Melioidosis: A Greater Threat Than Previously Suspected?

Melioidosis: A Greater Threat Than Previously Suspected?

Infection with Burkholderia pseudomallei may be more common and deadly than we think. Melioidosis is often thought of as a tropical disease affecting people and animals in Thailand, Northern Australia and SE Asia [1], [2] and [3] but a January 2016 article in Nature Microbiology[1] provides evidence that melioidosis may have a much greater endemic area, morbidity and mortality than previously suspected. With no vaccine available, possibly 89,000 human deaths (95% credible interval 36,000 – 227,000) and countless animal deaths per year, plus almost half the suspected endemic countries not reporting the disease, education about melioidosis is urgently needed among human and veterinary clinicians, laboratory staff, and policymakers worldwide.

In 1911, the pathologist Alfred Whitmore and his assistant C. S. Krishnaswami first described melioidosis as a “glanders-like” disease in Burma. During the last century, the etiologic Gram-negative bacillus has been variously known as Bacillus whitmorii (or Bacille de Whitmore), Malleomyces pseudomallei, Pseudomonas pseudomallei, and, since 1992, Burkholderia pseudomallei [4].

About

Melioidosis (aka “Whitmore disease” [5] and [6] “Whitmore’s disease” [3]and “pseudoglanders” [5] comprises a mixed purulent and granulomatous response that can lead to suppurative or caseous lesions of the skin or any other organ [5], [6] and [7]. In humans, the illness often presents as pneumonia [6] and [7] but also as sepsis or internal organ abscesses, [1], [2], [3], [6], [7] and [8] and suppurative parotiditis in children [4] and [6]. There is high case-fatality in both animals [4], [5] and [6] and humans [1], [2], [4], [6] and [7], up to 40% in resource-poor environments [7]. Chronic disease can also occur and mimic conditions such as tuberculosis or cancer [2] and [9]. Melioidosis has been traditionally difficult to diagnose because of its diverse clinical presentations and lack of adequate diagnostic capabilities [2] and [6]. Melioidosis is sometimes called “The Great Imitator” [6] or “Great Mimicker” [9].

Although the incubation is generally 1-21 days in humans [3] and [8] melioidosis has been known to present up to six decades later [2], [6] and [8] when activated by a weakening of the immune system [6], [8] and [10]. This potentially long incubation necessitates a complete travel history to see if there has been any exposure to endemic regions, or to plants and animals from those regions [2]. In light of recent evidence, that region may be much larger than previously suspected [1].

Numerous wild and captive animal species are susceptible to infection, with infection most often seen in sheep, goats and pigs. Introduction of naïve livestock to endemic regions appears to increase risk, as do immunocompromising conditions in dogs and cats. Diverse species affected include camels, wallabies and koala, tropical fish, captive marine mammals, tropical fish, birds, reptiles and non-human primates. Host susceptibility and disease manifestations vary between species [5] and [6]. Pigs seem to be more resistant to systemic infection than sheep and goats, and infections in cattle are rare [6]. Mastitis is a common manifestation in goats, leading to recommendations for pasteurization of goat’s milk in endemic regions [5] and [6].

Transmission

Transmission of B. pseudomallei is generally environmental [5] and [6]. The bacillus can survive for months or years in contaminated soil or water, including acidic soils, dehydrated soils, and soils with salt contents up to 0.4%. It does not survive UV light [4] and [6]. B. pseudomallei can exist in an infectious, non-cultivable state in the environment for prolonged periods. It can change its morphology to appear as Gram-positive coccoid organisms in acid pH, and also enter the cells of some protozoa or the mycorrhizal fungus Gigaspora decipiens, which may help B. pseudomallei to survive environmental stresses [11].

The bacillus often enters the system percutaneously, such as through open wounds on the hands or feet [2], [3], [5], [6] and [8]. It is often found in soil [3], [5] and [7], particularly moist clay “acrisol” soils [1] and [6] and heavily-worked “anthrosol” soils [1] such as are found in rice paddies [4] and [7]. It can also be found in surface water [2], [4], [5] and [6], and infection can occur from ingestion of contaminated water [3] or inhalation of contaminated dust and water droplets [3] and [5], including during severe weather events [4], [6] and [12]. There have been cases of infection from ingestion of or percutaneous exposure to contaminated milk [5], [6] and [10] and ingestion of or percutaneous exposure to contaminated carcasses [5] and [10]. Transmission does not usually occur from person to person or animal to animal, except transplacentally [5] and [6] or in families with close contact, such as nursing an infected patient [6].

Diagnosis

For melioidosis diagnosis, the recommendation is to suspect infection with B. pseudomallei in patients who present with community-acquired sepsis, pneumonia or abscesses, who have lived in or traveled to areas where the bacteria is endemic, particularly in the presence of predisposing risk factors such as diabetes, kidney disease, immunosuppression [2], [6], [8] and [9], excessive alcohol intake [1], [6], [8] and [9], lung disease [6], [8] and [9] or thalassemia [6]. Delays in diagnosis and appropriate treatment can often be fatal [1], [2], [4], [6] and [13]. In some symptomatic and asymptomatic patients, abscesses are found post-mortem [6].

Sampling from multiple sites is more likely to detect the organism [6]. Sample urine, pharynx, blood and pus, on selective media (Ashdown agar, if available, but B. cepacia selective agar may be more commonly available) and transport at room temperature, as the bacillus does not survive cold temperatures well. Culture is 100% specific, but sensitivity may be as low as 60%. It is strongly recommended that any non-Pseudomonas aeruginosa, oxidase positive, gram-negative bacillus isolated from a clinical specimen be suspect [2]. It can be distinguished from closely-related B. thailendensis because B. pseudomallei cannot assimililate arabinose [7].

If melioidosis is suspected, the receiving lab should be notified, as risk for occupational exposure via aerosolization is high [9]. Additionally, because B. pseudomallei is a select agent, the lab may need to notify appropriate authorities (such as the Laboratory Response Network in the United States). Work with the sample should be performed in a BSL-3 lab [6] and [10]. If melioidosis is suspected, but not immediately found, it is recommended to search for occult foci of infection with imaging [2]. Genetic testing may also be needed to distinguish between various Burkholderia spp. [13].

An IHA titer >1:160 is sometimes considered diagnostic for melioidosis in resource-poor settings [7]. ELISAs have also been developed for the exotoxin and bacterial components, as well as PCR testing, PFGE, 16S rRNA sequencing, variable number tandem repeat polymorphism and multilocus sequence typing (MLST) [6]. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) is also increasingly used for isolate identification [2] and [6].

There is support among researchers to make latex agglutination testing available for rapid identification, especially in resource-poor endemic areas. Additionally, a point-of-care lateral flow immunoassay (LFI) could help to rapidly identify isolates [2]. In non-endemic areas, broader detection tests such as 16S sequencing or multiplexed real-time PCR assays that include B. pseudomallei may be helpful to catch occasional cases or potential outbreaks [2].

Misconceptions and Misidentification

Although chronic infection has been described, B. pseudomallei does not generally colonize people. Isolation of B. pseudomallei from any body site should be considered diagnostic of infection. B. pseudomallei is often misidentified as a contaminant or as Pseudomonas spp [2] or other Burkholderia spp [2], [4] and [13] by standard identification methods, including API 20NE [2] MALDI-TOF and VITEK2 [2] and [10].

Treatment

Bacteremia can recur after days or weeks of seemingly adequate IV treatment [4], prompting the treatment guidelines that last for months. For the first 10-14 days of treatment, IV Ceftazidime is given q 6-8hours OR IV Meropenem q 8hours, followed by 3-6 months of PO TMP-SMX q12 hours [3] and [14]. Recommendations are sometimes extended for certain clinical presentations including lymphadenopathy, ICU admission, osteomyelitis, central nervous system infections and arterial infections [14]. Livestock are often destroyed rather than treated [5] and [6].

Vaccines for Military and Non-Military Use

There was a high seroprevalence (7%) of B. pseudomallei among soldiers returning from Vietnam [4], and much funding for vaccine development is for military use to prevent infection of soldiers in tropical areas or in the event of intentional release, as there is the possibility for use as a bioterrorism weapon [4] and [15]. Although the potential exists, the likelihood of B. pseudomallei being used for an “attack” is believed to be low. It has never been known to be weaponized, and its use against an immunocompetent population is undetermined [4] and [16].

The need is greatest for a public health vaccine helpful for those most affected—percutaneous exposures to immunocompromised patients in endemic areas, not inhaled exposures to young, healthy soldiers. For this reason, there is concern that a military vaccine would have limited usefulness as a public health vaccine in endemic areas [15].

Attempts to vaccinate laboratory animals has led to abscess formation [4] and [15] even with species believed to have lower virulence factors such as B. thailandensis. Additionally, repeated environmental exposure to B. pseudomallei does not appear to elicit protective humoral or cellular immunity [4]. For vaccine development, an external agency that could facilitate head-to-head comparison of vaccine candidates may be needed [10] and [15]. Even with such an agency, vaccine development is an estimated 5-20 years away [10].

Reporting in The United States

Mainly, melioidosis is reported to authorities in SE Asia, South Asia, China, Singapore, Taiwan and Northern Australia, but indigenous cases have also been documented in the Middle East, South and Central America, Africa and various islands [6]. Reporting of melioidosis in areas where it is less common could help to educate clinicians, laboratory personnel and public health officials to be alert to potential cases and outbreaks [2].

In the United States, melioidosis is not nationally notifiable, despite being a Tier 1 overlap select agent and Category B Priority Pathogen. Melioidosis is the only overlap select agent (bioweapon potential against humans and animals) where this is the case. Although identification of B. pseudomallei or occupational exposures must be reported to the Federal Select Agent Program within 24 hours, it is not required for states to report suspect or probable cases of human infection to the CDC’s Bacterial Special Pathogens Branch [9].

There have been U.S. cases where there was no foreign travel and the source of exposure was unknown [2], [6] and [9]. The authors of the Nature Microbiology paper propose that the U.S. states of Florida, Texas and Louisiana have soil suitable for B. pseudomallei to become established. [1] But the reporting websites of those 3 states show a patchwork of reporting by the counties to the state—urgently notifiable in Florida, reportable within 5 days in Louisiana, not reportable at all in Texas.

In the U.S., national notifiability is determined by the Council of State and Territorial Epidemiologists (CSTE), who have declined to make melioidosis nationally notifiable. As far as we know, the disease is rare in the United States, and some of the blood testing to identify B. pseudomallei is already performed at the CDC [17]. For veterinary patients, B. pseudomallei is currently on the USDA’s proposed National List of Reportable Animal Diseases [18].

How might prevalence increase?

The vast increase of areas where melioidosis may be endemic necessitates increased awareness among human and veterinary clinicians, lab personnel, and public health officials. We can expect to see an increase in reported cases if diagnosis and reporting improve, but other factors may also drive an increase in cases in coming years—worldwide increase in diabetes, increase of anthrasol soils, and increasingly global movement of people, animals and goods. [1].

Recommendations

Better testing and reporting are needed if we are to fully understand the global burden of melioidosis. We also need faster testing and increased awareness of the disease in order to prevent deadly delays in treatment.

In the United States, reporting may be indicated to see whether the numbers of imported and endemic cases begin to rise. Without such reporting, it will be difficult to detect outbreaks or the possible intentional release of the organism.

Worldwide, researchers need support for vaccine development, particularly for public health vaccines to protect people and animals in endemic areas. Because melioidosis can infect so many species, collaboration and communication between human and veterinary medicine experts will be key to preventing, tracking and treating B. pseudomallei infections.

1. Biosketch of T. Eoin West

Dr. Eoin West is a pulmonologist/intensivist at Harborview Medical Center, Seattle, WA, USA, and an Associate Professor of Medicine in the Division of Pulmonary and Critical Care Medicine and adjunct Associate Professor of Global Health at the University of Washington. He is a Visiting Associate Professor of Clinical Microbiology in the Faculty of Tropical Medicine at Mahidol University. He conducts translational research focused on lung infections and sepsis, illnesses that cause a significant burden of disease in low resources settings. Much of his work investigates melioidosis, Burkholderia pseudomallei infection. He directs the UW’s International Respiratory and Severe Illness Center (INTERSECT). Figure 4.

2. Interview with T. Eoin West

References

© 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.