Dr Rob Van Der Pluijm

Research Area: Global Health
Technology Exchange: Bioinformatics and Drug discovery
Scientific Themes: Tropical Medicine & Global Health
Keywords: Malaria, Drug resistance, TACT, Triple ACTs, ACT failure and Plasmodium falciparum

Dr Rob van der Pluijm is the project coordinator of the second iteration of the TRAC project, known as TRAC II.

TRAC II aims to map resistance to antimalarials and assess the tolerability, safety and efficacy of two new triple artemisinin combination treatments (TACTs): Dihydroartemisinin-Piperaquine combined with Mefloquine and Artemether-Lumefantrine combined with Amodiaquine. The triple combinations will hopefully restore efficacy in areas where ACTs are currently starting to fail dramatically, whereas TACTs also aim to prolong the longevity of the artemisinins and partner drugs in areas where ACTs still work.

In addition, from July 2017 TRAC II assesses the safety tolerability and safety of another Triple ACT (arterolane-piperaquine combined with mefloquine in collaboration with the Kenya Medical Research Institute (KEMRI). A team from the London School of Hygiene and Tropical Medicine (LSHTM) is currently assessing the feasibility and efficacy of community led malaria elimination efforts.

Finally, the entomological (i.e. mosquito) factors in the spread of artemisinin resistance will be studied.

The UK’s Department For International Development (DFID) is the funder of the TRAC II trial.

There are no collaborations listed for this principal investigator.

van der Pluijm RW, Watson J, Woodrow CJ. 2017. Antimalarial Resistance Unlikely To Explain U.K. Artemether-Lumefantrine Failures. Antimicrob Agents Chemother, 61 (7), pp. e00721-17-e00721-17. | Read more

Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H, Smithuis FM, Hlaing TM, Tun KM, van der Pluijm RW et al. 2017. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect Dis, 17 (5), pp. 491-497. | Show Abstract | Read more

BACKGROUND: Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion. METHODS: In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness. FINDINGS: As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014-15, a single long PfKelch13 C580Y haplotype (-50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin. INTERPRETATION: Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective. FUNDING: The Wellcome Trust and the Bill and Melinda Gates Foundation.

van Eijk LT, Heemskerk S, van der Pluijm RW, van Wijk SM, Peters WHM, van der Hoeven JG, Kox M, Swinkels DW, Pickkers P. 2014. The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial. Haematologica, 99 (3), pp. 579-587. | Show Abstract | Read more

In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433±37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6±9.7% of baseline at T=8 h in the placebo group versus 84±15% and 60.4±8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-α, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699).

van Eijk LT, van der Pluijm RW, Ramakers BP, Dorresteijn MJ, van der Hoeven JG, Kox M, Pickkers P. 2014. Body mass index is not associated with cytokine induction during experimental human endotoxemia. Innate Immun, 20 (1), pp. 61-67. | Show Abstract | Read more

A higher body mass index (BMI) appears to be associated with lower mortality in critically ill patients, possibly explained by an altered innate immune response. However, the precise relationship between BMI and the innate immune response in humans in vivo is unknown. We investigated the relationship between BMI and the systemic cytokine response during experimental human endotoxemia. Endotoxemia was induced in 112 healthy male volunteers by intravenous administration of 2 ng/kg Escherichia coli endotoxin. Plasma concentrations of TNF-α, IL-6, IL-10 and IL-1RA were serially determined. The relationship between BMI and the cytokine response, as well as body temperature, was investigated. The BMIs of the participants ranged from 18.3 to 33.6 kg/m(2), (median: 22.7 kg/m(2)). All participants showed a marked increase in plasma cytokine levels [median (interquartile range)] peak levels: TNF-α 509 (353-673) pg/ml; IL-6 757 (522-1098) pg/ml; IL-10 271 (159-401) pg/ml; IL-1RA 4882 (3927-6025) pg/ml; and an increase in body temperature [1.8(1.4-2.2)] during endotoxemia. No significant correlations were found between BMI and levels of any of the cytokines or body temperature. No relationship between BMI and the cytokine response was found in healthy volunteers subjected to experimental endotoxemia. These data question the relationship between BMI and cytokine responses in critical illness.

van der Pluijm RW, Lamers MJ, de Boer M, van der Graaf WTA, van Laarhoven HWM. 2012. A female with a leiomyosarcoma presenting with acute thoracic pain and dyspnoea. Neth J Med, 70 (8), pp. 377-380.

Nelen WLDM, van der Pluijm RW, Hermens RPMG, Bergh C, de Sutter P, Nygren KG, Wetzels AMM, Grol RPTM, Kremer JAM. 2008. The methodological quality of clinical guidelines of the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod, 23 (8), pp. 1786-1792. | Show Abstract | Read more

BACKGROUND: Clinical practice guidelines bridge the gap between the evidence from literature and clinical practice, and they may provide guidance in ethical, legal and societal dilemmas. To explore the potentials for future international guideline development within the field of human reproduction and embryology, we assessed the quality of existing guidelines produced by the European Society of Human Reproduction and Embryology (ESHRE). METHODS: We systematically searched for the ESHRE guidelines produced after 1996 in electronic databases and on the Internet. Subsequently, we assessed the methodological quality of these guidelines using the validated Appraisal of Guidelines for Research and Evaluation (AGREE) Instrument. RESULTS: The overall methodological quality of most of the 11 selected ESHRE guidelines was poor. Most of the guidelines scored <30% in the domains of 'stakeholder involvement', 'rigour of development', 'applicability' and 'editorial independence'. Only one guideline was rated 'strongly recommended'. CONCLUSIONS: The methodological quality of the guidelines produced under the auspices of ESHRE can be improved. We suggest a systematic, up-to-date methodology, investment in guideline development specialists, systematic quality control and the incorporation of indicator development. Furthermore, attention should be paid to the document nomenclature, and an ESHRE guidelines' summary on a special part of the ESHRE website would be a good initiative.

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