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Clinical trials to assess adjuvant therapeutics for severe malaria

Abstract

Despite potent anti-malarial treatment, mortality rates associated with severe falciparum malaria remain high. To attempt to improve outcome, several trials have assessed a variety of potential adjunctive therapeutics, however none to date has been shown to be beneficial. This may be due, at least partly, to the therapeutics chosen and clinical trial design used. Here, we highlight three themes that could facilitate the choice and evaluation of putative adjuvant interventions for severe malaria, paving the way for their assessment in randomized controlled trials. Most clinical trials of adjunctive therapeutics to date have been underpowered due to the large number of participants required to reach mortality endpoints, rendering these study designs challenging and expensive to conduct. These limitations may be mitigated by the use of risk-stratification of participants and application of surrogate endpoints. Appropriate surrogate endpoints include direct measures of pathways causally involved in the pathobiology of severe and fatal malaria, including markers of host immune and endothelial activation and microcirculatory dysfunction. We propose using circulating markers of these pathways to identify high-risk participants that would be most likely to benefit from adjunctive therapy, and further by adopting these biomarkers as surrogate endpoints; moreover, choosing interventions that target deleterious host immune responses that directly contribute to microcirculatory dysfunction, multi-organ dysfunction and death; and, finally, prioritizing where possible, drugs that act on these pathways that are already approved by the FDA, or other regulators, for other indications, and are known to be safe in target populations, including children. An emerging understanding of the critical role of the host response in severe malaria pathogenesis may facilitate both clinical trial design and the search of effective adjunctive therapeutics.

Background

Mortality and morbidity rates associated with falciparum malaria infection remain high. The World Health Organization (WHO) estimated that malaria accounted for 405,000 deaths in 2018 [1], mostly affecting sub-Saharan African (SSA) children [1]. Despite effective treatment with artesunate, between 8.5% and 18% of patients diagnosed with severe malaria (SM) die [2] and up to 50% of cerebral malaria (CM) survivors may develop long-term neurological sequelae [3,4,5]. The Global Technical Strategy for Malaria 2016–2030 Report calls for at least a 90% reduction in malaria incidence and mortality by 2030 [6]. However, without new and accelerated interventions this goal will not be achieved. Thus, there is an urgent need to develop adjuvant therapies to be used concurrently with anti-malarial drugs to improve clinical outcomes.

SM is a multi-organ syndrome resulting from a complex interaction between both pathogen and host determinants, and its pathophysiology is yet to be fully understood [7]. However, it is becoming increasingly clear that endothelial and immune mediators play key roles in determining disease severity and outcome and thus represent attractive targets for host-directed interventions [8, 9]. There have been multiple efforts to identify adjunctive therapeutics, although to date none of these has been successful [10]. This likely reflects both our limited understanding of malaria physiopathology, as well as the challenges, cost and feasibility of conducting suitably powered randomized controlled trials (RCT) to evaluate mortality outcomes [11]. Most RCTs have relied on specific population sub-groups and were largely underpowered. In addition, study design/characteristics diverge widely between RCTs making it difficult to compare and extrapolate results from the available data [10]. Here, we outline three areas that may help to address limitations of previous efforts to identify effective adjunctive therapeutics.

Risk-stratification of patients with malaria

In SSA, there are challenges in the early recognition and triage of SM, with as few as 10% of malaria cases appropriately triaged for care and < 30% of SM cases diagnosed and treated promptly, resulting in increased mortality and brain injury in survivors [12, 13]. WHO criteria for SM are commonly used to recruit patients for RCTs [14]. However, these criteria, which are a mixture of clinical and laboratory parameters, are broad, have widely variable prognosis [15], may overlap and can present with other co-morbidities, making it difficult to assess and classify children [16]. Taylor et al. showed, in a post-mortem study, that 23% of children clinically diagnosed with CM, had died from other causes [16]. A recent meta-analysis highlighted the variability between SM-defining criteria and fatal outcomes. Some criteria, such as impaired consciousness, severe anaemia or prostration, are weakly associated, while others, such as renal failure and hyperlactataemia, are strongly correlated with death/outcome [11, 15]. Additionally, the changing epidemiology of SM has caused a shift in its clinical characteristics (e.g., children that develop SM are no longer primarily restricted to < 5 years of age) [17, 18].

It is important to re-evaluate WHO criteria to include emerging insights of SM pathogenesis and new aspects of SM epidemiology. Additionally, complementing WHO criteria with prognostic biomarkers could help identify high-risk patients that would most benefit from RCTs. Histidine-rich protein-2 (HRP-2), lactate, C-reactive protein (CRP) and procalcitonin (PCT), have all shown to be associated with poor outcomes in patients with SM, and have been considered for risk-stratification of children with malaria [19,20,21,22,23,24]. More recently, host-biomarkers of endothelial and immune activation, which may better reflect the pathological pathways underlying SM, have been identified as independent and quantitative markers of disease severity and outcome in both children and adults with malaria, both in Africa and Asia [25]. The most promising candidates are those that may be involved in casual pathways leading to death such as Angiopoietin-2 (Ang-2), soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), soluble FMS-like tyrosine kinase-1 (sFt-1), soluble tumour necrosis factor receptor 1 (sTNFR-1) and others [26,27,28]. Additional prospective studies to evaluate their predictive accuracy are required to define their potential clinical utility in triage and risk stratification. The available evidence to date supports Ang-2 as one marker that best addresses the priorities in this article and is also associated with disease severity in Plasmodium vivax and Plasmodium knowlesi infections [29, 30].

Ang-2, an integral member of the Ang/Tie axis, is a promising candidate for risk stratification and triage. During normal physiological states, the Ang/Tie axis is involved in maintaining endothelial integrity through the binding of Angiopoietin-1 (Ang-1) to its receptor Tie-2. SM triggers a pro-inflammatory environment which promotes the expression and release of Ang-2, the antagonist of Ang-1, which competes for binding to Tie-2 and destabilizes the microvasculature [31]. Preclinical studies in mice have shown a casual and mechanistic link of the Ang/Tie axis in the pathogenesis of SM [32]. Data from human studies strongly support Ang-2 as an excellent biomarker for malaria disease severity and related multi-organ dysfunction and death; consequently, Ang-2 is a valuable new option for identifying high-risk patients for RCTs [26, 27, 33,34,35]. Ang-2 plasma concentrations are higher in children with SM compared to those with uncomplicated malaria (UM) [27, 34, 36, 37], and have also been linked to CM with retinopathy [36]. Importantly, the identification of retinal changes in children with CM has been a major advance in the risk-stratification of those patients [38].

Searching for surrogate endpoints of mortality

Conducting RCTs can be costly and time-consuming and in low-and middle-income countries the challenges are even greater [11]. To demonstrate efficacy of adjunctive therapeutics in reducing mortality requires the enrolment of very large numbers of participants, which may be untenable due to cost and/or logistics. Power calculations indicate that at least 30,000 participants would have to be enrolled in order to observe a 10% change (parting from a 9% mortality rate) [11]. In an effort to address this problem the Severe Malaria African Children: A Clinical Network (SMAC) was created [39]. This was a multicentre pan-African effort to coordinate RCTs with mortality endpoints. Still, with such a network in place, it may take 3–4 years to enrol the required participants, meaning only a limited number of interventions can be assessed [11, 39]. Ultimately, underpowered studies can result in the inappropriate rejection of novel therapeutics because of their failure to show beneficial effects [11]. The identification of new surrogate endpoints, such as biomarker levels, might help address these problems. However, it is important to note that mortality should always be measured as a secondary endpoint in these RCTs, to allow a better characterization of the trends and relationships between levels of biomarkers and groups of treatment.

An appropriate surrogate endpoint should be able to predict/measure a clinical outcome for a specific intervention and be part of the casual pathway of the disease. This is particularly true when considering biomarkers, as if they are not direct readouts of the underlying pathobiology of SM, but rather just correlated to disease outcome, they may lead to confounding findings. Moreover, biomarkers used as surrogate endpoints and the intervention being assessed should also converge on the same pathways [40]. To date, the only proposed surrogate endpoint that has been validated for SM is plasma lactate. A secondary analysis, on three datasets from clinical studies looking at anti-malarial efficacies, showed that measuring changes in plasma lactate concentration at 8 or 12 h after intervention is a valid surrogate endpoint for mortality for treatments aiming to improve microcirculation [11]. However, lactate has a number of limitations discussed in detail by Jeeyapant et al. [11]. Briefly, these include that only a proportion of patients with SM will present with metabolic acidosis and that patients have poor outcomes related to multiple organ dysfunction (e.g., coma or acute kidney injury). Therefore, adjunctive therapies could improve survival through mechanisms that do not involve lactate clearance, and interventions that reduce lactate may not be effective adjunctive therapies.

In contrast to lactate, the Ang/Tie2 axis has been shown to have a causal relationship to severity and death for malaria [32] and Ang-2 concentrations are associated with multi-organ dysfunction leading to death, including acute kidney injury and coma [26, 41]. High Ang-2 concentrations have been linked to multi-organ dysfunction and mortality for multiple causes of sepsis, including malaria [27, 42,43,44,45]. Specifically, Ang-2 has been demonstrated to be elevated in patients with SM and to be an independent and quantitative predictor of mortality [27, 33]. Importantly, Ang-2 levels at admission are higher in children who die in hospital, as well as being associated with longer recovery times in survivors and post-discharge mortality [26]. Reduction in plasma levels of Ang-2 has already been used as a primary outcome in a RCT assessing inhaled nitric oxide as adjunctive therapy for paediatric SM [46]. Moreover, interventions targeting this pathway improve outcome in preclinical models [32, 47]. Taking into consideration the central role that endothelial activation and microcirculatory dysfunction play in SM pathogenesis and the mechanistic link that the Ang/Tie axis plays, we propose Ang-2 as another possible surrogate endpoint candidate, either alone or in conjunction with other markers such as lactate. Furthermore, lactate can already be measured using a point-of-care (POC) test and there is ongoing research trying to design similar POC devices for Ang-2 and other markers. This could facilitate the implementation and impact of marker-based risk-stratification in resource-constrained settings.

Drug repurposing

Identification of novel therapeutics is expensive, time consuming and risky, with many promising new chemical entities never reaching or showing efficacy in Phase III trials. In the field of cancer research, it has been estimated that de novo therapeutic development takes between 10 and 17 years with cost estimates of 1–2 billion USD [8]. However, this can be de-risked, at least in part, by drug repurposing, which involves the search of new therapeutic indications for already marketed drugs with known safety profiles [48]. With this strategy, success rates may be enhanced with dramatically reduced costs and timelines to RCTs [8, 49, 50]. Therefore, drug repurposing is an attractive avenue for therapeutic development in common and rare diseases, including SM [8, 49, 50].

The primary hurdle in drug repurposing is the identification of appropriate drugs to test. A multitude of databases, data mining tools and compound libraries are emerging to help the scientific community sift through the plethora of potential candidates [50]. For example, Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME), is an open access screening library of 12,000 compounds compiled from commercial drug competitive intelligence databases [51]. Such tools could be used towards identifying adjunctive therapeutics for SM that target either deleterious host immune responses and/or protect/stabilize the microvasculature. A recent review explores the advantages and challenges of using licensed pharmaceuticals, developed originally as therapy for cancer and neurological disease, as possible candidates for CM. Furthermore, they emphasize the importance of targeting pathways of microvascular stability and blood brain barrier (BBB) function [52]. However, an accelerated strategy will still require that any promising candidate be prospectively evaluated in phase II RCTs and then, if proven to be effective, further assessed in larger Phase III trials evaluating adverse events and mortality before they can be more widely implemented.

A direct example of drug repurposing used in the context of SM is rosiglitazone [53, 54]. Rosiglitazone, a peroxisome proliferator-activated receptor (PPARγ) agonist, with immunomodulatory activity and capacity to promote endothelial integrity, was originally developed to treat type II diabetes. PPARγ-agonists were initially investigated because they were predicted to act on similar gene response elements as vitamin A metabolites (e.g., 9-cis retinoic acid), which were associated with protection in malaria preclinical models and in vitamin A malaria studies [55, 56]. Current evidence supports its utility to modulate multiple pathways in malaria pathogenesis. Preclinical models have shown that rosiglitazone reduces levels of Ang-2, increases levels of Ang-1, stabilizes the BBB and is neuroprotective [47, 57]. Adjunctive treatment with rosiglitazone has been shown to decrease inflammatory biomarkers associated with adverse outcomes, and reduce parasite burdens in adults [54]. In addition, rosiglitazone has been demonstrated to be safe and well tolerated in children with UM [53]. Cumulatively, this has led to its assessment as an adjuvant therapy in children with SM in an ongoing Phase II clinical trial (clinicaltrials.gov: NCT02694874). The primary endpoint of which is to determine whether rosiglitazone, in addition to parenteral artesunate (standard of care anti-malarial treatment), accelerates the rate of decline in Ang-2 from admission levels, compared to standard of care plus placebo. Atorvastatin is another FDA-approved drug that has been suggested as a possible adjuvant therapy due to its anti-inflammatory and neuroprotective effects [9].

Current barriers for biomarker implementation

The future use of Ang-2 and other biomarkers in RCTs has some important limitations that need to be considered. Although these molecules are independent and quantitative markers of severity and outcome, it is unlikely that any single clinical or laboratory measurement will be uniformly predictive. Therefore, algorithms that combine predictive clinical (e.g., LODs [58] or qSOFA [59]) and marker data may ultimately be most predictive. Importantly, these algorithms still need to be developed and validated. Moreover, evaluation of baseline malaria mortality (irrespective of being recruited to a trial using biomarkers for risk-stratification) in the study population will need to be conducted, and would allow a better understanding of ‘real mortality risk’ in those not captured by biomarker levels. In addition, there is a clear variability in the thresholds/cut-offs and confidence intervals (CI) currently reported for biomarkers (including lactate and Ang-2) in association with mortality endpoints. There are many technical and methodological issues that may contribute to this variability and that currently preclude providing specific data on cut-offs/ranges. These include: the sample source (finger-prick versus venipuncture) and matrix used (whole blood, plasma (EDTA, heparin, etc.), serum); fresh versus frozen samples; the platform used to detect and quantitate the marker(s) (e.g., ELISA, Luminex™, ELLA™, etc.); patient population (adult, paediatric, underlying disease, HIV-1 infection).

What is clear is that there is an urgent need for rigorous prospective evaluation of candidate markers head-to-head under standardized protocols to first determine, and then validate cut-offs and CIs in further multi-site prospective studies. These studies have not yet been rigorously conducted and these issues will remain major barriers to the use of surrogate markers as endpoints of studies.

Conclusions

Our improved understanding of the pathobiology of SM should facilitate enhanced clinical trial design. Specifically: by decreasing required sample sizes by using biomarkers (e.g., Ang-2) to risk-stratify children and adults into RCTs; through the use of validated surrogate endpoints of mortality; and, via the search for safe FDA-approved drugs that modulate these underlying causal pathways (Fig. 1).

Fig. 1
figure1

Dysregulated host immune and endothelial activation as the rationale to enhance clinical trial design and identify adjunctive therapeutics for severe malaria. The host-response plays a central role in the pathogenesis and outcome of severe malaria (SM). Therefore, measuring levels of biomarkers of immune and endothelial activation, could be used both to identify patients that would benefit most from randomized control trials and as surrogate endpoints. FDA-approved drugs that protect and/or stabilize the host microvasculature and/or that are immunomodulatory could be repurposed as adjunctive therapeutics for severe malaria. These candidate therapeutics should be paired with the enhanced design of clinical trials

Availability of data and materials

Not applicable.

Abbreviations

Ang:

Angiopoietin

BBB:

Blood brain barrier

CI:

Confidence intervals

CM:

Cerebral malaria

CRP:

C-reactive protein

HRP-2:

Histidine-rich protein-2

PCT:

Procalcitonin

PPARγ:

Peroxisome proliferator-activated receptor

POC:

Point-of-care

RCT:

Randomized controlled trial

SM:

Severe malaria

SSA:

Sub-Saharan Africa

UM:

Uncomplicated malaria

WHO:

World Health Organization

References

  1. 1.

    WHO. World malaria report. Geneva: World Health Organization; 2019.

    Google Scholar 

  2. 2.

    Wassmer SC, Taylor TE, Rathod PK, Mishra SK, Mohanty S, Arevalo-Herrera M, et al. Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am J Trop Med Hyg. 2015;93:42–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Ssenkusu JM, Hodges JS, Opoka RO, Idro R, Shapiro E, John CC, et al. Long-term behavioral problems in children with severe malaria. Pediatrics. 2016;138:e20161965.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Bangirana P, Opoka RO, Boivin MJ, Idro R, Hodges JS, John CC. Neurocognitive domains affected by cerebral malaria and severe malarial anemia in children. Learn Individ Differ. 2016;46:38–44.

    PubMed  Google Scholar 

  5. 5.

    Langfitt JT, McDermott MP, Brim R, Mboma S, Potchen MJ, Kampondeni SD, et al. Neurodevelopmental impairments 1 year after cerebral malaria. Pediatrics. 2019;143:e20181026.

    PubMed  Google Scholar 

  6. 6.

    WHO. Global technical strategy for malaria 2016–2030. Geneva: World Health Organization; 2015.

    Google Scholar 

  7. 7.

    Miller LH, Baruch DI, Marsh K, Doumbo OK. The pathogenic basis of malaria. Nature. 2002;415:673–9.

    CAS  PubMed  Google Scholar 

  8. 8.

    Glennon EKK, Dankwa S, Smith JD, Kaushansky A. Opportunities for host-targeted therapies for malaria. Trends Parasitol. 2018;34:843–60.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Erice C, Kain KC. New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria. Virulence. 2019;10:1034–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Varo R, Crowley VM, Sitoe A, Madrid L, Serghides L, Kain KC, et al. Adjunctive therapy for severe malaria: a review and critical appraisal. Malar J. 2018;17:47.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Jeeyapant A, Kingston HW, Plewes K, Maude RJ, Hanson J, Herdman MT, et al. Defining surrogate endpoints for clinical trials in severe falciparum malaria. PLoS ONE. 2017;12:e0169307.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Makumbe B, Tshuma C, Shambira G, Mungati M, Gombe NT, Bangure D, et al. Evaluation of severe malaria case management in Mazowe District, Zimbabwe, 2014. Pan Afr Med J. 2017;27:33.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Zurovac D, Machini B, Kiptui R, Memusi D, Amboko B, Kigen S, et al. Monitoring health systems readiness and inpatient malaria case-management at Kenyan county hospitals. Malar J. 2018;17:213.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    WHO. Severe malaria. Trop Med Int Health. 2014;19(Suppl 1):7–131.

    Google Scholar 

  15. 15.

    Sypniewska P, Duda JF, Locatelli I, Althaus CR, Althaus F, Genton B. Clinical and laboratory predictors of death in African children with features of severe malaria: a systematic review and meta-analysis. BMC Med. 2017;15:147.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med. 2004;10:143–5.

    CAS  PubMed  Google Scholar 

  17. 17.

    Okiro EA, Al-Taiar A, Reyburn H, Idro R, Berkley JA, Snow RW. Age patterns of severe paediatric malaria and their relationship to Plasmodium falciparum transmission intensity. Malar J. 2009;8:4.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Roca-Feltrer A, Carneiro I, Smith L, Schellenberg JRMA, Greenwood B, Schellenberg D. The age patterns of severe malaria syndromes in sub-Saharan Africa across a range of transmission intensities and seasonality settings. Malar J. 2010;9:282.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MMU, Maude RJ, et al. The role of previously unmeasured organic acids in the pathogenesis of severe malaria. Crit Care. 2015;19:317.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Bhardwaj N, Ahmed M, Sharma S, Nayak A, Anvikar A, Pande V. C-reactive protein as a prognostic marker of Plasmodium falciparum malaria severity. J Vector Borne Dis. 2019;56:122–6.

    CAS  PubMed  Google Scholar 

  21. 21.

    Carannante N, Rossi M, Fraganza F, Coppola G, Chiesa D, Attanasio V, et al. A high PCT level correlates with disease severity in Plasmodium falciparum malaria in children. New Microbiol. 2017;40:72–4.

    PubMed  Google Scholar 

  22. 22.

    Seydel KB, Fox LL, Glover SJ, Reeves MJ, Pensulo P, Muiruri A, et al. Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children. J Infect Dis. 2012;206:309–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hendriksen IC, White LJ, Veenemans J, Mtove G, Woodrow C, Amos B, et al. Defining falciparum-malaria-attributable severe febrile illness in moderate-to-high transmission settings on the basis of plasma PfHRP2 concentration. J Infect Dis. 2013;207:351–61.

    CAS  PubMed  Google Scholar 

  24. 24.

    Krishna S, Waller DW, ter Kuile F, Kwiatkowski D, Crawley J, Craddock CF, et al. Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. Trans R Soc Trop Med Hyg. 1994;88:67–73.

    CAS  PubMed  Google Scholar 

  25. 25.

    McDonald CR, Weckman A, Richard-Greenblatt M, Leligdowicz A, Kain KC. Integrated fever management: disease severity markers to triage children with malaria and non-malarial febrile illness. Malar J. 2018;17:353.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Conroy AL, Hawkes M, McDonald CR, Kim H, Higgins SJ, Barker KR, et al. Host biomarkers are associated with response to therapy and long-term mortality in pediatric severe malaria. Open Forum Infect Dis. 2016;3:ofw134.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Erdman LK, Dhabangi A, Musoke C, Conroy AL, Hawkes M, Higgins S, et al. Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case-control study. PLoS ONE. 2011;6:e17440.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Adukpo S, Gyan BA, Ofori MF, Dodoo D, Velavan TP, Meyer CG. Triggering receptor expressed on myeloid cells 1 (TREM-1) and cytokine gene variants in complicated and uncomplicated malaria. Trop Med Int Health. 2016;21:1592–601.

    CAS  PubMed  Google Scholar 

  29. 29.

    Woodford J, Yeo TW, Piera KA, Butler K, Weinberg JB, McCarthy JS, et al. Early endothelial activation precedes glycocalyx degradation and microvascular dysfunction in experimentally induced Plasmodium falciparum and Plasmodium vivax infection. Infect Immun. 2020;88:e00895–1019.

    CAS  PubMed  Google Scholar 

  30. 30.

    Barber BE, Grigg MJ, Piera KA, William T, Cooper DJ, Plewes K, et al. Intravascular haemolysis in severe Plasmodium knowlesi malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury. Emerg Microbes Infect. 2018;7:106.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Leligdowicz A, Richard-Greenblatt M, Wright J, Crowley VM, Kain KC. Endothelial activation: the Ang/Tie axis in sepsis. Front Immunol. 2018;9:838.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Higgins SJ, Purcell LA, Silver KL, Tran V, Crowley V, Hawkes M, et al. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Sci Transl Med. 2016;8:358ra128.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, Price RN, et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci USA. 2008;105:17097–102.

    CAS  PubMed  Google Scholar 

  34. 34.

    Lovegrove FE, Tangpukdee N, Opoka RO, Lafferty EI, Rajwans N, Hawkes M, et al. Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS ONE. 2009;4:e4912.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Conroy AL, Phiri H, Hawkes M, Glover S, Mallewa M, Seydel KB, et al. Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study. PLoS ONE. 2010;5:e15291.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Conroy AL, Glover SJ, Hawkes M, Erdman LK, Seydel KB, Taylor TE, et al. Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study. Crit Care Med. 2012;40:952–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Conroy AL, Lafferty EI, Lovegrove FE, Krudsood S, Tangpukdee N, Liles WC, et al. Whole blood angiopoietin-1 and -2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar J. 2009;8:295.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    MacCormick IJ, Beare NA, Taylor TE, Barrera V, White VA, Hiscott P, et al. Reply: Retinopathy, histidine-rich protein-2 and perfusion pressure in cerebral malaria. Brain. 2014;137:e299.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Taylor T, Olola C, Valim C, Agbenyega T, Kremsner P, Krishna S, et al. Standardized data collection for multi-center clinical studies of severe malaria in African children: establishing the SMAC network. Trans R Soc Trop Med Hyg. 2006;100:615–22.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012;31:2973–84.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Bangirana P, Conroy AL, Opoka RO, Hawkes MT, Hermann L, Miller C, et al. Inhaled nitric oxide and cognition in pediatric severe malaria: a randomized double-blind placebo controlled trial. PLoS ONE. 2018;13:e0191550.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Jain V, Lucchi NW, Wilson NO, Blackstock AJ, Nagpal AC, Joel PK, et al. Plasma levels of angiopoietin-1 and -2 predict cerebral malaria outcome in Central India. Malar J. 2011;10:383.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Ricciuto DR, dos Santos CC, Hawkes M, Toltl LJ, Conroy AL, Rajwans N, et al. Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med. 2011;39:702–10.

    CAS  PubMed  Google Scholar 

  44. 44.

    Wright JK, Hayford K, Tran V, Al Kibria GM, Baqui A, Manajjir A, et al. Biomarkers of endothelial dysfunction predict sepsis mortality in young infants: a matched case-control study. BMC Pediatr. 2018;18:118.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Mikacenic C, Hahn WO, Price BL, Harju-Baker S, Katz R, Kain KC, et al. Biomarkers of Endothelial activation are associated with poor outcome in critical illness. PLoS ONE. 2015;10:e0141251.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Hawkes MT, Conroy AL, Opoka RO, Hermann L, Thorpe KE, McDonald C, et al. Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial. Malar J. 2015;14:421.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Serghides L, McDonald CR, Lu Z, Friedel M, Cui C, Ho KT, et al. PPARgamma agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria. PLoS Pathog. 2014;10:e1003980.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673–83.

    CAS  PubMed  Google Scholar 

  49. 49.

    Bhattarai D, Singh S, Jang Y, Hyeon Han S, Lee K, Choi Y. An insight into drug repositioning for the development of novel anti-cancer drugs. Curr Top Med Chem. 2016;16:2156–68.

    CAS  PubMed  Google Scholar 

  50. 50.

    Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18:41–58.

    CAS  PubMed  Google Scholar 

  51. 51.

    Janes J, Young ME, Chen E, Rogers NH, Burgstaller-Muehlbacher S, Hughes LD, et al. The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Proc Natl Acad Sci USA. 2018;115:10750–5.

    CAS  PubMed  Google Scholar 

  52. 52.

    Brooks HM, Hawkes MT. Repurposing pharmaceuticals as neuroprotective agents for cerebral malaria. Curr Clin Pharmacol. 2017;12:62–72.

    CAS  PubMed  Google Scholar 

  53. 53.

    Varo R, Crowley VM, Sitoe A, Madrid L, Serghides L, Bila R, et al. Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria. Malar J. 2017;16:215.

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Boggild AK, Krudsood S, Patel SN, Serghides L, Tangpukdee N, Katz K, et al. Use of peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for Plasmodium falciparum malaria: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2009;49:841–9.

    CAS  PubMed  Google Scholar 

  55. 55.

    Serghides L, Kain KC. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet. 2002;359:1404–6.

    PubMed  Google Scholar 

  56. 56.

    Serghides L, Kain KC. Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-alpha secretion by monocytes/macrophages. J Immunol. 2001;166:6742–8.

    CAS  PubMed  Google Scholar 

  57. 57.

    Serghides L, Patel SN, Ayi K, Lu Z, Gowda DC, Liles WC, et al. Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria. J Infect Dis. 2009;199:1536–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Helbok R, Kendjo E, Issifou S, Lackner P, Newton CR, Kombila M, et al. The Lambarene Organ Dysfunction Score (LODS) is a simple clinical predictor of fatal malaria in African children. J Infect Dis. 2009;200:1834–41.

    PubMed  Google Scholar 

  59. 59.

    Teparrukkul P, Hantrakun V, Imwong M, Teerawattanasook N, Wongsuvan G, Day NP, et al. Utility of qSOFA and modified SOFA in severe malaria presenting as sepsis. PLoS ONE. 2019;14:e0223457.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. CISM is supported by the Government of Mozambique and the Spanish Agency for International Development (AECID).

Funding

This work was supported in part by grants from the Canadian Institutes of Health Research (CIHR FDN 148439 to KCK), the Canada Research Chairs program (KCK) and The Tesari Foundation.

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RV and CE contributed equally and share first co-authorship. QB and KCK share senior co-authorship. The manuscript was prepared with input from RV, CE, SJ, QB and KCK. All authors read and approved the final manuscript.

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Correspondence to Kevin C. Kain.

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Competing interests

KCK is a named inventor on a patent “Biomarkers for early determination of a critical or life-threatening response to illness and/or treatment response” held by the University Health Network. Remaining authors declare that they have no competing interests.

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Varo, R., Erice, C., Johnson, S. et al. Clinical trials to assess adjuvant therapeutics for severe malaria. Malar J 19, 268 (2020). https://doi.org/10.1186/s12936-020-03340-3

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Keywords

  • Severe malaria
  • Angiopoietin-2
  • Immune and endothelial activation
  • Microvascular dysfunction
  • Host-biomarkers
  • Surrogate endpoints
  • Drug repurposing