Pathophysiology

All the manifestations of malarial illness are caused by the infection of the red blood cells by the asexual forms of the malaria parasite and the involvement of the red cells makes malaria a potentially multisystem disease, as every organ of the body is reached by the blood.[1,2] All types of malaria manifest with common symptoms such as fever, some patients may progress into severe malaria. Although severe malaria is more often seen in cases of P. falciparum infection, complications and even deaths have been reported in non-falciparum malaria as well.

F1.medium

Induction of fever by malaria parasites [Source]3

At the completion of the schizogony within the red cells, each cycle lasting 24-72 hours depending on the species of the infecting parasite, newly developed merozoites are released by the lysis of infected erythrocytes and along with them, numerous known and unknown waste substances, such as red cell membrane products, hemozoin pigment, and other toxic factors such as glycosylphosphatidylinositol (GPI) are also released into the blood. These products, particularly the GPI, activate macrophages and endothelial cells to secrete cytokines and inflammatory mediators such as tumor necrosis factor, interferon-γ, interleukin-1, IL-6, IL-8, macrophage colony-stimulating factor, and lymphotoxin, as well as superoxide and nitric oxide(NO).Many studies have implicated the GPI tail, common to several merozoite surface proteins such as MSP-1, MSP-2, and MSP-4, as a key parasite toxin.[4,5] The systemic manifestations of malaria such as headache, fever and rigors, nausea and vomiting, diarrhea, anorexia, tiredness, aching joints and muscles, thrombocytopenia, immunosuppression, coagulopathy, and central nervous system manifestations have been largely attributed to the various cytokines released in response to these parasite and red cell membrane products.[6] In addition to these factors, the plasmodial DNA is also highly proinflammatory and can induce cytokinemia and fever. The plasmodial DNA is presented by hemozoin (produced during the parasite development within the red cell) to interact intracellularly with the Toll-like receptor-9, leading to the release of proinflammatory cytokines that in turn induce COX-2-upregulating prostaglandins leading to the induction of fever.[3,7] Hemozoin has also been linked to the induction of apoptosis in developing erythroid cells in the bone marrow, thereby causing anemia.[8,9]

Pathogenesis of Severe Malaria

The infection of the red cells by malaria parasites, particularly P. falciparum, results in progressive and dramatic structural, biochemical, and mechanical modifications of the red cells that can worsen into life-threatening complications of malaria. While the vast majority of severe malaria and related mortality are caused by P. falciparum infection, complications can occur in non-falciparum infections as well. In recent years, several cases of severe infection and even deaths have been reported following infections with P. vivax and P. knowlesi infections.[10-18] Several pathophysiological factors such as the parasite biomass; ‘malaria toxin(s)’ and inflammatory response; cytoadherence, resetting and sequestration; altered deformability and fragility of parasitized erythrocytes; endothelial activation, dysfunction and injury; and altered thrombostasis have been found to be involved in the development of severe malaria. All these phenomena are more profound and wide spread in P. falciparum infection compared to non-falciparum infections. As a result, except for severe anemia, complications such as cerebral malaria, hypoglycemia, metabolic acidosis, renal failure, and respiratory distress are more commonly seen in P. falciparum infections.[16,19,20]

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Schematic representation of pathogenesis of severe malaria [Louis Schofield, Georges E. Grau. Immunological processes in malaria pathogenesis. Nature Reviews Immunology September 2005;5:722-735][Source]

Parasite Biomass
With its wide array of receptor families and highly redundant, alternate invasion pathways,[21] P. falciparum has the ability to invade RBCs of all ages, and with repeated cycles of development within the red cells, the parasite numbers exponentially grow into very high parasite burdens if the infection is uninhibited by treatment or host immunity. On the contrary, P. vivax preferentially infects only young RBCs, thus limiting its reproductive capacity and resultant parasite loads. Thus, the parasite load in P. falciparum infections can be very high, even exceeding 20-30%, whereas in vivax malaria it rarely exceeds 2%, even in case of severe disease.[16,19]

Role of Cytokines in Severe Malaria

The cytokines of the proinflammatory cascade like tumor necrosis factor, interleukins, interferon-γ, and nitric oxide act as double-edged swords in the pathogenesis of malaria. Cytokines act as homeostatic agents and an early proinflammatory cytokine response helps in limiting the infection, with the cytokines inhibiting the growth of malarial parasites in lower concentrations. On the other, failure to down-regulate this inflammatory response results in progressive immune pathology, leading to complications. Excessive levels of cytokines can lead to decreased mitochondrial oxygen use and enhanced lactate production; increased cytoadherence that in turn causes microvascular obstruction and more hypoxia; disturbed auto-regulation of local blood flow leading to poor circulation and further tissue hypoxia; dyserythropoiesis, poor red cell deformability and multifactorial anemia; reduced gluconeogenesis and hypoglycemia; myocardial depression and cardiac insufficiency; loss of endothelial integrity and vascular damage in the lungs and brain; selective upregulation of vascular and intercellular adhesion molecules (ICAMs), particularly in the brain and placenta leading to cerebral malaria and placental dysfunction; and activation of leukocytes and platelets, promoting procoagulant activity.[2-5,20,22-28] It can therefore be said that the outcome of malaria infection is determined by the balance between the pro- and anti-inflammatory cytokines.[2,5,22]

Some of the complications seen in P. vivax malaria may be related to cytokine-mediated injury. P. vivax has been reported to induce a greater inflammatory response than P. falciparum (with equal or greater parasite load), resulting in higher levels of cytokine release. The pyrogenic threshold is also lower in P. vivax infections, resulting in fever at lower levels of parasitemia. Structural differences in the P. vivax GPI that MAY make it more pyrogenic and/or greater concentrations of Toll-like receptor-9-stimulating motifs within P. vivax hemozoin may be responsible for this greater pyrogenicity.[16] A cholesterol/triglyceride(s)-containing lipid, that has greater activity than GPI-like phospholipids, has also been proposed as a putative malaria toxin unique to P. vivax, and that may also contribute to the pyrogenicity of P. vivax.[29]

Cytoadherence, Sequestration, and Rosetting
Structural changes in the infected red cells and the resulting increase in their rigidity and adhesiveness are major contributors to the virulence for P. falciparum malaria. Owing to the increased adhesiveness, the red cells infected with late stages of P. falciparum (during the second half of the 48 hour life cycle) adhere to the capillary and postcapillary venular endothelium in the deep microvasculature (cytoadherence). The infected red cells also adhere to the uninfected red cells, resulting in the formation of red cell rosettes (rosetting). Cytoadherence leads to sequestration of the parasites in various organs such as the heart, lung, brain, liver, kidney, intestines, adipose tissue, subcutaneous tissues, and placenta. Sequestration of the growing P. falciparum parasites in these deeper tissues provides them the microaerophilic venous environment that is better suited for their maturation and the adhesion to endothelium allows them to escape clearance by the spleen and to hide from the immune system. These factors help the falciparum parasites to undergo unbridled multiplication, thereby increasing the parasite load to very high numbers. Due to the sequestration of the growing parasites in the deeper vasculature, only the ring-stage trophozoites of P. falciparum are seen circulating in the peripheral blood, while the more mature trophozoites and schizonts are bound in the deep microvasculature, hence seldom seen on peripheral blood examination. If the cytoadherence-rosetting-sequestration of infected and uninfected erythrocytes in the vital organs goes on uninhibited, it ultimately blocks blood flow, limits the local oxygen supply, hampers mitochondrial ATP synthesis, and stimulates cytokine production – all these factors contributing to the development of severe disease.[5,16,19,20,26,30-33]

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Cytoadherence and rosetting in postcapillary vasculature [Source]20

Certain proteins expressed on the surface of the infected red cells mediate the adhesion of parasitized RBCs to the endothelium and to uninfected red cells. The most important of such proteins is the P. falciparum erythrocyte membrane protein 1 (PfEMP1), an antigenically diverse protein family that is expressed on the thousands of knob-like excrescences on the surface of red cells infected with P. falciparum trophozoites and schizonts. PfEMP1 is anchored at the red cell membrane skeleton by the knob-associated histidine-rich protein. PfEMP1 appears on the surface of the P. falciparum-infected red cells about 16 hours after the invasion and that heralds the cytoadherence.[19,32] PfEMP1 can bind to several adhesion receptors expressed on the endothelial cells such as thrombospondin, CD36, ICAM-1, vascular cell adhesion molecule 1, platelet/EC adhesion molecule)/CD31, neural cell adhesion molecule, P-selectin and E-selectin, integrin αvβ3, globular C1q receptor (gC1qR)/hyaluronan binding protein 1/p32, chondroitin sulfate A (CSA), and hemagglutinin, and such binding can proceed synergistically.[4,20,26] Whereas ICAM-1 and CD36 are more commonly used receptors, CSA acts as the receptor for binding in the placenta. Activation of endothelial cells by cytokines as well as by the parasitized RBCs increases the expression of adhesion-promoting molecules and further promotes cytoadherence.[34] Differences in binding to these receptors (CD36 and ICAM-1) may determine the virulence of P. falciparum isolates from different parts of the world.[19,33]

Rosetting is mediated by binding of PfEMP1-DBLα on the surface of infected red cells to complement receptor 1, CD31, and heparan sulfate-like glycosaminoglycans of uninfected RBCs.[31,33,35] Rosetting is found to be lesser in blood group O erythrocytes compared with groups A, B, and AB, and thus patients with blood group O may be protected from severe malaria.[36,37]

Cytoadherance, sequestration, rosetting and aggregation of leukocytes have been reported in P. vivax infections as well. However, these are lesser in magnitude and extent in comparison to P. falciparum infections and their roles in pathophysiology of complications remain unclear.[16]

Red Cell Membrane Rigidity and Deformability
Altered red cell membrane rigidity and deformability also contribute to the pathogenesis of severe malaria. In patients with severe falciparum malaria, the entire red cell mass, comprising mostly of unparasitized red cells and also parasitized red cells, becomes rigid.[38-40] Several mechanisms such as hemin-induced oxidative damage of the red cell membrane, alterations in the phospholipid bilayer and attached spectrin network by the proteins transported to the red cell membrane, thermally driven membrane fluctuations due to fever, and inhibition of the Na+/K+ pump on the red cell membrane, possibly by nitric oxide (NO) may be responsible for the increase in rigidity and reduction in deformability of the red cells in falciparum malaria.[5,39,40] Reduced red cell deformability leads to increased splenic clearance and loss of red cells, causing anemia. Hemolysis, suppression of erythropoeisis by cytokines, and hemozoin-induced apoptosis in developing erythroid cells also contribute to the development of anemia in severe malaria.[5,8,40] Compared to infection with P. falciparum, in which red cell deformability is reduced, the red cell deformability is increased in P. vivax infection. While this may enable P. vivax infected red cells to survive the passage through the splenic sinusoids, the accompanying increase in fragility of both infected and noninfected red cells may contribute to severe anemia in P. vivax malaria. Increased deformability of P. vivax infected red cells also makes sequestration and obstruction to blood flow unlikely.[16,41]

The pathogenesis of severe malaria therefore involves a cascading interaction between parasite and red cell membrane products, cytokines and endothelial receptors, leading to inflammation, activation of platelets, hemostasis,  a procoagulant state, microcirculatory dysfunction and tissue hypoxia, resulting in various organ dysfunctions manifesting in severe malaria.[23]

Further Reading:

  1. Brian M. Greenwood, David A. Fidock, Dennis E. Kyle, Stefan H.I. Kappe, Pedro L. Alonso, Frank H. Collins, Patrick E. Duffy. Malaria: progress, perils, and prospects for eradication. J. Clin. Invest. 118:1266–1276 (2008). doi:10.1172/JCI33996 Full Text at http://www.jci.org/articles/view/33996/files/pdf
  2. Fakhreldin M. Omer, J. Brian de Souza, Eleanor M. Riley. Differential Induction of TGF-{beta} Regulates Proinflammatory Cytokine Production and Determines the Outcome of Lethal and Nonlethal Plasmodium yoelii Infections. J. Immunol. 2003;171;5430-5436 Full Text at http://www.jimmunol.org/cgi/reprint/171/10/5430.pdf
  3. Ralf R. Schumann. Malarial fever: Hemozoin is involved but Toll-free. PNAS 6 February, 2007;104(6):1743-1744. Full text athttp://www.pnas.org/content/104/6/1743.full.pdf+html
  4. Claire L. Mackintosh, James G. Beeson, Kevin Marsh. Clinical features and pathogenesis of severe malaria. Trends in Parasitology December 2004;20(12):597-603
  5. Srabasti J. Chakravorty, Katie R. Hughes, Alister G. Craig. Host response to cytoadherence in Plasmodium Falciparum. Biochem. Soc. Trans. 2008;36:221–228; doi:10.1042/BST0360221 Full text at http://www.biochemsoctrans.org/bst/036/0221/0360221.pdf
  6. Ian A Clark, Alison C Budd, Lisa M Alleva, William B Cowden. Human malarial disease: a consequence of inflammatory cytokine release. Malaria Journal. 2006;5:85. doi:10.1186/1475-2875-5-85. Full Text at http://www.malariajournal.com/content/pdf/1475-2875-5-85.pdf
  7. Peggy Parroche, Fanny N. Lauw, Nadege Goutagny, Eicke Latz, Brian G. Monks, Alberto Visintin, Kristen A. Halmen, Marc Lamphier, Martin Olivier, Daniella C. Bartholomeu, Ricardo T. Gazzinelli, Douglas T. Golenbock. Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. PNAS. 2007;104:1919–1924. Full Text at http://www.pnas.org/content/104/6/1919.full.pdf+html
  8. Lamikanra AA, Theron M, Kooij TWA, Roberts DJ Hemozoin (Malarial Pigment) Directly Promotes Apoptosis of Erythroid Precursors. PLoS ONE. 2009;4(12):e8446. doi:10.1371/journal.pone.0008446. Full Text at http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0008446
  9. Gordon A. Awandare, Yamo Ouma, Collins Ouma et al. Role of Monocyte-Acquired Hemozoin in Suppression of Macrophage Migration Inhibitory Factor in Children with Severe Malarial Anemia. Infection And Immunity. Jan.  2007;75(1):201–210. Full Text at http://iai.asm.org/cgi/reprint/75/1/201.pdf
  10. Ric N. Price, Emiliana Tjitra, Carlos A. Guerra, Shunmay Yeung, Nicholas J. White, Nicholas M. Anstey. Vivax Malaria: Neglected and Not Benign. In J G Breman, M S Alilio, Nicholas J White. (Editors) Defining and Defeating the Intolerable Burden of Malaria: III. Progress and Perspectives. In Breman, Joel G, Alilio, Martin S, Mills, Anne, White, Nicholas J. (Editors). The Intolerable Burden of Malaria: A Collection from the American Journal of Tropical Medicine and Hygiene. Boca Raton (FL): CRC Press, Taylor & Francis Group; c2001-2007. Full Text at http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi?book=mal3&part=pg79&blobtype=pdf
  11. Nicholas M. Anstey, Tjandra Handojo, Michael C. F. Pain, Enny Kenangalem, Emiliana Tjitra, Ric N. Price, Graeme P. Maguire. Lung Injury in vivax Malaria: Pathophysiological Evidence for Pulmonary Vascular Sequestration and Posttreatment Alveolar-Capillary Inflammation. The Journal of Infectious Diseases. 2007;195:589–596. Full Text at http://www.journals.uchicago.edu/doi/pdf/10.1086/510756
  12. Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, et al. Multidrug-Resistant Plasmodium vivax Associated with Severe and Fatal Malaria: A Prospective Study in Papua, Indonesia. PLoS Med 2008;5(6):e128. Full Text at http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050128
  13. Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV, Das A. Plasmodium vivax malaria. Emerg Infect Dis 2005;11:132–134. Full Text athttp://www.cdc.gov/Ncidod/EID/vol11no01/pdfs/04-0519.pdf.
  14. Kochar DK, Shubhakaran, Kumawat BL, Kochar SK, Halwai M, Makkar RK, Joshi A, Thanvi I. Cerebral malaria in Indian adults: A prospective study of 441 patients from Bikaner, North-West India. J Assoc Physicians India 2002;50:234-41
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  17. Janet Cox-Singh, Jessie Hiu, Sebastian B Lucas, Paul C Divis, Mohammad Zulkarnaen, Patricia Chandran, Kum T Wong, Patricia Adem, Sherif R Zaki, Balbir Singh, Sanjeev Krishna. Severe malaria – a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report. Malaria Journal 2010;9:10. Full Text athttp://www.malariajournal.com/content/pdf/1475-2875-9-10.pdf
  18. Cyrus Daneshvar, Timothy M. E. Davis, Janet Cox-Singh, Mohammad Zakri Rafa’ee, Siti Khatijah Zakaria, Paul C. S. Divis, Balbir Singh. Clinical and Laboratory Features of Human Plasmodium knowlesi Infection. Clinical Infectious Diseases 2009;49:852–860
  19. Louis H. Miller, Dror I. Baruch, Kevin Marsh, Ogobara K. Doumbo. The pathogenic basis of malaria. Nature February 2002;415(7):673-679. Full Text athttp://www.doh.gov.za/issues/malaria/red_reference/cross_cutting/cross20.pdf
  20. Qijun Chen, Martha Schlichtherle, Mats Wahlgren. Molecular Aspects of Severe Malaria. Clinical Microbiology Reviews, July 2000;13(3);439-450. full text at http://cmr.asm.org/cgi/content/full/13/3/439
  21. David J. Weatherall, Louis H. Miller, Dror I. Baruch, Kevin Marsh, Ogobara K. Doumbo, Climent Casals-Pascual, David J. Roberts. Malaria and the Red Cell.Haematology 2002;1:35-57. Full Text at http://asheducationbook.hematologylibrary.org/cgi/reprint/2002/1/35
  22. Ramachandra S. Naik, OraLee H. Branch, Amina S. Woods, Matam Vijaykumar, Douglas J. Perkins, Bernard L. Nahlen, Altaf A. Lal, Robert J. Cotter, Catherine E. Costello, Christian F. Ockenhouse, Eugene A. Davidson, D. Channe Gowda. Glycosylphosphatidylinositol Anchors of Plasmodium falciparum: Molecular Characterization and Naturally Elicited Antibody Response That May Provide Immunity to Malaria Pathogenesis. The Journal of Experimental Medicine. 4 December, 2000;192(11):1563-1576. Full Text at http://jem.rupress.org/cgi/reprint/192/11/1563
  23. Henri C. van der Heyde, John Nolan, Valéry Combes, Irene Gramaglia, Georges E. Grau. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends in Parasitology 2006;22(11):503-508. Full Text at http://www.ljbi.org/Nolan/Unified%20Hypothesis%20cerebral%20malaria.pdf
  24. Jayakumar S. Poovassery, Demba Sarr, Geoffrey Smith, Tamas Nagy, Julie M. Moore. Malaria-Induced Murine Pregnancy Failure: Distinct Roles for IFN-γ and TNF. The Journal of Immunology. 2009;183:5342-5349. Full text at http://www.jimmunol.org/cgi/reprint/183/8/5342
  25. Evelien Dekker, Marc K. Hellerstein, Johannes A. Romijn, Richard A. Neese, Norbert Peshu, Erik Endert, Kevin Marsh, Hans P. Sauerwein. Glucose Homeostasis in Children with Falciparum Malaria: Precursor Supply Limits Gluconeogenesis and Glucose Production. The Journal of Clinical Endocrinology & Metabolism 1997;82(8):2514-2521. Full text at http://jcem.endojournals.org/cgi/reprint/82/8/2514
  26. May Ho, Nicholas J. White. Molecular mechanisms of cytoadherence in malaria. Am J Physiol Cell Physiol 1999;276(6):C1231-C1242. Full text athttp://ajpcell.physiology.org/cgi/reprint/276/6/C1231
  27. Rachanee Udomsangpetch, Busaba Pipitaporn, Kamolrat Silamut, Robert Pinches, Sue Kyes, Sornchai Looareesuwan, Christopher Newbold, Nicholas J. White. Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum-infected erythrocytes. PNAS 3 September, 2002;99(18):11825-11829. Full text at http://www.pnas.org/content/99/18/11825.full.pdf+html
  28. Dorothée Faille Valéry Combes, Andrew J. Mitchell, Albin Fontaine, Irène Juhan-Vague, Marie-Christine Alessi, Giovanna Chimini, Thierry Fusaï, Georges E. Grau. Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium The FASEB Journal. 2009;23:3449-3458. Full text athttp://www.fasebj.org/cgi/content/abstract/23/10/3449
  29. Nadira Karunaweera, Deepani Wanasekara, Vishvanath Chandrasekharan, Kamini Mendis, Richard Carter. Plasmodium vivax: paroxysm-associated lipids mediate leukocyte aggregation Malaria Journal. 2007;6:62. Full Text at http://www.malariajournal.com/content/6/1/62
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