New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria

References

• Wassmer SC, Grau GE. Severe malaria: what’s new on the pathogenesis front? Int J Parasitol. 2017;47(2–3):145–152.
   Google Scholar
• Varo R, Crowley VM, Sitoe A, et al. Adjunctive therapy for severe malaria: a review and critical appraisal. Malar J. 2018;17(1):47.
   Google Scholar
• World Health Organization. World malaria report. Geneva: WHO; 2018.
   Google Scholar
• Manning L, Laman M, Davis WA, et al. Clinical features and outcome in children with severe Plasmodium falciparum malaria: a meta-analysis. PLoS One. 2014;9(2):e86737.
   Google Scholar
• Wassmer SC, Taylor TE, Rathod PK, et al. Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am J Trop Med Hyg. 2015;93(3 Suppl):42–56.
   Google Scholar
• Barber BE, William, T, Grigg, MJ, et al. A prospective comparative study of knowlesi, falciparum, and vivax malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium vivax but no mortality with early referral and artesunate therapy. Clin Infect Dis. 2013;56(3):383–397.
   Google Scholar
• William T, Menon J, Rajahram G, et al. Severe Plasmodium knowlesi malaria in a tertiary care hospital, Sabah, Malaysia. Emerg Infect Dis. 2011;17(7):1248–1255.
   Google Scholar
• Barber BE, William T, Grigg MJ, et al. Parasite biomass-related inflammation, endothelial activation, microvascular dysfunction and disease severity in vivax malaria. PLoS Pathog. 2015;11(1):e1004558.
   Google Scholar
• Conroy AL, Datta D, John CC. What causes severe malaria and its complications in children? Lessons learned over the past 15 years. BMC Med. 2019;17(1):52.
   Google Scholar
• Sypniewska P, Duda JF, Locatelli I, et al. Clinical and laboratory predictors of death in African children with features of severe malaria: a systematic review and meta-analysis. BMC Med. 2017;15(1):147.
   Google Scholar
• Miller LH, Ackerman HC, Su X-Z, et al. Malaria biology and disease pathogenesis: insights for new treatments. Nat Med. 2013;19(2):156–167.
   Google Scholar
• Langfitt JT, McDermott MP, Brim R, et al. Neurodevelopmental impairments 1 year after cerebral malaria. Pediatrics. 2019;143(2):e20181026.
   Google Scholar
• John CC, Bangirana P, Byarugaba J, et al. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics. 2008;122(1):e92–e99.
   Google Scholar
• Idro R, Marsh K, John CC, et al. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res. 2010;68(4):267–274.
   Google Scholar
• Bangirana P, Opoka RO, Boivin MJ, et al. Severe malarial anemia is associated with long-term neurocognitive impairment. Clinl Infect Dis. 2014;59(3):336–344.
   Google Scholar
• Makumbe B, Tshuma C, Shambira G, et al. Evaluation of severe malaria case management in Mazowe District, Zimbabwe, 2014. Pan Afr Med J. 2017;27:33.
   Google Scholar
• Zurovac D, Machini B, Kiptui R, et al. Monitoring health systems readiness and inpatient malaria case-management at Kenyan county hospitals. Malar J. 2018;17(1):213.
   Google Scholar
• Namuyinga RJ, Mwandama D, Moyo D, et al. Health worker adherence to malaria treatment guidelines at outpatient health facilities in southern Malawi following implementation of universal access to diagnostic testing. Malar J. 2017;16(1):40.
   Google Scholar
• Glennon EKK, Dankwa S, Smith JD, et al. Opportunities for host-targeted therapies for malaria. Trends Parasitol. 2018;34(10):843–860.
   Google Scholar
• McDonald CR, Weckman A, Richard-Greenblatt M, et al. Integrated fever management: disease severity markers to triage children with malaria and non-malarial febrile illness. Malar J. 2018;17(1):353.
   Google Scholar
• Conroy AL, Hawkes M, McDonald CR, et al. Host biomarkers are associated with response to therapy and long-term mortality in pediatric severe malaria. Open Forum Infect Dis. 2016;3(3):ofw134.
   Google Scholar
• Bassat Q. The perks of prognostic biomarkers: A paradigm switch in the triage of sick febrile patients. Clin Infect Dis. 2019. doi: 10.1093/cid/ciz420
   Google Scholar
• Grau GE, Craig AG. Cerebral malaria pathogenesis: revisiting parasite and host contributions. Future Microbiol. 2012;7(2):291–302.
   Google Scholar
• David PH, Hommel M, Miller LH, et al. Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes. Proc Natl Acad Sci U S A. 1983;80(16):5075–5079.
   Google Scholar
• Smith JD, Rowe JA, Higgins MK, et al. Malaria’s deadly grip: cytoadhesion of Plasmodium falciparum-infected erythrocytes. Cell Microbiol. 2013;15(12):1976–1983.
   Google Scholar
• van der Heyde HC, Nolan J, Combes V, et al. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol. 2006;22(11):503–508.
   Google Scholar
• Fox LL, Taylor TE, Pensulo P, et al. Histidine-rich protein 2 plasma levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum infection. J Infect Dis. 2013;208(3):500–503.
   Google Scholar
• Duffy F, Bernabeu M, Babar PH, et al. Meta-analysis of plasmodium falciparum var signatures contributing to severe malaria in African children and Indian adults. MBio. 2019;10(2):e00217-19.
   Google Scholar
• Storm J, Jespersen JS, Seydel KB, et al. Cerebral malaria is associated with differential cytoadherence to brain endothelial cells. EMBO Mol Med. 2019;11(2):e9164.
   Google Scholar
• Bernabeu M, Smith JD. EPCR and malaria severity: the center of a perfect storm. Trends Parasitol. 2017;33(4):295–308.
   Google Scholar
• Turner L, Lavstsen T, Berger SS, et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature. 2013;498(7455):502–505.
   Google Scholar
• Kessler A, Dankwa S, Bernabeu M, et al. Linking EPCR-Binding PfEMP1 to brain swelling in pediatric cerebral malaria. Cell Host Microbe. 2017;22(5):601–614. e5.
   Google Scholar
• Wang CW, Hviid L. Rifins, rosetting, and red blood cells. Trends Parasitol. 2015;31(7):285–286.
   Google Scholar
• David PH, Mendis KN, Handunnetti SM, et al. Uninfected erythrocytes form “rosettes” around Plasmodium falciparum infected erythrocytes. Am J Trop Med Hyg. 1989;40(2):115–118.
   Google Scholar
• Yam XY, Niang M, Madnani KG, et al. Three is a crowd - new insights into rosetting in plasmodium falciparum. Trends Parasitol. 2017;33(4):309–320.
   Google Scholar
• Doumbo OK, Plowe CV, Lyke KE, et al. High levels of Plasmodium falciparum rosetting in all clinical forms of severe malaria in African children. Am J Trop Med Hyg. 2009;81(6):987–993.
   Google Scholar
• Pain A, Ferguson DJP, Kai O, et al. Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc Natl Acad Sci U S A. 2001;98(4):1805–1810.
   Google Scholar
• Wassmer SC, Taylor T, MacLennan C, et al. Platelet-induced clumping of Plasmodium falciparum-infected erythrocytes from Malawian patients with cerebral malaria-possible modulation in vivo by thrombocytopenia. J Infect Dis. 2008;197(1):72–78.
   Google Scholar
• Auer-Hackenberg L, Winkler S, Graninger W, et al. Current evidence and future of automated erythrocyte exchange in the treatment of severe malaria. Wien Klin Wochenschr. 2012;124(Suppl 3):23–26.
   Google Scholar
• Leslie M. Immunology. The new view of complement. Science. 2012;337(6098):1034–1037.
   Google Scholar
• Biryukov S, Stoute JA. Complement activation in malaria: friend or foe? Trends Mol Med. 2014;20(5):293–301.
   Google Scholar
• O’Sullivan JM, Preston RJS, O’Regan N, et al. Emerging roles for hemostatic dysfunction in malaria pathogenesis. Blood. 2016;127(19):2281–2288.
   Google Scholar
• Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res. 2016;118(9):1392–1408.
   Google Scholar
• Keragala CB, Draxler DF, McQuilten ZK, et al. Haemostasis and innate immunity - a complementary relationship: A review of the intricate relationship between coagulation and complement pathways. Br J Haematol. 2018;180(6):782–798.
   Google Scholar
• Francischetti IM. Does activation of the blood coagulation cascade have a role in malaria pathogenesis? Trends Parasitol. 2008;24(6):258–263.
   Google Scholar
• Francischetti IM, Seydel KB, Monteiro RQ, et al. Plasmodium falciparum-infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes. J Thromb Haemost. 2007;5(1):155–165.
   Google Scholar
• Silver KL, Higgins SJ, McDonald CR, et al. Complement driven innate immune response to malaria: fuelling severe malarial diseases. Cell Microbiol. 2010;12(8):1036–1045.
   Google Scholar
• Conroy A, Serghides L, Finney C, et al. C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria. PLoS One. 2009;4(3):e4953.
   Google Scholar
• Helegbe GK, Goka BQ, Kurtzhals JA, et al. Complement activation in Ghanaian children with severe Plasmodium falciparum malaria. Malar J. 2007;6:165.
   Google Scholar
• Wenisch C, Spitzauer S, Florris-Linau K, et al. Complement activation in severe Plasmodium falciparum malaria. Clin Immunol Immunopathol. 1997;85(2):166–171.
   Google Scholar
• Frimat M, Tabarin F, Dimitrov JD, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood. 2013;122(2):282–292.
   Google Scholar
• Patel SN, Berghout J, Lovegrove FE, et al. C5 deficiency and C5a or C5aR blockade protects against cerebral malaria. J Exp Med. 2008;205(5):1133–1143.
   Google Scholar
• Higgins SJ, Kain KC, Liles WC. Immunopathogenesis of falciparum malaria: implications for adjunctive therapy in the management of severe and cerebral malaria. Expert Rev Anti Infect Ther. 2011;9(9):803–819.
   Google Scholar
• Kern P, Hemmer CJ, Damme JV, et al. Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria. Am J Med. 1989;87(2):139–143.
   Google Scholar
• Dunst J, Kamena F, Matuschewski K. Cytokines and Chemokines in Cerebral Malaria Pathogenesis. Front Cell Infect Microbiol. 2017;7:324.
   Google Scholar
• Kumar M, Varun CN, Dey G, et al. Identification of host-response in cerebral malaria patients using quantitative proteomic analysis. Proteomics Clin Appl. 2018;12(4):e1600187.
   Google Scholar
• Sobota RS, Dara A, Manning JE, et al. Expression of complement and toll-like receptor pathway genes is associated with malaria severity in Mali: a pilot case control study. Malar J. 2016;15:150.
   Google Scholar
• Kim H, Erdman LK, Lu Z, et al. Functional roles for C5a and C5aR but not C5L2 in the pathogenesis of human and experimental cerebral malaria. Infect Immun. 2014;82(1):371–379.
   Google Scholar
• Berg A, Otterdal K, Patel S, et al. Complement activation correlates with disease severity and contributes to cytokine responses in plasmodium falciparum malaria. J Infect Dis. 2015;212(11):1835–1840.
   Google Scholar
• Nyakoe NK, Taylor RP, Makumi JN, et al. Complement consumption in children with Plasmodium falciparum malaria. Malar J. 2009;8:7.
   Google Scholar
• Stoute JA, Odindo A, Owuor B, et al. Loss of red blood cell-complement regulatory proteins and increased levels of circulating immune complexes are associated with severe malarial anemia. J Infect Dis. 2003;187(3):522–525.
   Google Scholar
• Oyong DA, Kenangalem E, Poespoprodjo JR, et al. Loss of complement regulatory proteins on uninfected erythrocytes in vivax and falciparum malaria anemia. JCI Insight. 2018;3(22):e124854.
   Google Scholar
• Perkins DJ, Were T, Davenport GC, et al. Severe malarial anemia: innate immunity and pathogenesis. Int J Biol Sci. 2011;7(9):1427–1442.
   Google Scholar
• McDonald CR, Cahill LS, Ho KT, et al. Experimental malaria in pregnancy induces neurocognitive injury in uninfected offspring via a C5a-C5a receptor dependent pathway. PLoS Pathog. 2015;11(9):e1005140.
   Google Scholar
• McDonald CR, Tran V, Kain KC. Complement activation in placental malaria. Front Microbiol. 2015;6:1460.
   Google Scholar
• Conroy AL, Glover SJ, Hawkes M, 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(3):952–959.
   Google Scholar
• Combes V, Taylor TE, Juhan-Vague I, et al. Circulating endothelial microparticles in malawian children with severe falciparum malaria complicated with coma. JAMA. 2004;291(21):2542–2544.
   Google Scholar
• Hollestelle MJ, Donkor C, Mantey EA, et al. von Willebrand factor propeptide in malaria: evidence of acute endothelial cell activation. Br J Haematol. 2006;133(5):562–569.
   Google Scholar
• Larkin D, de Laat B, Jenkins PV, et al. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. PLoS Pathog. 2009;5(3):e1000349.
   Google Scholar
• Jakobsen PH, Morris-Jones S, Rønn A, et al. Increased plasma concentrations of sICAM-1, sVCAM-1 and sELAM-1 in patients with Plasmodium falciparum or P. vivax malaria and association with disease severity. Immunology. 1994;83(4):665–669.
   Google Scholar
• Turner GD, Ly VC, Nguyen TH, et al. Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. Am J Pathol. 1998;152(6):1477–1487.
   Google Scholar
• Tchinda VH, Tadem AD, Tako EA, et al. Severe malaria in Cameroonian children: correlation between plasma levels of three soluble inducible adhesion molecules and TNF-alpha. Acta Trop. 2007;102(1):20–28.
   Google Scholar
• Erdman LK, Dhabangi A, Musoke C, et al. Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case-control study. PLoS One. 2011;6(2):e17440.
   Google Scholar
• Conroy AL, Phiri H, Hawkes M, et al. Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study. PLoS One. 2010;5(12):e15291.
   Google Scholar
• Conroy AL, Hawkes MT, Elphinstone R, et al. Chitinase-3-like 1 is a biomarker of acute kidney injury and mortality in paediatric severe malaria. Malar J. 2018;17(1):82.
   Google Scholar
• Graham SM, Chen J, Chung DW, et al. Endothelial activation, haemostasis and thrombosis biomarkers in Ugandan children with severe malaria participating in a clinical trial. Malar J. 2016;15:56.
   Google Scholar
• Tripathi AK, Sha W, Shulaev V, et al. Plasmodium falciparum-infected erythrocytes induce NF-kappaB regulated inflammatory pathways in human cerebral endothelium. Blood. 2009;114(19):4243–4252.
   Google Scholar
• de Jong GM, Slager JJ, Verbon A, et al. Systematic review of the role of angiopoietin-1 and angiopoietin-2 in Plasmodium species infections: biomarkers or therapeutic targets? Malar J. 2016;15(1):581.
   Google Scholar
• Leligdowicz A, Richard-Greenblatt M, Wright J, et al. Endothelial activation: the ang/tie axis in sepsis. Front Immunol. 2018;9:838.
   Google Scholar
• Page AV, Liles WC. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence. 2013;4(6):507–516.
   Google Scholar
• Dai C, Gong Q, Cheng Y, et al. Regulatory mechanisms of Robo4 and their effects on angiogenesis. Biosci Rep. 2019;39(7):BSR20190513.
   Google Scholar
• Jones CA, Nishiya N, London NR, et al. Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nat Cell Biol. 2009;11(11):1325–1331.
   Google Scholar
• Mulik S, Sharma S, Suryawanshi A, et al. Activation of endothelial roundabout receptor 4 reduces the severity of virus-induced keratitis. J Immunol. 2011;186(12):7195–7204.
   Google Scholar
• Zhao H, Anand AR, Ganju RK. Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. J Immunol. 2014;192(1):385–393.
   Google Scholar
• London NR, Zhu W, Bozza FA, et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med. 2010;2(23):23ra19.
   Google Scholar
• Kim H, Higgins S, Liles WC, et al. Endothelial activation and dysregulation in malaria: a potential target for novel therapeutics. Curr Opin Hematol. 2011;18(3):177–185.
   Google Scholar
• Yeo TW, Lampah DA, Gitawati R, et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A. 2008;105(44):17097–17102.
   Google Scholar
• Conroy AL, Lafferty EI, Lovegrove FE, et al. Whole blood angiopoietin-1 and −2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar J. 2009;8:295.
   Google Scholar
• Lovegrove FE, Tangpukdee N, Opoka RO, 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(3):e4912.
   Google Scholar
• Jain V, Lucchi NW, Wilson NO, et al. Plasma levels of angiopoietin-1 and −2 predict cerebral malaria outcome in Central India. Malar J. 2011;10:383.
   Google Scholar
• Higgins SJ, Purcell LA, Silver KL, et al. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Sci Transl Med. 2016;8(358):358ra128.
   Google Scholar
• Canavese M, Spaccapelo R. Protective or pathogenic effects of vascular endothelial growth factor (VEGF) as potential biomarker in cerebral malaria. Pathog Glob Health. 2014;108(2):67–75.
   Google Scholar
• Casals-Pascual C, Idro R, Gicheru N, et al. High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria. Proc Natl Acad Sci U S A. 2008;105(7):2634–2639.
   Google Scholar
• Jain V, Armah HB, Tongren JE, et al. Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar J. 2008;7:83.
   Google Scholar
• Yeo TW, Lampah DA, Gitawati R, et al. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med. 2007;204(11):2693–2704.
   Google Scholar
• Anstey NM, Weinberg JB, Hassanali MY, et al. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med. 1996;184(2):557–567.
   Google Scholar
• Lopansri BK, Anstey NM, Weinberg JB, et al. Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production. Lancet. 2003;361(9358):676–678.
   Google Scholar
• Weinberg JB, Lopansri BK, Mwaikambo E, et al. Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria. Curr Opin Infect Dis. 2008;21(5):468–475.
   Google Scholar
• Gladwin MT, Kanias T, Kim-Shapiro DB. Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease. J Clin Invest. 2012;122(4):1205–1208.
   Google Scholar
• Ferreira A, Balla J, Jeney V, et al. A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med (Berl). 2008;86(10):1097–1111.
   Google Scholar
• Hunt NH, Stocker R. Heme moves to center stage in cerebral malaria. Nat Med. 2007;13(6):667–669.
   Google Scholar
• Belcher JD, Beckman JD, Balla G, et al. Heme degradation and vascular injury. Antioxid Redox Signal. 2010;12(2):233–248.
   Google Scholar
• Figueiredo RT, Fernandez PL, Mourao-Sa DS, et al. Characterization of heme as activator of Toll-like receptor 4. J Biol Chem. 2007;282(28):20221–20229.
   Google Scholar
• Porto BN, Alves LS, Fernández PL, et al. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J Biol Chem. 2007;282(33):24430–24436.
   Google Scholar
• Yeo TW, Lampah DA, Tjitra E, et al. Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria. J Infect Dis. 2009;200(10):1522–1529.
   Google Scholar
• Guarda CCD, Santiago RP, Fiuza LM, et al. Heme-mediated cell activation: the inflammatory puzzle of sickle cell anemia. Expert Rev Hematol. 2017;10(6):533–541.
   Google Scholar
• Pawluczkowycz AW, Lindorfer MA, Waitumbi JN, et al. Hematin promotes complement alternative pathway-mediated deposition of C3 activation fragments on human erythrocytes: potential implications for the pathogenesis of anemia in malaria. J Immunol. 2007;179(8):5543–5552.
   Google Scholar
• Elphinstone RE, Riley F, Lin T, et al. Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children. Malar J. 2015;14:511.
   Google Scholar
• Pamplona A, Ferreira A, Balla J, et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med. 2007;13(6):703–710.
   Google Scholar
• Dalko E, Das B, Herbert F, et al. Multifaceted role of heme during severe plasmodium falciparum infections in India. Infect Immun. 2015;83(10):3793–3799.
   Google Scholar
• Elphinstone RE, Conroy AL, Hawkes M, et al. Alterations in systemic extracellular heme and hemopexin are associated with adverse clinical outcomes in Ugandan children with severe malaria. J Infect Dis. 2016;214(8):1268–1275.
   Google Scholar
• Ssenkusu JM, Hodges JS, Opoka RO, et al. Long-term behavioral problems in children with severe malaria. Pediatrics. 2016;138(5):e20161965.
   Google Scholar
• Idro R, Kakooza-Mwesige A, Asea B, et al. Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort. Malar J. 2016;15:184.
   Google Scholar
• Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–389.
   Google Scholar
• Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci. 2012;8(9):1254–1266.
   Google Scholar
• Erice C, Calhan OY, Kisiswa L, et al. Regional differences in the contributions of TNF reverse and forward signaling to the establishment of sympathetic innervation. Dev Neurobiol. 2019;79(4):317–334.
   Google Scholar
• Carriba P, Davies AM. CD40 is a major regulator of dendrite growth from developing excitatory and inhibitory neurons. Elife. 2017;6:e30442.
   Google Scholar
• Lawford HLS, Lee AC, Kumar S, et al. Establishing a conceptual framework of the impact of placental malaria on infant neurodevelopment. Int J Infect Dis. 2019;84:54–65.
   Google Scholar
• Khedraki R, Noor Z, Rick J. The most expensive drug in the world: to continue or discontinue, that is the question. Fed Pract. 2016;33(7):22–28.
   Google Scholar
• Hawkes MT, Conroy AL, Opoka RO, et al. Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial. Malar J. 2015;14:421.
   Google Scholar
• Mwanga-Amumpaire J, Carroll RW, Baudin E, et al. Inhaled nitric oxide as an adjunctive treatment for cerebral malaria in children: a phase II randomized open-label clinical trial. Open Forum Infect Dis. 2015;2(3):ofv111.
   Google Scholar
• Bangirana P, Conroy AL, Opoka RO, et al. Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial. PLoS One. 2018;13(1):e0191550.
   Google Scholar
• Gallego-Delgado J, Basu-Roy U, Ty M, et al. Angiotensin receptors and beta-catenin regulate brain endothelial integrity in malaria. J Clin Invest. 2016;126(10):4016–4029.
   Google Scholar
• Pandey A, Gaikwad AB. AT2 receptor agonist Compound 21: A silver lining for diabetic nephropathy. Eur J Pharmacol. 2017;815:251–257.
   Google Scholar
• Dormoi J, Briolant S, Pascual A, et al. Improvement of the efficacy of dihydroartemisinin with atorvastatin in an experimental cerebral malaria murine model. Malar J. 2013;12:302.
   Google Scholar
• Serghides L, Patel SN, Ayi K, et al. Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria. J Infect Dis. 2009;199(10):1536–1545.
   Google Scholar
• Serghides L, McDonald CR, Lu Z, et al. PPARgamma agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria. PLoS Pathog. 2014;10(3):e1003980.
   Google Scholar
• Boggild AK, Krudsood S, Patel SN, et al. Use of peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for plasmodium falcipurum malaria: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2009;49(6):841–849.
   Google Scholar
• Varo R, Crowley VM, Sitoe A, et al. Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria. Malar J. 2017;16(1):215.
   Google Scholar
• Lee WL, Liles WC. Endothelial activation, dysfunction and permeability during severe infections. Curr Opin Hematol. 2011;18(3):191–196.
   Google Scholar
• Parikh SM, Mammoto T, Schultz A, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 2006;3(3):e46.
   Google Scholar
• Ricciuto DR, Dos Santos CC, Hawkes M, et al. Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med. 2011;39(4):702–710.
   Google Scholar
• Page AV, Kotb M, McGeer A, et al. Systemic dysregulation of angiopoietin-1/2 in streptococcal toxic shock syndrome. Clin Infect Dis. 2011;52(8):e157–e161.
   Google Scholar
• Agrawal A, Matthay MA, Kangelaris KN, et al. Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med. 2013;187(7):736–742.
   Google Scholar
• Page AV, Tarr PI, Watkins SL, et al. Dysregulation of angiopoietin 1 and 2 in Escherichia coli O157: h7infection and the hemolytic-uremic syndrome. J Infect Dis. 2013;208(6):929–933.
   Google Scholar
• Parikh SM. Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence. 2013;4(6):517–524.
   Google Scholar
• Wright JK, Hayford K, Tran V, et al. Biomarkers of endothelial dysfunction predict sepsis mortality in young infants: a matched case-control study. BMC Pediatr. 2018;18(1):118.
   Google Scholar
• Richard-Greenblatt M, Boillat-Blanco N, Zhong K, et al. Prognostic accuracy of sTREM-1-based algorithms in febrile adults presenting to Tanzanian outpatient clinics. Clin Infect Dis. 2019. doi: 10.1093/cid/ciz419.
   Google Scholar