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Bart J. Currie - One of the best experts on this subject based on the ideXlab platform.
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2020 Review and revision of the 2015 Darwin Melioidosis treatment guideline; paradigm drift not shift.
PLoS neglected tropical diseases, 2020Co-Authors: Richard P. Sullivan, Bart J. Currie, Catherine S. Marshall, Nicholas M. Anstey, Linda WardAbstract:Melioidosis therapy is divided into an intravenous intensive phase and an oral eradication phase. The Darwin Melioidosis treatment guideline has evolved over two decades, with over 1150 consecutive patients with culture-confirmed Melioidosis managed under the Darwin Prospective Melioidosis Study. The current guideline, published in 2015, has been associated with low rates of recrudescence, relapse and mortality, and together with the treatment trials in Thailand, forms the basis for consensus global guidelines. We aimed to reassess the Darwin guideline and determine if any adjustments to the recommendations better reflect current practice in Melioidosis therapy at Royal Darwin Hospital. This retrospective cohort study reviews the characteristics, admission duration, duration of intravenous antibiotics, recrudescence, recurrence and mortality in all patients presenting with first episode culture-confirmed Melioidosis in the tropical north of Australia’s Northern Territory from 1st October 2012 until 1st January 2017. 234 patients were available for analysis. 16 (6.8%) died during the intensive phase treatment and 6 (2.6%) did not have complete treatment at Royal Darwin Hospital, leaving 212 patients for analysis. Six (2.8%) patients had recrudescence during therapy and 10 (4.7%) had recurrent Melioidosis (relapse or new infection) after completion of therapy. Persisting osteomyelitis requiring surgery was an important reason for recrudescence as was unrecognized osteomyelitis for relapse. For patients presenting with an antibiotic duration determining focus of pneumonia, durations of intravenous antibiotics were often prolonged beyond the current 2-week minimum treatment recommendation. Prolongation of therapy in pneumonia mostly occurred in patients presenting with multi-lobar disease or with concurrent blood culture positivity. The 2015 Darwin Melioidosis guideline is working well with low rates of recrudescence, relapse and mortality. Based on the practice of the treating clinicians, the 2020 revision of the guideline has been adjusted to include a duration of a minimum of 3 weeks of intravenous antibiotics for those with concurrent bacteraemia and pneumonia involving only a single lobe and those with bilateral and unilateral multi-lobar pneumonias who do not have bacteraemia. We also extend to a minimum of 4 weeks intravenous therapy for those with concurrent bacteraemia and bilateral or unilateral multi-lobar pneumonia. Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an infectious disease with diverse clinical presentations including pneumonia, localised cutaneous lesion, bacteraemia without evident focus, septic arthritis and osteomyelitis, and severe sepsis with multiple organ abscesses. Therapy is prolonged, consisting of an intensive intravenous phase and an oral eradication phase. Guidelines from northern Australia have evolved and now recommend an often-longer duration of intravenous antibiotics than in prior recommendations. The Darwin Melioidosis guideline, which was first published internationally in 2015 and described as a new treatment paradigm, has been associated with relatively low rates of recrudescence and relapse. We have reassessed use of this guideline and have again demonstrated low rates of recrudescence, relapse and mortality. There has been a tendency for treating clinicians to prolong intravenous phase therapy beyond the 2-week recommendation in those presenting with concurrent bacteraemia and pneumonia and in those with multi-lobar pneumonia. The 2015 guideline remains the standard for treatment recommendations for our region, but the 2020 revision now includes multi-lobar pneumonia as an indication for a minimum of 3 weeks intravenous treatment if bacteraemia is not present and 4 weeks if bacteraemia is present, while a minimum of 3 weeks is recommended for those with concurrent bacteraemia and pneumonia involving only a single lobe.
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Melioidosis fatalities in captive slender tailed meerkats suricata suricatta combining epidemiology pathology and whole genome sequencing supports variable mechanisms of transmission with one health implications
BMC Veterinary Research, 2019Co-Authors: Audrey Rachlin, Cathy Shilton, Jessica R Webb, Mark Mayo, Mirjam Kaestli, Mariana Kleinecke, Vanessa Rigas, Ian Gurry, Suresh Benedict, Bart J. CurrieAbstract:Melioidosis is a tropical infectious disease which is being increasingly recognised throughout the globe. Infection occurs in humans and animals, typically through direct exposure to soil or water containing the environmental bacterium Burkholderia pseudomallei. Case clusters of Melioidosis have been described in humans following severe weather events and in exotic animals imported into Melioidosis endemic zones. Direct transmission of B. pseudomallei between animals and/or humans has been documented but is considered extremely rare. Between March 2015 and October 2016 eight fatal cases of Melioidosis were reported in slender-tailed meerkats (Suricata suricatta) on display at a Wildlife Park in Northern Australia. To further investigate the Melioidosis case cluster we sampled the meerkat enclosure and adjacent park areas and performed whole-genome sequencing (WGS) on all culture-positive B. pseudomallei environmental and clinical isolates. WGS confirmed that the fatalities were caused by two different B. pseudomallei sequence types (STs) but that seven of the meerkat isolates were highly similar on the whole-genome level. Used concurrently with detailed pathology data, our results demonstrate that the seven cases originated from a single original source, but routes of infection varied amongst meerkats belonging to the clonal outbreak cluster. Moreover, in some instances direct transmission may have transpired through wounds inflicted while fighting. Collectively, this study supports the use of high-resolution WGS to enhance epidemiological investigations into transmission modalities and pathogenesis of Melioidosis, especially in the instance of a possible clonal outbreak scenario in exotic zoological collections. Such findings from an animal outbreak have important One Health implications.
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the association of Melioidosis with climatic factors in darwin australia a 23 year time series analysis
Journal of Infection, 2016Co-Authors: Mirjam Kaestli, Mark Mayo, Linda Ward, Eric P M Grist, Audrey A Hill, Bart J. CurrieAbstract:Summary Objectives Melioidosis is an often fatal disease in humans and animals and endemic in Southeast Asia and northern Australia. It is caused by the environmental bacterium Burkholderia pseudomallei . We analysed weather and climate factors preceding new Melioidosis cases in Darwin and compared the time between weather event and admission to hospital for severe and average wet season rainfall. Methods In a time-series analysis from 1990 to 2013 we applied a boosted regression tree and a negative binomial model to investigate the association between Melioidosis cases and weather events. Fitted Fourier terms controlled for long-term seasonal trends. Results We found a rise in the dew point, cloud cover, rainfall, maximum temperature and groundwater to be associated with an increased risk to acquire Melioidosis. A shorter ‘putative' incubation period was evident after severe rainfall events. Rainfall occurring early in the wet season was linked to more cases as was an increase in the local sea surface temperature reflecting local weather dynamics and precipitation. Conclusions Our findings demonstrate a statistical association between frequency of recorded Melioidosis cases and the nature and timing of rainfall related events and suggest a future rise in the sea surface and ambient temperature may lead to increased Melioidosis.
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Melioidosis evolving concepts in epidemiology pathogenesis and treatment
Seminars in Respiratory and Critical Care Medicine, 2015Co-Authors: Bart J. CurrieAbstract:Infection with Burkholderia pseudomallei can result in asymptomatic seroconversion, a single skin lesion that may or may not heal spontaneously, a pneumonia which can be subacute or chronic and mimic tuberculosis or rapidly progressive resulting in fatal overwhelming sepsis. Latency with subsequent activation of disease is well recognized, but very uncommon. Melioidosis also has a myriad of other clinical presentations and diagnosis is often delayed because of this and because of difficulties with laboratory diagnosis and lack of recognition outside Melioidosis-endemic regions. The perception of B. pseudomallei as a top tier biothreat agent has driven large funding for research, yet resources for diagnosis and therapy of Melioidosis in many endemic locations remain extremely limited, with mortality as high as 50% in comparison to around 10% in regions where state-of-the-art intensive care therapy for sepsis is available. Fatal Melioidosis is extremely unlikely from natural infection in a healthy person, provided the diagnosis is made early, ceftazidime or meropenem is commenced and intensive care therapy is available. While biothreat research is directed toward potential aerosol exposure to B. pseudomallei, the overall proportion of Melioidosis cases resulting from inhalation rather than from percutaneous inoculation remains entirely uncertain, although the epidemiology supports a shift to inhalation during severe weather events such as cyclones and typhoons. What makes B. pseudomallei such a dangerous organism for patients with diabetes and other selective risk factors remains unclear, but microbial genome-wide association studies linking clinical aspects of Melioidosis cases to nonubiquitous or polymorphic B. pseudomallei genes or genomic islands are beginning to uncover specific virulence signatures. Finally, what also remains uncertain is the global phylogeography of B. pseudomallei and whether Melioidosis is spreading beyond historical locations or is just being unmasked in Africa and the Americas by better recognition and increased surveillance.
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clinical presentation and medical management of Melioidosis in children a 24 year prospective study in the northern territory of australia and review of the literature
Clinical Infectious Diseases, 2015Co-Authors: Charlie Mcleod, Linda Ward, Peter S Morris, Paul A Bauert, Charles Kilburn, Robert W Baird, Bart J. CurrieAbstract:Background. Melioidosis is less common in children than adults. The clinical spectrum of disease varies greatly between the 2 groups. Treatment guidelines are currently based on adult studies, and revision of existing guidelines is necessary to instruct specific pediatric management. Methods. Culture-confirmed cases of Melioidosis in the Northern Territory between 1989 and 2013 were identified from the Prospective Melioidosis Study. The epidemiology and clinical spectrum of disease for children aged ≤16 years were analyzed and compared with the adult data. Results. Forty-five pediatric patients were identified, representing 5% of the total 820 Melioidosis cases over 24 years. Most children (84%) had no recognized risk factors for Melioidosis, and 80% presented during the wet season. Primary cutaneous Melioidosis was the commonest presentation in children (60% vs 13%; P< .001), whereas pneumonia predominated in adults (54% vs 20%; P< .001). Bacteremia was less common in children than in adults (16% vs 59%; P< .001). Brainstem encephalitis occurred in 3 children without risk factors. Children were more likely to report an inoculating event (42%; P< .001). There was no difference in mortality between the groups (P= .178), with 3 children dying (7%); all had identifiable risk factors. Four children with cutaneous Melioidosis were successfully treated with oral therapy alone, while 2 had skin lesions that resolved spontaneously. Conclusions. Pediatric Melioidosis commonly manifests as localized cutaneous disease in immunocompetent hosts. The disease can be fatal, especially in individuals with risk factors for disease. Melioidosis with encephalomyelitis can result in severe residual disability. Prompt diagnosis requires a high index of clinical suspicion in endemic areas.
Direk Limmathurotsakul - One of the best experts on this subject based on the ideXlab platform.
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effectiveness of a multifaceted prevention programme for Melioidosis in diabetics premel a stepped wedge cluster randomised controlled trial
PLOS Neglected Tropical Diseases, 2021Co-Authors: Pornpan Suntornsut, Wipada Chaowagul, Direk Limmathurotsakul, Nicholas P J Day, Gumphol Wongsuvan, Prapit Teparrukkul, Susan MichieAbstract:Background Melioidosis, an often-fatal infectious disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei, is endemic in tropical countries. Diabetes mellitus and environmental exposure are important risk factors for Melioidosis acquisition. We aim to evaluate the effectiveness of a multifaceted prevention programme for Melioidosis in diabetics in northeast Thailand. Methodology/Principal findings From April 2014 to December 2018, we conducted a stepped-wedge cluster-randomized controlled behaviour change trial in 116 primary care units (PCUs) in Ubon Ratchathani province, northeast Thailand. The intervention was a behavioural support group session to help diabetic patients adopt recommended behaviours, including wearing rubber boots and drinking boiled water. We randomly allocated the PCUs to receive the intervention starting in March 2016, 2017 and 2018. All diabetic patients were contacted by phone yearly, and the final follow-up was December 2018. Two primary outcomes were hospital admissions involving infectious diseases and culture-confirmed Melioidosis. Of 9,056 diabetics enrolled, 6,544 (72%) received a behavioural support group session. During 38,457 person-years of follow-up, we observed 2,195 (24%) patients having 3,335 hospital admissions involved infectious diseases, 80 (0.8%) Melioidosis, and 485 (5%) deaths. In the intention-to-treat analysis, implementation of the intervention was not associated with primary outcomes. In the per-protocol analysis, patients who received a behavioural support group session had lower incidence rates of hospital admissions involving infectious diseases (incidence rate ratio [IRR] 0.89; 95%CI 0.80–0.99, p = 0.03) and of all-cause mortality (IRR 0.54; 95%CI 0.43–0.68, p<0.001). However, the incidence rate of culture-confirmed Melioidosis was not significantly lower (IRR 0.96, 95%CI 0.46–1.99, p = 0.66). Conclusions/Significance Clear benefits of this multifaceted prevention programme for Melioidosis were not observed. More compelling invitations for the intervention, modification of or addition to the behaviour change techniques used, and more frequent intervention may be needed. Trial registration This trial is registered with ClinicalTrials.gov, number NCT02089152.
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Global burden of Melioidosis in 2015: a systematic review and data synthesis
Lancet Infectious Diseases, 2019Co-Authors: Emma Birnie, Harjeet S Virk, Jelmer Savelkoel, Eric Bertherat, Rene Spijker, Brecht Devleesschauwer, Direk Limmathurotsakul, David A. B. Dance, Juanita A Haagsma, W. Joost WiersingaAbstract:Background: Melioidosis is an infectious disease caused by the environmental bacterium Burkholderia pseudomallei. It is often fatal, with a high prevalence in tropical areas. Clinical presentation can vary from abscess formation to pneumonia and sepsis. We assessed the global burden of Melioidosis, expressed in disability-adjusted life-years (DALYs), for 2015. Methods: We did a systematic review of the peer-reviewed literature for human Melioidosis cases between Jan 1, 1990, and Dec 31, 2015. Quantitative data for cases of Melioidosis were extracted, including mortality, age, sex, infectious and post-infectious sequelae, antibiotic treatment, and symptom duration. These data were combined with established disability weights and expert panel discussions to construct an incidence-based disease model. The disease model was integrated with established global incidence and mortality estimates to calculate global Melioidosis DALYs. The study is registered with PROSPERO, number CRD42018106372. Findings: 2888 articles were screened, of which 475 eligible studies containing quantitative data were retained. Pneumonia, intra-abdominal abscess, and sepsis were the most common outcomes, with pneumonia occurring in 3633 (35·7%, 95% uncertainty interval [UI] 34·8–36·6) of 10 175 patients, intra-abdominal abscess in 1619 (18·3%, 17·5–19·1) of 8830 patients, and sepsis in 1526 (18·0%, 17·2–18·8) of 8469 patients. We estimate that in 2015, the global burden of Melioidosis was 4·6 million DALYs (UI 3·2–6·6) or 84·3 per 100 000 people (57·5–120·0). Years of life lost accounted for 98·9% (UI 97·7–99·5) of the total DALYs, and years lived with disability accounted for 1·1% (0·5–2·3). Interpretation: Melioidosis causes a larger disease burden than many other tropical diseases that are recognised as neglected, and so it should be reconsidered as a major neglected tropical disease. Funding: European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Research Grant 2018, AMC PhD Scholarship, The Netherlands Organisation for Scientific Research (NWO), H2020 Marie Sklodowska-Curie Innovative Training Network European Sepsis Academy.
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thrombocytopenia impairs host defense against burkholderia pseudomallei Melioidosis
The Journal of Infectious Diseases, 2019Co-Authors: Emma Birnie, Direk Limmathurotsakul, Gavin C K W Koh, Nicholas P J Day, Theodora A M Claushuis, Joris J T H Roelofs, Jerry Ware, Baidong HouAbstract:Background Infection with the gram-negative bacillus Burkholderia pseudomallei (Melioidosis) is an important cause of pneumosepsis in Southeast Asia and has a mortality of up to 40%. We aimed to assess the role of platelets in the host response against B. pseudomallei infection. Methods Association between platelet counts and mortality was determined in 1160 patients with culture-proven Melioidosis. Mice treated with (low- or high-dose) platelet-depleting antibody were inoculated intranasally with B. pseudomallei and killed. Additional studies using functional glycoprotein Ibα-deficient mice were conducted. Results Thrombocytopenia was present in 31% of patients at admission and predicted mortality in Melioidosis patients even after adjustment for confounders. In our murine-Melioidosis model, platelet counts decreased, and mice treated with a platelet-depleting antibody showed enhanced mortality and higher bacterial loads compared to mice with normal platelet counts. Low platelet counts had a modest impact on early-pulmonary neutrophil influx. Reminiscent of their role in hemostasis, platelet depletion impaired vascular integrity, resulting in early lung bleeding. Glycoprotein Ibα-deficient mice had reduced platelet counts during B. pseudomallei infection together with an impaired local host defense in the lung. Conclusions Thrombocytopenia predicts mortality in Melioidosis patients and, during experimental Melioidosis, platelets play a protective role in both innate immunity and vascular integrity.
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predicted global distribution of burkholderia pseudomallei and burden of Melioidosis
Nature microbiology, 2016Co-Authors: Direk Limmathurotsakul, Eric Bertherat, David A. B. Dance, Nicholas P J Day, Nick Golding, Jane P Messina, David M Pigott, Catherine L Moyes, Dionne B Rolim, Sharon J. PeacockAbstract:Burkholderia pseudomallei, a highly pathogenic bacterium that causes Melioidosis, is commonly found in soil in Southeast Asia and Northern Australia1,2. Melioidosis can be difficult to diagnose due to its diverse clinical manifestations and the inadequacy of conventional bacterial identification methods3. The bacterium is intrinsically resistant to a wide range of antimicrobials, and treatment with ineffective antimicrobials may result in case fatality rates (CFRs) exceeding 70%4,5. The importation of infected animals has, in the past, spread Melioidosis to non-endemic areas6,7. The global distribution of B. pseudomallei and burden of Melioidosis, however, remain poorly understood. Here, we map documented human and animal cases, and the presence of environmental B. pseudomallei, and combine this in a formal modelling framework8-10 to estimate the global burden of Melioidosis. We estimate there to be 165,000 (95% credible interval 68,000-412,000) human Melioidosis cases per year worldwide, of which 89,000 (36,000-227,000) die. Our estimates suggest that Melioidosis is severely underreported in the 45 countries in which it is known to be endemic and that Melioidosis is likely endemic in a further 34 countries which have never reported the disease. The large numbers of estimated cases and fatalities emphasise that the disease warrants renewed attention from public health officials and policy makers.
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A retrospective analysis of Melioidosis in Cambodian children, 2009–2013
BMC, 2016Co-Authors: Paul Turner, Vanaporn Wuthiekanun, Sabine Kloprogge, Thyl Miliya, Sona Soeng, Pisey Tan, Poda Sar, Pagnarith Yos, Catrin E. Moore, Direk LimmathurotsakulAbstract:Abstract Background Melioidiosis, infection by Burkholderia pseudomallei, is an important but frequently under-recognised cause of morbidity and mortality in Southeast Asia and elsewhere in the tropics. Data on the epidemiology of paediatric Melioidosis in Cambodia are extremely limited. Methods Culture-positive Melioidosis cases presenting to Angkor Hospital for Children, a non-governmental paediatric hospital located in Siem Reap, Northern Cambodia, between 1st January 2009 and 31st December 2013 were identified by searches of hospital and laboratory databases and logbooks. Results One hundred seventy-three evaluable cases were identified, presenting from eight provinces. For Siem Reap province, the median commune level incidence was estimated to be 28-35 cases per 100,000 children
Nicholas P J Day - One of the best experts on this subject based on the ideXlab platform.
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effectiveness of a multifaceted prevention programme for Melioidosis in diabetics premel a stepped wedge cluster randomised controlled trial
PLOS Neglected Tropical Diseases, 2021Co-Authors: Pornpan Suntornsut, Wipada Chaowagul, Direk Limmathurotsakul, Nicholas P J Day, Gumphol Wongsuvan, Prapit Teparrukkul, Susan MichieAbstract:Background Melioidosis, an often-fatal infectious disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei, is endemic in tropical countries. Diabetes mellitus and environmental exposure are important risk factors for Melioidosis acquisition. We aim to evaluate the effectiveness of a multifaceted prevention programme for Melioidosis in diabetics in northeast Thailand. Methodology/Principal findings From April 2014 to December 2018, we conducted a stepped-wedge cluster-randomized controlled behaviour change trial in 116 primary care units (PCUs) in Ubon Ratchathani province, northeast Thailand. The intervention was a behavioural support group session to help diabetic patients adopt recommended behaviours, including wearing rubber boots and drinking boiled water. We randomly allocated the PCUs to receive the intervention starting in March 2016, 2017 and 2018. All diabetic patients were contacted by phone yearly, and the final follow-up was December 2018. Two primary outcomes were hospital admissions involving infectious diseases and culture-confirmed Melioidosis. Of 9,056 diabetics enrolled, 6,544 (72%) received a behavioural support group session. During 38,457 person-years of follow-up, we observed 2,195 (24%) patients having 3,335 hospital admissions involved infectious diseases, 80 (0.8%) Melioidosis, and 485 (5%) deaths. In the intention-to-treat analysis, implementation of the intervention was not associated with primary outcomes. In the per-protocol analysis, patients who received a behavioural support group session had lower incidence rates of hospital admissions involving infectious diseases (incidence rate ratio [IRR] 0.89; 95%CI 0.80–0.99, p = 0.03) and of all-cause mortality (IRR 0.54; 95%CI 0.43–0.68, p<0.001). However, the incidence rate of culture-confirmed Melioidosis was not significantly lower (IRR 0.96, 95%CI 0.46–1.99, p = 0.66). Conclusions/Significance Clear benefits of this multifaceted prevention programme for Melioidosis were not observed. More compelling invitations for the intervention, modification of or addition to the behaviour change techniques used, and more frequent intervention may be needed. Trial registration This trial is registered with ClinicalTrials.gov, number NCT02089152.
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longitudinal profiling of plasma cytokines in Melioidosis and their association with mortality a prospective cohort study
Clinical Microbiology and Infection, 2020Co-Authors: Taniya Kaewarpai, Nicholas P J Day, Rungnapa Phunpang, Peeraya Ekchariyawat, Adul Dulsuk, Ekkachai Thiansukhon, Shelton W Wright, B Moonmueangsan, C MorakotAbstract:Abstract Objectives To characterize plasma cytokine responses in Melioidosis and analyse their association with mortality. Methods A prospective longitudinal study was conducted in two hospitals in Northeast Thailand to enrol 161 individuals with Melioidosis, plus 13 uninfected healthy individuals and 11 uninfected individuals with diabetes to act as controls. Blood was obtained from all individuals at enrolment (day 0), and at days 5, 12 and 28 from surviving Melioidosis patients. Interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-23, and tumour necrosis factor-α (TNF-α) were assayed in plasma. The association of each cytokine and its dynamics with 28-day mortality was determined. Results Of the individuals with Melioidosis, 131/161 (81%) were bacteraemic, and 68/161 (42%) died. On enrolment, median levels of IFN-γ, IL-6, IL-8, IL-10, IL-23 and TNF-α were higher in individuals with Melioidosis compared with uninfected healthy individuals and all but IFN-γ were positively associated with 28-day mortality. Interleukin-8 provided the best discrimination of mortality (area under the receiver operating characteristic curve 0.78, 95% CI 0.71–0.85). Over time, non-survivors had increasing IL-6, IL-8 and IL-17A levels, in contrast to survivors. In joint modelling, temporal trajectories of IFN-γ, IL-6, IL-8, IL-10 and TNF-α predicted survival. Conclusions In a severely ill cohort of individuals with Melioidosis, specific pro- and anti-inflammatory and T helper type 17 cytokines were associated with survival from Melioidosis, at enrolment and over time. Persistent inflammation preceded death. These findings support further evaluation of these mediators as prognostic biomarkers and to guide targeted immunotherapeutic development for severe Melioidosis.
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distinct classes and subclasses of antibodies to hemolysin co regulated protein 1 and o polysaccharide and correlation with clinical characteristics of Melioidosis patients
Scientific Reports, 2019Co-Authors: Apinya Pumpuang, Rungnapa Phunpang, Peeraya Ekchariyawat, Adul Dulsuk, Siriorn Loupha, Kochnipa Kwawong, Yaowaree Charoensawat, Ekkachai Thiansukhon, Nicholas P J DayAbstract:Melioidosis is a tropical infectious disease caused by Burkholderia pseudomallei that results in high mortality. Hemolysin co-regulated protein 1 (Hcp1) and O-polysaccharide (OPS) are vaccine candidates and potential diagnostic antigens. The correlation of classes/subclasses of antibodies against these antigens with clinical characteristics of Melioidosis patients is unknown. Antibodies in plasma samples from Melioidosis patients and healthy donors were quantified by ELISA and compared with clinical features. In Melioidosis patients, Hcp1 induced high IgG levels. OPS induced high IgG and IgA levels. The area under receiver operating characteristic curve (AUROCC) to discriminate Melioidosis cases from healthy donors was highest for anti-Hcp1 IgG (0.92) compared to anti-Hcp1 IgA or IgM. In contrast, AUROCC for anti-OPS for IgG (0.91) and IgA (0.92) were comparable. Anti-Hcp1 IgG1 and anti-OPS IgG2 had the greatest AUROCCs (0.87 and 0.95, respectively) compared to other IgG subclasses for each antigen. Survivors had significantly higher anti-Hcp1 IgG3 levels than non-survivors. Male Melioidosis patients with diabetes had higher anti-OPS IgA levels than males without diabetes. Thus, diverse and specific antibody responses are associated with distinct clinical characteristics in Melioidosis, confirming the diagnostic utility of these responses and providing new insights into immune mechanisms.
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thrombocytopenia impairs host defense against burkholderia pseudomallei Melioidosis
The Journal of Infectious Diseases, 2019Co-Authors: Emma Birnie, Direk Limmathurotsakul, Gavin C K W Koh, Nicholas P J Day, Theodora A M Claushuis, Joris J T H Roelofs, Jerry Ware, Baidong HouAbstract:Background Infection with the gram-negative bacillus Burkholderia pseudomallei (Melioidosis) is an important cause of pneumosepsis in Southeast Asia and has a mortality of up to 40%. We aimed to assess the role of platelets in the host response against B. pseudomallei infection. Methods Association between platelet counts and mortality was determined in 1160 patients with culture-proven Melioidosis. Mice treated with (low- or high-dose) platelet-depleting antibody were inoculated intranasally with B. pseudomallei and killed. Additional studies using functional glycoprotein Ibα-deficient mice were conducted. Results Thrombocytopenia was present in 31% of patients at admission and predicted mortality in Melioidosis patients even after adjustment for confounders. In our murine-Melioidosis model, platelet counts decreased, and mice treated with a platelet-depleting antibody showed enhanced mortality and higher bacterial loads compared to mice with normal platelet counts. Low platelet counts had a modest impact on early-pulmonary neutrophil influx. Reminiscent of their role in hemostasis, platelet depletion impaired vascular integrity, resulting in early lung bleeding. Glycoprotein Ibα-deficient mice had reduced platelet counts during B. pseudomallei infection together with an impaired local host defense in the lung. Conclusions Thrombocytopenia predicts mortality in Melioidosis patients and, during experimental Melioidosis, platelets play a protective role in both innate immunity and vascular integrity.
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increased von willebrand factor decreased adamts13 and thrombocytopenia in Melioidosis
PLOS Neglected Tropical Diseases, 2017Co-Authors: Emma Birnie, Sharon J. Peacock, Gavin C K W Koh, Ester C Lowenberg, Joost C M Meijers, Rapeephan R Maude, Nicholas P J Day, Tom Van Der PollAbstract:BACKGROUND Melioidosis, caused by bioterror treat agent Burkholderia pseudomallei, is an important cause of community-acquired Gram-negative sepsis in Southeast Asia and Northern Australia. New insights into the pathogenesis of Melioidosis may help improve treatment and decrease mortality rates from this dreadful disease. We hypothesized that changes in Von Willebrand factor (VWF) function should occur in Melioidosis, based on the presence of endothelial stimulation by endotoxin, pro-inflammatory cytokines and thrombin in Melioidosis, and investigated whether this impacted on outcome. METHODS/PRINCIPAL FINDINGS We recruited 52 controls and 34 culture-confirmed Melioidosis patients at Sappasithiprasong Hospital in Ubon Ratchathani, Thailand. All subjects were diabetic. Platelet counts in Melioidosis patients were lower compared to controls (p = 0.0001) and correlated with mortality (p = 0.02). VWF antigen levels were higher in patients (geometric mean, 478 U/dl) compared to controls (166 U/dL, p<0.0001). The high levels of VWF in Melioidosis appeared to be due to increased endothelial stimulation (VWF propeptide levels were elevated, p<0.0001) and reduced clearance (ADAMTS13 reduction, p<0.0001). However, VWF antigen levels did not correlate with platelet counts implying that thrombocytopenia in acute Melioidosis has an alternative cause. CONCLUSIONS/SIGNIFICANCE Thrombocytopenia is a key feature of Melioidosis and is correlated with mortality. Additionally, excess VWF and ADAMTS13 deficiency are features of acute Melioidosis, but are not the primary drivers of thrombocytopenia in Melioidosis. Further studies on the role of thrombocytopenia in B. pseudomallei infection are needed.
Nicholas J. White - One of the best experts on this subject based on the ideXlab platform.
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a randomized controlled trial of granulocyte colony stimulating factor for the treatment of severe sepsis due to Melioidosis in thailand
Clinical Infectious Diseases, 2007Co-Authors: Allen C Cheng, Direk Limmathurotsakul, Vanaporn Wuthiekanun, Wirongrong Chierakul, Nicholas J. White, Nicholas P J Day, Nongluk Getchalarat, Dianne P StephensAbstract:Background. Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis. Methods. In this randomized, placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor [G-CSF], 263 µg per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected Melioidosis in Thailand. Results. Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed Melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed Melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61–1.06; P = .2), including among patients with confirmed Melioidosis (83% vs. 96%; P = .3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31–1.00; P = .05). Conclusions. Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having Melioidosis in Thailand. We hypothesize that G-CSF may “buy time” for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis.
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A Comparison of Chloramphenicol, Trimethoprim-Sulfamethoxazole, and Doxycycline with Doxycycline Alone as Maintenance Therapy for Melioidosis
Clinical Infectious Diseases, 1999Co-Authors: Wipada Chaowagul, Andrew J. H. Simpson, Brian Angus, Yupin Suputtamongkol, Michael D. Smith, Nicholas J. WhiteAbstract:A prospective, open, randomized, comparative treatment trial was conducted to compare the therapeutic efficacy of the conventional four-drug combination (chloramphenicol, trimethoprimsulfamethoxazole, and doxycycline) with that of doxycycline alone in oral maintenance treatment of Melioidosis. Adult Thai patients with culture-confirmed Melioidosis were randomized to receive treatment with either regimen for a minimum of 12 weeks, usually following intravenous treatment of severe disease. The main outcome measure was culture-confirmed relapse. One hundred sixteen patients were enrolled; 109 had culture-confirmed Melioidosis, and 87 were considered evaluable (43 had received doxycycline). Culture-confirmed relapse occurred in one patient randomized to the conventional regimen and in 11 (25.6%) randomized to the doxycycline regimen (P = .009), and treatment failed for 8 (18.2%) versus 20 (46.5%), respectively (P = .009). Adverse effects occurred in 26% of patients overall. Doxycycline alone cannot be recommended for a first-line regimen of oral maintenance treatment of Melioidosis.
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comparison of imipenem and ceftazidime as therapy for severe Melioidosis
Clinical Infectious Diseases, 1999Co-Authors: Andrew J. H. Simpson, Wipada Chaowagul, Vanaporn Wuthiekanun, Brian Angus, Yupin Suputtamongkol, M D Smith, Adul Rajanuwong, P A Howe, Amanda L Walsh, Nicholas J. WhiteAbstract:An open, prospective, randomized, comparative treatment trial was conducted to compare the therapeutic efficacy of high-dose intravenous imipenem and ceftazidime for acute severe Melioidosis. Adult Thai patients with suspected acute, severe Melioidosis were randomized to receive either imipenem, at a dosage of 50 mg/(kg.d), or ceftazidime, at a dosage of 120 mg/(kg.d), for a minimum of 10 days. The main outcome measures were death or treatment failure. Of the 296 patients enrolled, 214 had culture-confirmed Melioidosis, and 132 (61.7%) of them had positive blood cultures. Mortality among patients with Melioidosis was 36.9% overall. There were no differences in survival overall (P = .96) or after 48 hours (P = .3). Treatment failure after 48 hours was more common among patients treated with ceftazidime (P = .011). Both treatments were well tolerated. Imipenem is a safe and effective treatment for acute severe Melioidosis and may be considered an alternative to ceftazidime.
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ceftazidime vs amoxicillin clavulanate in the treatment of severe Melioidosis
Clinical Infectious Diseases, 1994Co-Authors: Yupin Suputtamongkol, Wipada Chaowagul, Vanaporn Wuthiekanun, David A. B. Dance, M D Smith, Amanda L Walsh, A Rajchanuwong, S Pukrittayakamee, Nicholas J. WhiteAbstract:An open, paired, randomized, controlled trial of high-dose parenteral ceftazidime (120 mg/[kg.d]) vs. amoxicillin/clavulanate (160 mg/[kg.d]) for the treatment of severe Melioidosis was conducted in Ubon Ratchatani in northeastern Thailand. Of 379 patients enrolled in the study, 212 (56%) had culture-proven Melioidosis; 106 patients were in each treatment group. The overall mortality rate (47%) was similar for both treatment groups. However, 4 of 75 surviving patients in the ceftazidime group compared with 16 of 69 surviving patients in the amoxicillin/clavulanate group were switched to the alternate regimen because of an unsatisfactory clinical response after > or = 72 hours of treatment (P = .004). The overall therapeutic failure rate (i.e., treatment failure or death due to uncontrolled Melioidosis) was significantly higher for the amoxicillin/clavulanate group than for the ceftazidime group (P = .02). Clinical and bacteriologic responses for successfully treated patients were similar in both groups, and both treatments were well tolerated. Parenteral amoxicillin/clavulanate is a safe and effective initial treatment, but parenteral ceftazidime remains the treatment of choice for severe Melioidosis.
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the epidemiology of Melioidosis in ubon ratchatani northeast thailand
International Journal of Epidemiology, 1994Co-Authors: Yupin Suputtamongkol, Wipada Chaowagul, David A. B. Dance, Nicholas J. White, A J Hall, A Rajchanuvong, M D SmithAbstract:BACKGROUND Melioidosis, or infection with Pseudomonas pseudomallei is an important cause of morbidity and mortality in South East Asia and Northern Australia. The epidemiology of Melioidosis in Ubon Ratchatani, Northeast Thailand was studied over a 5-year period from 1987 to 1991. METHODS Rates and, when possible, the risks of developing Melioidosis were calculated. The numerator was the number of culture-proven cases of Melioidosis seen in the 1000-bed referral hospital of the province. The denominators were obtained from the population census, a survey of Health, Welfare and Use of Traditional Medicine, and the North Eastern Meterological Centre, Thailand. RESULTS The average incidence of human Melioidosis was 4.4 (95% confidence interval [CI]: 3.8-5.0) per 100,000. The disease affected all ages with the highest incidence in 40-60 years olds. Melioidosis was 1.4 (95% CI: 0.4-5.3) times more common in males than females. The disease showed a significant seasonal variation in incidence, and a strong linear correlation with rainfall (r = 0.7, 95% CI: 0.5-0.9) Adults exposed to soil and water in their work (most were rice farmers) had an increased risk of Melioidosis (in the 40-59 year age group, relative risk = 4.1, 95% CI: 2.4-6.9). Most adult patients had an underlying disease (mainly diabetes mellitus) predisposing them to this infection. CONCLUSION Melioidosis may result from either acute exposure to the organism in the soil and water, or 're-activation' of an asymptomatic childhood infection (by an unidentified possibly infective seasonal cofactor). The results from this analysis are consistent with both hypotheses. Further epidemiological studies are needed to identify risk factors so that optimal strategies for control of Melioidosis may be developed.
Sharon J. Peacock - One of the best experts on this subject based on the ideXlab platform.
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increased von willebrand factor decreased adamts13 and thrombocytopenia in Melioidosis
PLOS Neglected Tropical Diseases, 2017Co-Authors: Emma Birnie, Sharon J. Peacock, Gavin C K W Koh, Ester C Lowenberg, Joost C M Meijers, Rapeephan R Maude, Nicholas P J Day, Tom Van Der PollAbstract:BACKGROUND Melioidosis, caused by bioterror treat agent Burkholderia pseudomallei, is an important cause of community-acquired Gram-negative sepsis in Southeast Asia and Northern Australia. New insights into the pathogenesis of Melioidosis may help improve treatment and decrease mortality rates from this dreadful disease. We hypothesized that changes in Von Willebrand factor (VWF) function should occur in Melioidosis, based on the presence of endothelial stimulation by endotoxin, pro-inflammatory cytokines and thrombin in Melioidosis, and investigated whether this impacted on outcome. METHODS/PRINCIPAL FINDINGS We recruited 52 controls and 34 culture-confirmed Melioidosis patients at Sappasithiprasong Hospital in Ubon Ratchathani, Thailand. All subjects were diabetic. Platelet counts in Melioidosis patients were lower compared to controls (p = 0.0001) and correlated with mortality (p = 0.02). VWF antigen levels were higher in patients (geometric mean, 478 U/dl) compared to controls (166 U/dL, p<0.0001). The high levels of VWF in Melioidosis appeared to be due to increased endothelial stimulation (VWF propeptide levels were elevated, p<0.0001) and reduced clearance (ADAMTS13 reduction, p<0.0001). However, VWF antigen levels did not correlate with platelet counts implying that thrombocytopenia in acute Melioidosis has an alternative cause. CONCLUSIONS/SIGNIFICANCE Thrombocytopenia is a key feature of Melioidosis and is correlated with mortality. Additionally, excess VWF and ADAMTS13 deficiency are features of acute Melioidosis, but are not the primary drivers of thrombocytopenia in Melioidosis. Further studies on the role of thrombocytopenia in B. pseudomallei infection are needed.
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predicted global distribution of burkholderia pseudomallei and burden of Melioidosis
Nature microbiology, 2016Co-Authors: Direk Limmathurotsakul, Eric Bertherat, David A. B. Dance, Nicholas P J Day, Nick Golding, Jane P Messina, David M Pigott, Catherine L Moyes, Dionne B Rolim, Sharon J. PeacockAbstract:Burkholderia pseudomallei, a highly pathogenic bacterium that causes Melioidosis, is commonly found in soil in Southeast Asia and Northern Australia1,2. Melioidosis can be difficult to diagnose due to its diverse clinical manifestations and the inadequacy of conventional bacterial identification methods3. The bacterium is intrinsically resistant to a wide range of antimicrobials, and treatment with ineffective antimicrobials may result in case fatality rates (CFRs) exceeding 70%4,5. The importation of infected animals has, in the past, spread Melioidosis to non-endemic areas6,7. The global distribution of B. pseudomallei and burden of Melioidosis, however, remain poorly understood. Here, we map documented human and animal cases, and the presence of environmental B. pseudomallei, and combine this in a formal modelling framework8-10 to estimate the global burden of Melioidosis. We estimate there to be 165,000 (95% credible interval 68,000-412,000) human Melioidosis cases per year worldwide, of which 89,000 (36,000-227,000) die. Our estimates suggest that Melioidosis is severely underreported in the 45 countries in which it is known to be endemic and that Melioidosis is likely endemic in a further 34 countries which have never reported the disease. The large numbers of estimated cases and fatalities emphasise that the disease warrants renewed attention from public health officials and policy makers.
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nlrc4 and tlr5 each contribute to host defense in respiratory Melioidosis
PLOS Neglected Tropical Diseases, 2014Co-Authors: Nicolle D Myers, Eoin T West, Direk Limmathurotsakul, Vanaporn Wuthiekanun, Wirongrong Chierakul, Adeline M Hajjar, Narisara Chantratita, Edward A Miao, Sharon J. PeacockAbstract:Burkholderia pseudomallei causes the tropical infection Melioidosis. Pneumonia is a common manifestation of Melioidosis and is associated with high mortality. Understanding the key elements of host defense is essential to developing new therapeutics for Melioidosis. As a flagellated bacterium encoding type III secretion systems, B. pseudomallei may trigger numerous host pathogen recognition receptors. TLR5 is a flagellin sensor located on the plasma membrane. NLRC4, along with NAIP proteins, assembles a canonical caspase-1-dependent inflammasome in the cytoplasm that responds to flagellin (in mice) and type III secretion system components (in mice and humans). In a murine model of respiratory Melioidosis, Tlr5 and Nlrc4 each contributed to survival. Mice deficient in both Tlr5 and Nlrc4 were not more susceptible than single knockout animals. Deficiency of Casp1/Casp11 resulted in impaired bacterial control in the lung and spleen; in the lung much of this effect was attributable to Nlrc4, despite relative preservation of pulmonary IL-1β production in Nlrc4−/− mice. Histologically, deficiency of Casp1/Casp11 imparted more severe pulmonary inflammation than deficiency of Nlrc4. The human NLRC4 region polymorphism rs6757121 was associated with survival in Melioidosis patients with pulmonary involvement. Co-inheritance of rs6757121 and a functional TLR5 polymorphism had an additive effect on survival. Our results show that NLRC4 and TLR5, key components of two flagellin sensing pathways, each contribute to host defense in respiratory Melioidosis.
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clinical definitions of Melioidosis
American Journal of Tropical Medicine and Hygiene, 2013Co-Authors: Allen C Cheng, Andrew J. H. Simpson, Direk Limmathurotsakul, David A. B. Dance, Bart J. Currie, Simon G P Funnell, Sharon J. PeacockAbstract:Clinical definitions of Melioidosis and inhalation-acquired Melioidosis (Burkholderia pseudomallei infection) are described together with the evidence used to develop these definitions. Such definitions support accurate public health reporting, preparedness planning for deliberate B. pseudomallei release, design of experimental models, and categorization of naturally acquired Melioidosis.
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Impaired TLR5 Functionality Is Associated with Survival in Melioidosis
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: T. Eoin West, Nicolle D Myers, Direk Limmathurotsakul, Vanaporn Wuthiekanun, Wirongrong Chierakul, Narisara Chantratita, Mary J. Emond, Mark M. Wurfel, Thomas R. Hawn, Sharon J. PeacockAbstract:Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR51174C>T, to elucidate the role of TLR5 in Melioidosis. We measured NF-κB activation induced by B. pseudomallei in human embryonic kidney–293 cells transfected with TLR5 and found that B. pseudomallei induced TLR51174C- but not TLR51174T-dependent activation of NF-κB. We tested the association of TLR51174C>T with outcome in 600 Thai subjects with Melioidosis. In a dominant model, TLR51174C>T was associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08–0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19–0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR51174C>T genotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-α, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1β in carriers of TLR51174T compared with carriers of TLR51174C. B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR51174T. We conclude that the hypofunctional genetic variant TLR51174C>T is associated with reduced organ failure and improved survival in Melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in Melioidosis.