals after onset of symptomatic dengue fever. The sensitivity of the Bio-Rad Platelia (Bio-Rad Laboratories, Marnes-La-Coquette, France) dengue NS1 assay was 73.6% (95% confidence interval [CI], 63.7-81.6). The Panbio Early ELISA (Panbio Diagnostics, Brisbane, Australia) had a sensitivity of 63.7% (95% CI, 53.5-72.9). Four samples were equivocal in the Panbio assay. The sensitivity of both assays was highest on the 2nd to 4th day after illness onset and in primary dengue infections. Both assays will be useful for the detection of dengue viral infections early in the course of the infection, especially in nonendemic countries.

Antifungal Therapy and Management of Complications of Cryptococcosis due to Cryptococcus gattii

BACKGROUND We describe antifungal therapy and management of complications due to Cryptococcus gattii infection in 86 Australian patients followed for at least 12 months. METHODS Patient data from culture-confirmed cases (2000-2007) were recorded at diagnosis, 6 weeks, 6 months, and 12 months. Clinical, laboratory, and treatment variables associated with raised intracranial pressure (ICP) and immune reconstitution inflammatory syndrome (IRIS) were determined. RESULTS Seven of 10 patients with lung infection received amphotericin B (AMB) induction therapy (6 with 5-flucytosine [5-FC] for a median of 2 weeks); median duration of therapy including azole eradication therapy was 41 weeks, with a complete/partial clinical response in 78%. For neurologic disease, 88% of patients received AMB, 78% with 5-FC, for a median of 6 weeks. The median total course was 18 months. Nine patients receiving fluconazole induction therapy were reinduced with AMB plus 5-FC for clinical failure. Raised ICP (31 patients) was associated with initial abnormal neurology, and neurologic sequelae and/or death at 12 months (both P = .02); cerebrospinal fluid drains/shunts were placed in 58% of patients and in 64% of 22 patients with hydrocephalus. IRIS developed 2-12 months after starting antifungals in 8 patients, who presented with new/enlarging brain lesions. Risk factors included female sex, brain involvement at presentation, and higher median CD4 counts (all P < .05); corticosteroids reduced cryptococcoma-associated edema. CONCLUSIONS Induction AMB plus 5-FC is indicated for C. gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks). Shunting was often required to control raised ICP. IRIS presents with cerebral manifestations.

Cutaneous chancroid in a visitor from Vanuatu

A 23‐year‐old woman from Vanuatu presented to an Australian hospital with a 3‐week history of a non‐healing ulcer on the lower leg. A swab was submitted for a multiplex polymerase chain reaction designed to investigate genital ulcerative conditions. Haemophilus ducreyi was detected and the gene product was subsequently sequenced, confirming the diagnosis of cutaneous chancroid. The lesion responded to intramuscular benzathine penicillin. This report adds further evidence that cutaneous chancroid should be considered in the evaluation of skin ulcers in the south Pacific.

The 1993 dengue 2 epidemic in Charters Towers, North Queensland : clinical features and public health impact

In 1993 an epidemic caused by dengue virus type 2 occurred in several North Queensland population centres. Charters Towers, estimated population 10,000, had 155 officially notified cases. An analysis of symptoms was undertaken using a random sample of 1000 residents to determine specificity of symptoms, the subclinical infection rate, and to establish the true extent of the epidemic. Retrospective diagnoses of dengue fever were based on the presence of both serum dengue 2 neutralizing antibody and presence of symptoms. An estimated 20% of the population had dengue fever. The rate of subclinical infections in this epidemic was 14.6%. There were no symptoms that were specific for dengue fever. Bleeding occurred more frequently in people who recalled a previous dengue infection during a dengue 1 epidemic 12 years earlier (55.6% vs. 16.8%, P = 0.003). Surveillance for future epidemics should be based on serological and virological confirmation of dengue virus infection amongst symptomatic patient.

Histoplasmosis in Australia: Report of 16 Cases and Literature Review

We describe 16 previously unreported patients with histoplasmosis from Queensland and northern New South Wales, Australia, and review all previous Australian reports, providing 63 cases in total to study (17 cases of acute pulmonary histoplasmosis, 2 cases of chronic pulmonary disease, and 44 cases of systemic disease, including 17 cases of single-organ infection and 27 instances of disseminated disease). All acute pulmonary disease was acquired in Australia, with 52% of systemic disease definitely autochthonous. Most cases of single-organ disease occurred in immunocompetent patients (76%), and were oropharyngeal (53%) in location. Forty-one percent of disseminated disease occurred in patients with human immunodeficiency virus (HIV). Patients with HIV had high rates of systemic symptoms, pancytopenia, fungemia, and hepatosplenomegaly. Oropharyngeal and adrenal involvement as well as systemic symptoms were prominent in immunocompetent patients with disseminated disease, with 6 of 7 cases of adrenal involvement leading to Addison disease. Most systemic disease was diagnosed by culture of Histoplasma capsulatum. Where serology was assessed in cases other than acute pulmonary disease, it was positive in only 32%. Prognosis for patients with single-organ disease was excellent. Disseminated disease was associated with recurrence in 30% and death in 37%. The results of this study confirm several previously known patterns of disease but also provide new insights into this rare but endemic condition in Australia. Abbreviation: HIV = human immunodeficiency virus.

Implications of Dengue Outbreaks for Blood Supply, Australia

Dengue outbreaks have increased in size and frequency in Australia, and transfusion-transmitted dengue poses a risk to transfusion safety. Using whole blood samples collected during the large 2008–2009 dengue epidemic, we estimated the risk for a dengue-infectious blood donation as ≈1 in 7,146 (range 2,218–50,021).

Severe Spotted Fever Group Rickettsiosis, Australia

We report 3 cases of spotted fever group rickettsial infection (presumed Queensland tick typhus) in residents of northern Queensland, Australia, who had unusually severe clinical manifestations. Complications included renal failure, purpura fulminans, and severe pneumonia. Clinical illness caused by Rickettsia australis may not be as benign as previously described.

Contribution of Dengue Fever to the Burden of Acute Febrile Illnesses in Papua New Guinea: An Age-Specific Prospective Study

Malaria is a major contributor to the burden of febrile illnesses in Papua New Guinea (PNG). Dengue fever (DF) is likely to contribute; however, its epidemiology in PNG is poorly understood. We performed a prospective age-stratified study in outpatient clinics investigating the prevalence of DF; 578 patients were enrolled, and 317 patients with a negative rapid diagnostic test (RDT) for malaria were tested for dengue. Malaria was confirmed in 52% (301/578, 95% confidence interval [CI] = 48-56%), DF was diagnosed in 8% (46/578, 95% CI = 6-10%), and 40% (95% CI = 36-44%) had neither diagnosis. Among the 317 malaria RDT-negative patients, 14% (45/317, 95% CI = 10-18%) had DF. The seroprevalence of dengue immunoglobulin G (IgG) was 83% (204/247, 95% CI = 78-87%), and no dengue hemorrhagic fever was seen. This study provides good evidence for the first time that DF is common in PNG and is responsible for 8% of fever episodes. The common occurrence of DF in a population with presumed previous exposure to dengue is an important observation.

Mycobacterium ulcerans infection in North Queensland: the ‘Daintree ulcer’

Background:  As the third most common mycobacterial infection in the world after tuberculosis and leprosy, Mycobacterium ulcerans is a major health and development problem that has become the focus of a World Health Organisation (WHO) initiative seeking to reduce the burden of this disease. The Daintree River catchment in north Queensland is an endemic focus for Mycobacterium ulcerans infection, known locally as the ‘Daintree Ulcer’. The aim of this study is to analyse the changing pattern of the disease over the last 44 years in the region.