Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis

Weehuizen, Tassili A. F.; Lankelma, Jacqueline M.; Jong, Hanna K. de; Boer, Onno J. de; Roelofs, Joris J. T. H.; Day, Nicholas P. J.; Gram, Hermann; Vos, Alex F. de; Wiersinga, W. Joost

doi:10.1097/shk.0000000000000625

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…Patients with sepsis associated MAS might benefit from interleukin-1 receptor blockade [50]. In this respect, it is of interest that both the administration of anti-IL-1ra as well as anti-IL-1b protects against experimental melioidosis [52, 53]. …”

Section: Discussionmentioning

confidence: 99%

Increased Von Willebrand factor, decreased ADAMTS13 and thrombocytopenia in melioidosis

et al. 2017

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BackgroundMelioidosis, 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 findingsWe 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/SignificanceThrombocytopenia 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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Section: Discussionmentioning

confidence: 99%

Increased Von Willebrand factor, decreased ADAMTS13 and thrombocytopenia in melioidosis

et al. 2017

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“…A subsequent randomized controlled trial in Thailand showed no overall survival benefit with addition of G-CSF 200 ; nevertheless, survival was significantly longer in the G-CSF group in settings with limited intensive care resources, and adjuvant G-CSF is still used for melioidosis-associated septic shock in some hospitals with state-of-the-art intensive care facilities. Preclinical studies have shown that administration of clinically available IL-1β blocking agents can protect mice against overt B. pseudomallei infection and mortality 105,201 . This finding is in line with reports that patients with melioidosis who have diabetes mellitus and take glibenclamide (also known as glyburide) have a lower mortality and attenuated inflammatory responses compared with patients who do not take glibenclamide 202 (BOX 1).…”

Section: Managementmentioning

confidence: 99%

Melioidosis

Wiersinga

Virk

Torres

et al. 2018

Nat Rev Dis Primers

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525

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Burkholderia pseudomallei is a Gram-negative environmental bacterium and the aetiological agent of melioidosis, a life-threatening infection that is estimated to account for ∼89,000 deaths per year worldwide. Diabetes mellitus is a major risk factor for melioidosis, and the global diabetes pandemic could increase the number of fatalities caused by melioidosis. Melioidosis is endemic across tropical areas, especially in southeast Asia and northern Australia. Disease manifestations can range from acute septicaemia to chronic infection, as the facultative intracellular lifestyle and virulence factors of B. pseudomallei promote survival and persistence of the pathogen within a broad range of cells, and the bacteria can manipulate the host's immune responses and signalling pathways to escape surveillance. The majority of patients present with sepsis, but specific clinical presentations and their severity vary depending on the route of bacterial entry (skin penetration, inhalation or ingestion), host immune function and bacterial strain and load. Diagnosis is based on clinical and epidemiological features as well as bacterial culture. Treatment requires long-term intravenous and oral antibiotic courses. Delays in treatment due to difficulties in clinical recognition and laboratory diagnosis often lead to poor outcomes and mortality can exceed 40% in some regions. Research into B. pseudomallei is increasing, owing to the biothreat potential of this pathogen and increasing awareness of the disease and its burden; however, better diagnostic tests are needed to improve early confirmation of diagnosis, which would enable better therapeutic efficacy and survival.

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“…IL-1RA has been previously considered for the tempering of severe sepsis, and, despite interesting preliminary data, the clinical trial was halted. A non-statistically significant 9% enhancement of survival was observed in the IL-1RA treated sepsis patients [106]. Anakinra has been shown to have efficacy in a murine model of respiratory melioidosis [42,107].…”

Section: Therapeutics To Rebalance the Cytokine Networkmentioning

confidence: 98%

The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review

Laws

Taylor

Russell

et al. 2019

Expert Review of Anti-infective Therapy

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Introduction: Melioidosis is a significant health problem within endemic areas such as Southeast Asia and Northern Australia. The varied presentation of melioidosis and the intrinsic antibiotic resistance of Burkholderia pseudomallei, the causative organism, make melioidosis a difficult infection to manage. Often prolonged courses of antibiotic treatments are required with no guarantee of clinical success. Areas covered: B. pseudomallei is able to enter phagocytic cells, affect immune function, and replicate, via manipulation of the caspase system. An examination of this mechanism, and a look at other factors in the pathogenesis of melioidosis, shows that there are multiple potential points of therapeutic intervention, some of which may be complementary. These include the directed use of antimicrobial compounds, blocking virulence mechanisms, balancing or modulating cytokine responses, and ameliorating sepsis. Expert commentary: There may be therapeutic options derived from drugs in clinical use for unrelated conditions that may have benefit in melioidosis. Key compounds of interest primarily affect the disequilibrium of the cytokine response, and further preclinical work is needed to explore the utility of this approach and encourage the clinical research needed to bring these into beneficial use.

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Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis

Abstract: Supplemental Digital Content is available in the text

Cited by 14 publications

References 36 publications

Increased Von Willebrand factor, decreased ADAMTS13 and thrombocytopenia in melioidosis

Increased Von Willebrand factor, decreased ADAMTS13 and thrombocytopenia in melioidosis

Melioidosis

The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review

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