Malaria pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Alison Leibowitz [2] , Marjan Khan M.B.B.S.[3]

Overview

Malaria in humans develops in two phases: an exo-erythrocytic (hepatic) and an erythrocytic phase. When an infected mosquito pierces an individual's skin for blood, sporozoites in the mosquito's saliva enter the bloodstream and subsequently migrate to the liver.

Pathophysiology

  • Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa).
  • In humans, malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and Plasmodium knowlesi.
  • P. vivax is the most common cause of infection, responsible for about 80% of all malaria cases. P. falciparum, the most significant cause of disease, is responsible for about 15% of infections and 90% of deaths.[1][2]

Life Cycle

  • The life cycle of Plasmodium parasites begin when the sporozoite, a haploid form of the parasite, is injected into the human bloodstream by the female Anopheles mosquito.[3]
  • The sporozoites travel in the bloodstream to the liver and invade human hepatocytes. Over 1-2 weeks later, in the exo-erythrocytic phase, the sporozoites grow into schizonts and produce thousands of merozoites in each hepatocyte.
  • The merozoite is a haploid form of the parasite.[3] While some hepatocytes rupture and release the merozoites, other parasites remain dormant within the liver.[3] The release of merozoites, by the hepatocytes, into the bloodsteam results in the manifestation of the malarial symptoms.
  • The latency of cell rupture between various hepatocytes and the consequent merozoite release into the bloodstream, is responsible for the characteristic periodic fever associated with malarial infections.[3]
  • As merozoites are released into the bloodstream, they infect erythrocytes and undergo asexual multiplication (mitosis). Some merozoites continue the cycle of asexual replication into mature trophozoites and schizonts, which rupture to re-release merozoites. Others develop into sexual forms, the gametocytes, which involve male (microgametocyte) and female (macrogametocyte) parasites.[3]
  • Though biting, Anopheles mosquitos ingest the gametocytes within the red blood cells, initiating the sporogonic cycle inside the mosquito. In the mosquito's gut, the cells burst and the gametocytes are then released, allowing their development into mature gametes.
  • The fusion of male and female gametes forms diploid zygotes, which become ookinetes, motile and elongated forms of the parasites. Within the mosquito midgut wall, they develop into oocysts.[3]
  • As oocysts continue to grow, they divide into active haploid forms, the sporozoites. Thousands of sporozoites are produced in each oocyst. When oocysts burst following 1-2 weeks, sporozoites travel to the mosquito's salivary glands, so that when the mosquito bites other humans they inject the sporozoites into their bloodstream, leading the cycle to restart.[3]
  • Some species, such as P. vivax and P. ovale are characterized by their ability to produce hypnozoites, an intermediate stage where the parasite remains dormant for a few months/years before reactivation into merozoites. The hypnozoite stage allows teh species to demonstrate late relapses and long incubation periods.[4]
The life cycle of malaria parasites in the human body. The various stages in this process are discussed in the text.

Human Factors

  • Some human factors may provide a protective advantage against malarial infection. Individuals with sickle cell trait, defined as the heterozygous for the abnormal globin gene, HbS, are protected against P. falciparum.
  • In individuals with sickle cell trait, red blood cells invaded by P. falciparum tend to sickle more readily than other red blood cells, leading them to be eliminated from the bloodstream by macrophages.[5]
  • The preventative advantage demonstrated in heterozygous sickle cell patients is not observed in patients who have sickle cell anemia and carry a homozygous sickle gene. Contrarily, these patients are more susceptible to lethal complications of severe anemia.[5]
  • Other similar hematological diseases that provide a protective effect against malaria are thalassemia, hemoglobin C, and G6PD deficiency.
  • Individuals who have a negative Duffy blood group are resistant to infection by P. vivax. These individuals are still susceptible to other species of malaria, especially P. ovale, which frequently infects individuals with negative Duffy blood group.[6]
  • P. falciparum infection have higher mean parasitaemia index, P. vivax infection generally exhibit low parasitaemia index due to its preference to invade reticulocytes rather than erythrocytes.[7]

Associated Conditions

Severe malarial anaemia

  • Severe malarial anaemia is defined as a haemoglobin concentration of <5 g/dL and the presence of high parasitaemia >10,000 parasites/μl.[8]
  • The proposed mechanisms involved in severe malaria anaemia is a cumulative of loss of RBCs due to infection, lysis of uninfected RBCs in the circulation, and impaired RBC production.[9]
  • In P. vivax infections, ~34 uninfected RBCs are removed for every infected RBCs in the circulation whereas in P.falciparum infections, about 8 uninfected RBCs are lysed for every infected RBC.[10]

Acute respiratory distress syndrome (ARDS)

  • This condition is associated with deep breathing, respiratory distress, pulmonary oedema, airway obstruction, impaired function of the alveoli and decreased gas exchange.[11]
  • Autopsy studies in ARDS cases from P. vivax prior to antimalarial treatment has showed heavy infiltrates of intravascular mononuclear cells, endothelial and alveolar damages, and absence of parasite sequestration in the pulmonary vasculature.[12]
  • Study from Brazil has reported an infiltration of neutrophils in alveolar capillaries even after parasites were cleared from peripheral blood by antimalarial drug treatment.[13]

Pregnancy-associated malaria

  • Pregnants are more susceptible to malaria infections because of their somewhat compromised immune status, especially during the first and second trimesters of pregnancy.[14]
  • P. falciparum parasite has the ability to massively sequester in the placenta.[15]
  • The sequestration of parasite-infected RBCs in the intervillous space of placenta and the adherence of infected RBCs to the syncytiotrophoblast cell layer are the contributors to pregnancy associated malaria pathogenesis.[16]
  • The wide spread clinical conditions resulting from pregnancy associated malaria are severe anemia, intrauterine growth retardation, low birth weight, preterm delivery, miscarriage, perinatal mortality, and death in the mother.[17]

References

  1. Mendis K, Sina B, Marchesini P, Carter R (2001). "The neglected burden of Plasmodium vivax malaria" (PDF). Am J Trop Med Hyg. 64 (1-2 Suppl): 97–106. PMID 11425182.
  2. Long CA, Zavala F (2017). "Immune Responses in Malaria". Cold Spring Harb Perspect Med. doi:10.1101/cshperspect.a025577. PMID 28389518.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Malaria". National Institute of Allergy and Infectious Diseases. NIH. Apr. 3 2012. Retrieved Jul 24 2014. Check date values in: |accessdate=, |date= (help)
  4. Cogswell F (1992). "The hypnozoite and relapse in primate malaria". Clin Microbiol Rev. 5 (1): 26–35. PMID 1735093.
  5. 5.0 5.1 Luzzatto L (2012). "Sickle cell anaemia and malaria". Mediterr J Hematol Infect Dis. 4 (1): e2012065. doi:10.4084/MJHID.2012.065. PMC 3499995. PMID 23170194.
  6. "Malaria". Centers for Disease Control and Prevention. CDC. Nov 9 2012. Retrieved Jul 24 2014. Check date values in: |accessdate=, |date= (help)
  7. Mueller I, Galinski MR, Baird JK, Carlton JM, Kochar DK, Alonso PL, del Portillo HA (September 2009). "Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite". Lancet Infect Dis. 9 (9): 555–66. doi:10.1016/S1473-3099(09)70177-X. PMID 19695492.
  8. Lamikanra AA, Brown D, Potocnik A, Casals-Pascual C, Langhorne J, Roberts DJ (July 2007). "Malarial anemia: of mice and men". Blood. 110 (1): 18–28. doi:10.1182/blood-2006-09-018069. PMID 17341664.
  9. Anstey NM, Russell B, Yeo TW, Price RN (May 2009). "The pathophysiology of vivax malaria". Trends Parasitol. 25 (5): 220–7. doi:10.1016/j.pt.2009.02.003. PMID 19349210.
  10. Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ (November 2001). "Factors contributing to anemia after uncomplicated falciparum malaria". Am. J. Trop. Med. Hyg. 65 (5): 614–22. PMC 4337986. PMID 11716124.
  11. Douglas NM, Anstey NM, Buffet PA, Poespoprodjo JR, Yeo TW, White NJ, Price RN (April 2012). "The anaemia of Plasmodium vivax malaria". Malar. J. 11: 135. doi:10.1186/1475-2875-11-135. PMC 3438072. PMID 22540175.
  12. Valecha N, Pinto RG, Turner GD, Kumar A, Rodrigues S, Dubhashi NG, Rodrigues E, Banaulikar SS, Singh R, Dash AP, Baird JK (November 2009). "Histopathology of fatal respiratory distress caused by Plasmodium vivax malaria". Am. J. Trop. Med. Hyg. 81 (5): 758–62. doi:10.4269/ajtmh.2009.09-0348. PMID 19861606.
  13. Lacerda MV, Fragoso SC, Alecrim MG, Alexandre MA, Magalhães BM, Siqueira AM, Ferreira LC, Araújo JR, Mourão MP, Ferrer M, Castillo P, Martin-Jaular L, Fernandez-Becerra C, del Portillo H, Ordi J, Alonso PL, Bassat Q (October 2012). "Postmortem characterization of patients with clinical diagnosis of Plasmodium vivax malaria: to what extent does this parasite kill?". Clin. Infect. Dis. 55 (8): e67–74. doi:10.1093/cid/cis615. PMID 22772803.
  14. Rogerson SJ, Mwapasa V, Meshnick SR (December 2007). "Malaria in pregnancy: linking immunity and pathogenesis to prevention". Am. J. Trop. Med. Hyg. 77 (6 Suppl): 14–22. PMID 18165470.
  15. Beeson JG, Duffy PE (2005). "The immunology and pathogenesis of malaria during pregnancy". Curr. Top. Microbiol. Immunol. 297: 187–227. PMID 16265906.
  16. Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW (February 2007). "Malaria in pregnancy: pathogenesis and immunity". Lancet Infect Dis. 7 (2): 105–17. doi:10.1016/S1473-3099(07)70022-1. PMID 17251081.
  17. Souza RM, Ataíde R, Dombrowski JG, Ippólito V, Aitken EH, Valle SN, Álvarez JM, Epiphanio S, Epiphânio S, Marinho CR (2013). "Placental histopathological changes associated with Plasmodium vivax infection during pregnancy". PLoS Negl Trop Dis. 7 (2): e2071. doi:10.1371/journal.pntd.0002071. PMC 3573078. PMID 23459254.



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