Bart J. Currie

Melioidosis: Epidemiology, Pathophysiology, and Management

SUMMARY Melioidosis, caused by the gram-negative saprophyte Burkholderia pseudomallei, is a disease of public health importance in southeast Asia and northern Australia that is associated with high case-fatality rates in animals and humans. It has the potential for epidemic spread to areas where it is not endemic, and sporadic case reports elsewhere in the world suggest that as-yet-unrecognized foci of infection may exist. Environmental determinants of this infection, apart from a close association with rainfall, are yet to be elucidated. The sequencing of the genome of a strain of B. pseudomallei has recently been completed and will help in the further identification of virulence factors. The presence of specific risk factors for infection, such as diabetes, suggests that functional neutrophil defects are important in the pathogenesis of melioidosis; other studies have defined virulence factors (including a type III secretion system) that allow evasion of killing mechanisms by phagocytes. There is a possible role for cell-mediated immunity, but repeated environmental exposure does not elicit protective humoral or cellular immunity. A vaccine is under development, but economic constraints may make vaccination an unrealistic option for many regions of endemicity. Disease manifestations are protean, and no inexpensive, practical, and accurate rapid diagnostic tests are commercially available; diagnosis relies on culture of the organism. Despite the introduction of ceftazidime- and carbapenem-based intravenous treatments, melioidosis is still associated with a significant mortality attributable to severe sepsis and its complications. A long course of oral eradication therapy is required to prevent relapse. Studies exploring the role of preventative measures, earlier clinical identification, and better management of severe sepsis are required to reduce the burden of this disease.

Disseminated Penicillium marneffei: presenting illness of advanced HIV infection; A clinicopathological review, illustrated by a case report

&NA; Background Until recently Penicillium marneffei rarely caused human disease. It is now a frequently encountered opportunistic mycosis in HIV positive residents of, and travellers to, south‐east Asia. Aims To review aspects of clinical presentation, pathology, treatment, epidemiology and ecology of P. marneffei. To report a case of disseminated P. marneffei occurring in the Northern Territory which illustrates many typical clinical and pathological features of this infection. Case presentation A Burmese immigrant presented to Royal Darwin Hospital, Australia with a non‐specific, subacute, febrile illness and a diffuse papular rash. The etiological agent was Penicillium marneffei, disseminated in association with advanced HIV infection. The typical travel history and umbilicated papular rash were recognized on admission. Fungal stains of skin biopsies and touch smears facilitated rapid diagnosis, and early antifungal therapy resulted in clinical cure. Conclusions Early distinction of penicilliosis from other opportunistic mycoses, tuberculosis, Leishmaniasis, and molluscum contagiosum is critical for effective management. The characteristic histological and mycological properties of P. marneffei are easily recognizable if the diagnosis is considered. In view of geographic proximity, travel and immigration from endemic areas, Australia should expect further imported penicilliosis as illustrated by this case report.

Endemic Melioidosis in Tropical Northern Australia: A 10-Year Prospective Study and Review of the Literature

In a prospective study of melioidosis in northern Australia, 252 cases were found over 10 years. Of these, 46% were bacteremic, and 49 (19%) patients died. Despite administration of ceftazidime or carbapenems, mortality was 86% (43 of 50 patients) among those with septic shock. Pneumonia accounted for 127 presentations (50%) and genitourinary infections for 37 (15%), with 35 men (18%) having prostatic abscesses. Other presentations included skin abscesses (32 patients; 13%), osteomyelitis and/or septic arthritis (9; 4%), soft tissue abscesses (10; 4%), and encephalomyelitis (10; 4%). Risk factors included diabetes (37%), excessive alcohol intake (39%), chronic lung disease (27%), chronic renal disease (10%), and consumption of kava (8%). Only 1 death occurred among the 51 patients (20%) with no risk factors (relative risk, 0.08; 95% confidence interval, 0.01-0.58). Intensive therapy with ceftazidime or carbapenems, followed by at least 3 months of eradication therapy with trimethoprim-sulfamethoxazole, was associated with decreased mortality. Strategies are needed to decrease the high mortality with melioidosis septic shock. Preliminary data on granulocyte colony-stimulating factor therapy are very encouraging.

Epidemiology and Host- and Variety-Dependent Characteristics of Infection Due to Cryptococcus neoformans in Australia and New Zealand

A prospective population-based study was conducted in Australia and New Zealand during 1994-1997 to elucidate the epidemiology of cryptococcosis due to Cryptococcus neoformans var. neoformans (CNVN) and C. neoformans var. gattii (CNVG) and to relate clinical manifestations to host immune status and cryptococcal variety. The mean annual incidence per 10(6) population was 6.6 in Australia and 2.2 in New Zealand. Of 312 episodes, CNVN caused 265 (85%; 98% of the episodes in immunocompromised hosts) and CNVG caused 47 (15%; 44% of the episodes in immunocompetent hosts). The incidence of AIDS-associated cases in Australia declined annually (P<.001). Aborigines in rural or semirural locations (P<.001) and immunocompetent males (P<.001) were at increased risk of CNVG infection. Cryptococcomas in lung or brain were more common in immunocompetent hosts (P< or =.03) in whom there was an association only between lung cryptococcomas and CNVG. An AIDS-associated genetic profile of CNVN serotype A was confirmed by random amplification of polymorphic DNA analysis. Resistance to antifungal drugs was uncommon. The epidemiology of CNVN infection has changed substantially. Clinical manifestations of disease are influenced more strongly by host immune status than by cryptococcal variety.

The global distribution of Burkholderia pseudomallei and melioidosis: an update

While Southeast Asia and northern Australia are well recognized as the major endemic regions for melioidosis, recent reports have expanded the endemic zone. Severe weather events and environmental disasters such as the 2004 Asian tsunami have unmasked locations of sporadic cases and have reconfirmed endemicity in Indonesia. The endemic region now includes the majority of the Indian subcontinent, southern China, Hong Kong and Taiwan. Sporadic cases have occurred in Brazil and elsewhere in the Americas and in island communities such as New Caledonia, in the Pacific Ocean, and Mauritius in the Indian Ocean. Some of the factors that are critical to further elucidating the global distribution of Burkholderia pseudomallei and melioidosis include improved access to diagnostic laboratory facilities and formal confirmation of the identity of bacterial isolates from suspected cases.

Problems in Diagnosing Scabies, a Global Disease in Human and Animal Populations

SUMMARY Scabies is a worldwide disease and a major public health problem in many developing countries, related primarily to poverty and overcrowding. In remote Aboriginal communities in northern Australia, prevalences of up to 50% among children have been described, despite the availability of effective chemotherapy. Sarcoptic mange is also an important veterinary disease engendering significant morbidity and mortality in wild, domestic, and farmed animals. Scabies is caused by the ectoparasitic mite Sarcoptes scabiei burrowing into the host epidermis. Clinical symptoms include intensely itchy lesions that often are a precursor to secondary bacterial pyoderma, septicemia, and, in humans, poststreptococcal glomerulonephritis. Although diagnosed scabies cases can be successfully treated, the rash of the primary infestation takes 4 to 6 weeks to develop, and thus, transmission to others often occurs prior to therapy. In humans, the symptoms of scabies infestations can mimic other dermatological skin diseases, and traditional tests to diagnose scabies are less than 50% accurate. To aid early identification of disease and thus treatment, a simple, cheap, sensitive, and specific test for routine diagnosis of active scabies is essential. Recent developments leading to the expression and purification of S. scabiei recombinant antigens have identified a number of molecules with diagnostic potential, and current studies include the investigation and assessment of the accuracy of these recombinant proteins in identifying antibodies in individuals with active scabies and in differentiating those with past exposure. Early identification of disease will enable selective treatment of those affected, reduce transmission and the requirement for mass treatment, limit the potential for escalating mite resistance, and provide another means of controlling scabies in populations in areas of endemicity.

Intensity of Rainfall and Severity of Melioidosis, Australia

In a 12-year prospective study of 318 culture-confirmed cases of melioidosis from the Top End of the Northern Territory of Australia, rainfall data for individual patient locations were correlated with patient risk factors, clinical parameters, and outcomes. Median rainfall in the 14 days before admission was highest for those dying with melioidosis (211 mm), in comparison to 110 mm for those surviving (p = 0.0002). Median 14-day rainfall was also significantly higher for those admitted with pneumonia. On univariate analysis, a prior 14-day rainfall of ≥125 mm was significantly correlated with pneumonia (odds ratio [OR] 1.70 [confidence interval [CI] 1.09 to 2.65]), bacteremia (OR 1.93 [CI 1.24 to 3.02]), septic shock (OR 1.94 [CI 1.14 to 3.29]), and death (OR 2.50 [CI 1.36 to 4.57]). On multivariate analysis, rainfall in the 14 days before admission was an independent risk factor for pneumonia (p = 0.023), bacteremic pneumonia (p = 0.001), septic shock (p = 0.005), and death (p < 0.0001). Heavy monsoonal rains and winds may cause a shift towards inhalation of Burkholderia pseudomallei.

First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei.

Ivermectin is increasingly being used to treat scabies, especially crusted (Norwegian) scabies. However, treatment failures, recrudescence, and reinfection can occur, even after multiple doses. Ivermectin resistance has been documented for some intestinal helminths in animals with intensive ivermectin exposure. Ivermectin resistance has also been induced in arthropods in laboratory experiments but, to date, has not been documented among arthropods in nature. We report clinical and in vitro evidence of ivermectin resistance in 2 patients with multiple recurrences of crusted scabies who had previously received 30 and 58 doses of ivermectin over 4 and 4.5 years, respectively. As predicted, ivermectin resistance in scabies mites can develop after intensive ivermectin use.

Skin infections and infestations in Aboriginal communities in northern Australia

The most important skin infections in Aboriginal communities in central and northern Australia are scabies and streptococcal pyoderma. Scabies is endemic in many remote Aboriginal communities, with prevalences in children up to 50%. The cycles of scabies transmission underlie much of the pyoderma. Up to 70% of children have skin sores, with group A streptococcus (GAS) the major pathogen. Group A streptococcus is responsible for the continuing outbreaks of post‐streptococcal glomerulonephritis and acute rheumatic fever (ARF). The cycles of scabies transmission in dogs and humans do not appear to significantly overlap. Guidelines have been developed for community control of scabies and skin sores and successful community initiated coordinated programmes have occurred. The anthropophilic dermatophyte Trichophyton rubrum is ubiquitous in many communities, again reflecting living conditions. Other skin infections related to the tropical environment include melioidosis, nocardiosis, Chromobacterium violaceum and chromoblastomycosis. Sustainable and long‐term improvements in scabies, skin sores and GAS‐related disease and tinea require fundamental changes that address social and economic inequities and, in particular, living conditions and overcrowding.

Permethrin and ivermectin for scabies.

In a remote aboriginal community in tropical northern Australia, a mother comes to the health center with her 4-year-old son, who has multiple sores on the skin of his arms and legs. He is treated with a single dose of intramuscular penicillin G benzathine and with the application of topical 5% permethrin cream over his whole body. A week later, the pyoderma has substantially resolved, but the boy continues to scratch his hands and feet. The clinic nurse visits the family house and finds that skin sores are present on both infants who live in the household, three of the six young children, and one of the three adolescents. Some also have scratches and small interdigital excoriations, which are consistent with scabies. An infirm elderly aunt living in the house is found to have widespread areas of extensively crusted and scaly skin, which are especially prominent on her hands, elbows, armpits, knees, and buttocks. All the household members are given topical permethrin, and the aunt is referred to the hospital for oral ivermectin therapy.