Pathological basis of severe malaria in children: investigating immune dysregulation, organ-specific damage, and long-term outcomes
DOI:
https://doi.org/10.18203/2394-6040.ijcmph20252145Keywords:
Severe malaria, Children, Immune dysregulation, Organ-specific damage, OutcomesAbstract
Malaria is a globally endemic parasitic disease, particularly prevalent in tropical regions and primarily affecting children and pregnant women. Comprehending the pathological mechanisms underlying severe malaria is crucial for enhancing treatment outcomes and decreasing mortality rates. This study aims to investigate immune dysregulation in severe malaria, explore organ-specific damage resulting from malaria infections in children, and examine long-term health consequences in survivors of severe malaria. This literature review involved an extensive literature search across electronic databases including PubMed, Google Scholar, Scopus, and Web of Science using keywords such as: severe malaria, children, immune dysregulation, organ-specific damage, and outcomes from 2015 to 2025. The study found cytokine imbalance and endothelial dysfunction due to immune dysregulation, liver and kidney dysfunction, and hematological changes due to severe malaria. To prevent the consequences of severe malaria in children, awareness and early detection of malaria signs and symptoms, next-generation sequencing, proteomics, and metabolomics, as well as regional and community-based malaria research, are required.
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Chiabi A, Djimafo ANM, Nguefack S, Mah E, Nguefack Dongmo F, Angwafo F. Severe malaria in Cameroon: Pattern of disease in children at the Yaounde Gynaeco-Obstetric and Pediatric hospital. J Infect Public Health. 2020;13(10):1469-72. DOI: https://doi.org/10.1016/j.jiph.2020.02.038
Ashley EA, Poespoprodjo JR. Treatment and prevention of malaria in children. Lancet Child Adolesc Health. 2020;4(10):775-89. DOI: https://doi.org/10.1016/S2352-4642(20)30127-9
Newton CR, Krishna S. Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther. 1998;79(1):1-53. DOI: https://doi.org/10.1016/S0163-7258(98)00008-4
Friedman-Klabanoff DJ, Adu-Gyasi D, Asante KP. Malaria prevention in children: an update. Curr Opin Pediatr. 2024;36(2):164-70. DOI: https://doi.org/10.1097/MOP.0000000000001332
Sato S. Plasmodium: brief introduction to the parasites causing human malaria and their basic biology. J Physiol Anthropol. 2021;40(1):1. DOI: https://doi.org/10.1186/s40101-020-00251-9
Milner DA. Malaria Pathogenesis. Cold Spring Harb Perspect Med. 2018;8(1):a025569. DOI: https://doi.org/10.1101/cshperspect.a025569
Blatch GL. Plasmodium falciparum Molecular Chaperones: Guardians of the Malaria Parasite Proteome and Renovators of the Host Proteome. Front Cell Dev Biol. 2022;10:921739. DOI: https://doi.org/10.3389/fcell.2022.921739
Wassmer SC, Grau GER. Severe malaria: what’s new on the pathogenesis front? Int J Parasitol. 2017;47(2-3):145-52. DOI: https://doi.org/10.1016/j.ijpara.2016.08.002
Wahlgren M, Goel S, Akhouri RR. Variant surface antigens of Plasmodium falciparum and their roles in severe malaria. Nat Rev Microbiol. 2017;15(8):479-91. DOI: https://doi.org/10.1038/nrmicro.2017.47
Buffet PA, Safeukui I, Deplaine G. The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology. Blood. 2011;117(2):381-92. DOI: https://doi.org/10.1182/blood-2010-04-202911
Silver KL, Higgins SJ, McDonald CR, Kain KC. Complement-driven innate immune response to malaria: fuelling severe malarial diseases. Cell Microbiol. 2010;12(8):1036-45. DOI: https://doi.org/10.1111/j.1462-5822.2010.01492.x
Gowda DC, Wu X. Parasite Recognition and Signaling Mechanisms in Innate Immune Responses to Malaria. Front Immunol. 2018;9:3006. DOI: https://doi.org/10.3389/fimmu.2018.03006
Pohl K, Cockburn IA. Innate immunity to malaria: The good, the bad and the unknown. Front Immunol. 2022;13:914598. DOI: https://doi.org/10.3389/fimmu.2022.914598
Farrington L, Vance H, Rek J. Both inflammatory and regulatory cytokine responses to malaria are blunted with increasing age in highly exposed children. Malar J. 2017;16(1):499. DOI: https://doi.org/10.1186/s12936-017-2148-6
Perkins DJ, Were T, Davenport GC, Kempaiah P, Hittner JB, Ong’echa JM. Severe malarial anemia: innate immunity and pathogenesis. Int J Biol Sci. 2011;7(9):1427-42. DOI: https://doi.org/10.7150/ijbs.7.1427
Popa GL, Popa MI. Recent Advances in Understanding the Inflammatory Response in Malaria: A Review of the Dual Role of Cytokines. J Immunol Res. 2021;2021:7785180. DOI: https://doi.org/10.1155/2021/7785180
Obeagu EI. Role of cytokines in immunomodulation during malaria clearance. Ann Med Surg 2012. 2024;86(5):2873-82. DOI: https://doi.org/10.1097/MS9.0000000000002019
Okpokor DO, Peter AM, Olusola A, Dakul AD. Pro and anti-inflammatory immune response profiling prevents severe malaria among Nigerians infected with Plasmodium falciparum: the future for malaria vaccines and therapeutics. Research Square. 2020. DOI: https://doi.org/10.21203/rs.2.22063/v1
Nkansah C, Osei-Boakye F, Abbam G, Appiah SK, Daud S, Boakye B, et al. Pro and anti-inflammatory cytokines mediate the progression of severe anemia in malaria-infected children: A prospective study. Immun Inflamm Dis. 2024;12(9):e70013. DOI: https://doi.org/10.1002/iid3.70013
Lourembam SD, Sawian CE, Baruah S. Dysregulation of cytokines expression in complicated falciparum malaria with increased TGF-β and IFN-γ and decreased IL-2 and IL-12. Cytokine. 2013;64(2):503-8. DOI: https://doi.org/10.1016/j.cyto.2013.08.007
Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev. 2010;64(2):328-63. DOI: https://doi.org/10.1016/j.brainresrev.2010.05.003
Neuwelt EA, Bauer B, Fahlke C, Gert F, Constantino I, Damir J, et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci. 2011;12(3):169-82. DOI: https://doi.org/10.1038/nrn2995
Brown H, Hien TT, Day N, Mai NT, Chuong LV, Chau TT, et al. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol. 1999;25(4):331-40. DOI: https://doi.org/10.1046/j.1365-2990.1999.00188.x
Faille D, El-Assaad F, Alessi MC, Fusai T, Combes V, Grau GE. Platelet-endothelial cell interactions in cerebral malaria: the end of a cordial understanding. Thromb Haemost. 2009;102(6):1093-102. DOI: https://doi.org/10.1160/TH09-05-0337
Medana IM, Turner GDH. Human cerebral malaria and the blood-brain barrier. Int J Parasitol. 2006;36(5):555-68. DOI: https://doi.org/10.1016/j.ijpara.2006.02.004
Ogutu BR, Newton CRJC. Management of seizures in children with falciparum malaria. Trop Doct. 2004;34(2):71-5. DOI: https://doi.org/10.1177/004947550403400204
Shi Z, Chen Y, Lu C, Li-Ming D, Jing-Wei L, Qin-Hui T, et al. Resolving neuroinflammation, the therapeutic potential of the anti-malaria drug family of artemisinin. Pharmacol Res. 2018;136:172-80. DOI: https://doi.org/10.1016/j.phrs.2018.09.002
Silva GB da, Pinto JR, Barros EJG, Farias GMN, Daher EDF. Kidney involvement in malaria: an update. Rev Inst Med Trop Sao Paulo. 2017;59:e53. DOI: https://doi.org/10.1590/s1678-9946201759053
Brown DD, Solomon S, Lerner D, Del Rio M. Malaria and acute kidney injury. Pediatr Nephrol Berl Ger. 2020;35(4):603-8. DOI: https://doi.org/10.1007/s00467-018-4191-0
Cabezón Estévanez I, Górgolas Hernández-Mora M. [Pulmonary complications of malaria: An update]. Med Clin (Barc). 2016;146(8):354-8. DOI: https://doi.org/10.1016/j.medcle.2016.06.017
Siagian FE. Pulmonary Complications in Severe Malaria. Int J Pathog Res. 2021;19-27. DOI: https://doi.org/10.9734/ijpr/2021/v8i130194
Candido Moura G, Barcelos D, Epiphanio S, Santos Ortolan LD. Physiopathology of Malaria-Associated Acute Respiratory Distress Syndrome. J Ancient Dis Prevent Remed. 2017;5:4. DOI: https://doi.org/10.4172/2329-8731.1000171
Ray HN, Doshi D, Rajan A, Singh AK, Singh SB, Das MK. Cardiovascular involvement in severe malaria: A prospective study in Ranchi, Jharkhand. J Vector Borne Dis. 2017;54(2):177-82. DOI: https://doi.org/10.4103/0972-9062.211700
White NJ. Anaemia and malaria. Malar J. 2018;17(1):371. DOI: https://doi.org/10.1186/s12936-018-2509-9
Abdulkareem BO, Adam AO, Ahmed AO, Mariam AA, Samuel UU. Malaria-induced anaemia and serum micronutrients in asymptomatic Plasmodium falciparum-infected patients. J Parasit Dis Off Organ Indian Soc Parasitol. 2017;41(4):1093-7. DOI: https://doi.org/10.1007/s12639-017-0940-4
Zaidi SMF, Amjad A, Sohail K, Rehman FU. A complex case of recurrent intracranial bleeds due to malaria-induced coagulopathy: A case report and literature review. Surg Neurol Int. 2024;15:304. DOI: https://doi.org/10.25259/SNI_553_2024
Milner EM, Kariger P, Pickering AJ, Christine PS, Kendra B, Audrie L, et al. Association between Malaria Infection and Early Childhood Development Mediated by Anemia in Rural Kenya. Int J Environ Res Public Health. 2020;17(3):902. DOI: https://doi.org/10.3390/ijerph17030902
Boivin MJ, Mohanty A, Sikorskii A, Vokhiwa M, Magen JG, Gladstone M. Early and middle childhood developmental, cognitive, and psychiatric outcomes of Malawian children affected by retinopathy-positive cerebral malaria. Child Neuropsychol J Norm Abnorm Dev Child Adolesc. 2019;25(1):81-102. DOI: https://doi.org/10.1080/09297049.2018.1451497
Carter JA, Ross AJ, Neville BGR, Elizabeth O, Khamis K, Mung'ala-Odera V, et al. Developmental impairments following severe falciparum malaria in children. Trop Med Int Health TM IH. 2005;10(1):3-10. DOI: https://doi.org/10.1111/j.1365-3156.2004.01345.x
Idro R, Kakooza-Mwesige A, Asea B, Keron S, Bangirana P, Opoka RO, 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. DOI: https://doi.org/10.1186/s12936-016-1233-6
Ssenkusu JM, Hodges JS, Opoka RO, Richard I, Shapiro E, John CC, et al. Long-term Behavioral Problems in Children With Severe Malaria. Pediatrics. 2016;138(5):e20161965. DOI: https://doi.org/10.1542/peds.2016-1965
Vorasan N, Pan-Ngum W, Jittamala P, Maneeboonyang W, Rukmanee P, Lawpoolsri S. Long-term impact of childhood malaria infection on school performance among school children in a malaria endemic area along the Thai-Myanmar border. Malar J. 2015;14:401. DOI: https://doi.org/10.1186/s12936-015-0917-7
Boivin MJ, Sikorskii A, Familiar-Lopez I, Ruiseñor-Escudero H, Muhindo M, Kapisi J, et al. Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children. Malar J. 2016;15:210. DOI: https://doi.org/10.1186/s12936-016-1266-x
Balaji SN, Deshmukh R, Trivedi V. Severe malaria: Biology, clinical manifestation, pathogenesis and consequences. J Vector Borne Dis. 2020;57(1):1-13. DOI: https://doi.org/10.4103/0972-9062.308793
Akanbi O. The influence of malaria infection on kidney and liver function in children in Akoko area of Ondo state, Nigeria. 2015. Available at: https://www.semanticscholar.org/paper/The-influence-of-malaria-infection-on-kidney-and-in-Akanbi/2dfcebfc3f82764463e9eae58f81aa936577890d. Accessed on 05 March 2025.
Conroy AL, Opoka RO, Bangirana P, Idro R, Ssenkusu JM, Datta D, et al. Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria. BMC Med. 2019;17(1):98. DOI: https://doi.org/10.1186/s12916-019-1332-7
Obeagu E, Obeagu G. Hematological Changes Following Blood Transfusion in Young Children with Severe Malaria and HIV: A Critical Review. 2024;2:33-45.
Holm AE, Gomes LC, Marinho CRF, Odilson MS, Lasse SV, Biering-Sørensen T, et al. Prevalence of Cardiovascular Complications in Malaria: A Systematic Review and Meta-Analysis. Am J Trop Med Hyg. 2021;104(5):1643-50. DOI: https://doi.org/10.4269/ajtmh.20-1414
Etyang AO, Kapesa S, Odipo E, Evasius B, Kyobutungi C, Abdalla M, et al. Effect of Previous Exposure to Malaria on Blood Pressure in Kilifi, Kenya: A Mendelian Randomization Study. J Am Heart Assoc. 2019;8(6):e011771. DOI: https://doi.org/10.1161/JAHA.118.011771
Wooldridge G, Nandi D, Chimalizeni Y, O’Brien N. Cardiovascular Findings in Severe Malaria: A Review. Glob Heart. 2020;15(1):75. DOI: https://doi.org/10.5334/gh.789
Weil DN. Chapter 3 - Health and Economic Growth. In: Aghion P, Durlauf SN, eds. Handbook of Economic Growth. Vol 2. Handbook of Economic Growth. Elsevier; 2014:623-82. DOI: https://doi.org/10.1016/B978-0-444-53540-5.00003-3
Elnour Z, Grethe H, Siddig K, Munga S. Malaria control and elimination in Kenya: economy-wide benefits and regional disparities. Malar J. 2023;22(1):117. DOI: https://doi.org/10.1186/s12936-023-04505-6
Patouillard E, Han S, Lauer J, Barschkett M, Arcand JL. The Macroeconomic Impact of Increasing Investments in Malaria Control in 26 High Malaria Burden Countries: An Application of the Updated EPIC Model. Int J Health Policy Manag. 2023;12:7132. DOI: https://doi.org/10.34172/ijhpm.2023.7132
Castaldo N, Tascini C, Della Siega P, Peghin M, Pecori D. Clinical presentation and immunological features of Post-Malaria Neurologic Syndrome: a case report and review of literature. Malar J. 2020;19(1):419. DOI: https://doi.org/10.1186/s12936-020-03476-2
Yadava SK, Laleker A, Fazili T. Post-malaria neurological syndrome: a rare neurological complication of malaria. Infection. 2019;47(2):183-93. DOI: https://doi.org/10.1007/s15010-019-01267-9
Bellazreg F, Slama D, Lasfar NB, Abid M, Zaghouani H, Rouis S, et al. Neurological manifestations following cured malaria: don’t forget post-malaria neurological syndrome. Afr Health Sci. 2021;21(1):273-6. DOI: https://doi.org/10.4314/ahs.v21i1.35
Obeagu EI, Okoroiwu GIA, Ubosi NI, Obeagu GU, Onohuean H, Muhammad T, et al. Revolution in malaria detection: unveiling current breakthroughs and tomorrow’s possibilities in biomarker innovation. Ann Med Surg 2012. 2024;86(10):5859-76. DOI: https://doi.org/10.1097/MS9.0000000000002383
Proietti C, Krause L, Trieu A, Daniel D, Gyan B, Koram KA, et al. Immune Signature Against Plasmodium falciparum Antigens Predicts Clinical Immunity in Distinct Malaria Endemic Communities. Mol Cell Proteomics MCP. 2020;19(1):101-3. DOI: https://doi.org/10.1074/mcp.RA118.001256
Kyriazopoulou E, Giamarellos-Bourboulis EJ, Akinosoglou K. Biomarkers to guide immunomodulatory treatment: where do we stand? Expert Rev Mol Diagn. 2023;23(11):945-58. DOI: https://doi.org/10.1080/14737159.2023.2258063
Strzelec M, Detka J, Mieszczak P, Sobocińska MK, Majka M. Immunomodulation-a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system. Front Immunol. 2023;14:1127704. DOI: https://doi.org/10.3389/fimmu.2023.1127704
Wykes MN, Lewin SR. Immune checkpoint blockade in infectious diseases. Nat Rev Immunol. 2018;18(2):91-104. DOI: https://doi.org/10.1038/nri.2017.112
Dunican C, Andradi-Brown C, Ebmeier S, Georgiadou A, Cunnington AJ. The malarial blood transcriptome: translational applications. Biochem Soc Trans. 2024;52(2):651-60. DOI: https://doi.org/10.1042/BST20230497
Varo R, Erice C, Johnson S, Bassat Q, Kain KC. Clinical trials to assess adjuvant therapeutics for severe malaria. Malar J. 2020;19(1):268. DOI: https://doi.org/10.1186/s12936-020-03340-3