Melioidosis: exposing the ‘Great Mimicker’

It is, to quote poet T. S.  Eliot, “fear in a handful of dust”. Not an allusion to mortality as the poet meant, but a killer that lives in the soil itself.

Melioidosis is caused by Burkholderia pseudomallei, a bacterium that resides in the soil of Southeast Asia and northern Australia. In some locales, the number of people who die after developing melioidosis is as high as 40%, and in northeast Thailand it causes as many deaths as does tuberculosis. What makes the disease so menacing is that not only is the bacterium resistant to all but a narrow range of antibiotics but it is also frequently under- or misdiagnosed, with fatal and often rapid consequences.

Yet, according to Cambridge scientist Professor Sharon Peacock, a world expert on melioidosis, this infection and its related deaths are potentially preventable. Not through vaccination (indeed, none exists) but through simple public health measures. “Because individuals acquire infection after contact with soil containing the pathogen, and not from person-to-person contact, it’s potentially avoidable through behavioural changes,” explained Peacock. “Simple guidelines that make people aware of the risks associated with certain activities could ease a major disease burden.”

Although much progress has been made in the past decade towards understanding how the bacterium causes disease, little is known about the global distribution of the bacterium in the environment, and therefore where people (including travellers) are at risk. In addition, the US Centers for Disease Control and Prevention has classified the bacterium as a Category B ‘select agent’ (potential biological weapon). Preparedness against melioidosis in the event of a deliberate release has therefore become a security concern.

Peacock has been working in collaboration with a team led by Dr Direk Limmathurotsakul, Deputy Head of Microbiology at the Wellcome Trust Major Overseas Programme in Thailand, to trace the routes of infection for melioidosis. Their aim has been to drive down the incidence of disease by providing the first evidence-based guidelines worldwide for its prevention.

‘Tip of the iceberg’

Although melioidosis was first described in 1911 in Burma, the disease has been little studied over the past century. Not until US soldiers returned home infected with the bacterium after their service in Vietnam did the disease begin to attract attention in the West. Even then, the disease was largely regarded as chronic rather than acute – patients tended to develop symptoms so long after acquiring the infection that it became known as the ‘Vietnamese time bomb’.

Only since the 1970s has melioidosis begun to be taken seriously as a public health threat in Southeast Asia, said Peacock: “It’s been a hidden disease – we’re only really now seeing what many believe is the tip of the iceberg in terms of numbers of people infected.” Under-reporting, she believes, is the consequence both of it taking up to a week to diagnose the disease by culturing the bacterium in a microbiology lab, and of the scarcity of such diagnostic facilities across the region.

Misdiagnosis is common because melioidosis can cause infected individuals to present with a wide range of clinical manifestations. Unhappily, in the absence of an accurate diagnosis, the specific and long-term antibiotic treatment the patient requires is rarely given, and death occurs swiftly from severe sepsis and associated organ failure. “The single most important objective therefore has to be to prevent people from acquiring the disease in the first place,” asserted Peacock.

Inoculation, ingestion, inhalation?

Peacock, Limmathurotsakul and colleagues have now completed the first prospective hospital-based case-control study in Asia to identify what aspects of daily living put individuals at risk of B. pseudomallei infection.

“Current advice in northern Australia, where melioidiosis is also common, includes avoiding contact with soil and washing hands and feet. But this is largely based on common sense rather than evidence, and compliance and efficacy are unknown,” explained Peacock, whose research was funded by the Wellcome Trust. “In Asia, no advice is given to people living in melioidosis-endemic areas. A programme of prevention could be relatively inexpensive, readily implementable and applicable to all.”

Over an 18-month period, patients presenting to hospital with melioidosis were recruited to the study. Using a questionnaire and home visits, the team have been tracing the route of infection – investigating whether disease has resulted from inoculation through abrasions in the skin, ingestion of water and food, or inhalation of aerosols – and using genotyping to define the bacterial strains present in the patients and environment.

“There are major knowledge gaps in Asia regarding the frequency with which water supplies are contaminated with B. pseudomallei simply because no-one has looked before,” explained Peacock. “We are also uncertain whether being outside during severe weather could be a risk factor associated with inhalation of the bacterium.”

The results of the research have been collated and a set of guidelines will be developed and disseminated to a network of public health officials. The main recommendations are likely to be to not drink untreated water, to avoid exposure to severe weather, and for agricultural workers to use protective clothing and footwear. Now, Limmathurotsakul and colleagues are developing a public engagement campaign to raise awareness of melioidosis in Thailand.

A previous study by Peacock and colleagues has shown that another strong risk factor for melioidosis is diabetes, which puts individuals at a vastly increased risk of B. pseudomallei infection. Given that the prevalence of diabetes is rising in Thailand, an additional aim is to provide public health guidance targeted towards education programmes in diabetic clinics.

Thinking globally

The team are now widening their scope to consider other regions of Asia and the world. Melioidosis is known to occur in areas of Southeast Asia such as Laos and Cambodia, but incidence rates are poorly defined and may be grossly underestimated, as Peacock highlighted: “It was very telling that the first time it was realised that melioidosis was in Laos was when the bacterium was cultured from the soil in 1998. Once detected, a study was carried out in the capital and within a few years several hundred cases had been diagnosed.”

“We predict that melioidosis will become recognised as a major pathogen throughout this region in the wake of laboratory strengthening and use of standard guidelines,” she added.

Worldwide, the paucity of information about the geographical distribution of the organism has meant that there is an incomplete global risk map, with vast regions of the world completely unmapped, including Indonesia, India, Africa and most of South America. Peacock and colleagues have initiated an international working party that will facilitate the mapping process. First, however, they had to devise consensus guidelines on how to carry out soil sampling using the simplest and cheapest of techniques, to maximise use in resource-poor settings. Guidelines have now been agreed and the team is in the process of developing a website (www.melioidosis.info/) from which protocols for sampling can be downloaded, and complete data from sampling studies can be deposited to build a global map of the distribution of environmental B. pseudomallei.

Melioidosis has recently been described in southern India, and soil-sampling studies are under way there. With the support of the Cambridge-Hamied Visiting Lecture Scheme,  Peacock has been working with researchers at Kasturba Medical College, Karnataka, India, to provide practical advice and knowledge on environmental sampling. Local initiatives will enable researchers in the region to monitor, manage and reduce the effects of an emerging infectious disease.

“These initiatives in Thailand and India have the potential to reduce the impact of an emerging infectious disease,” Peacock explained. “While the true incidence of melioidosis is unknown, it is likely that many millions of people are repeatedly exposed to B. pseudomallei.”