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Malaria

Last updated: January 20, 2021

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Malaria is a potentially life‑threatening tropical disease caused by Plasmodium parasites, which are transmitted through the bite of an infected female Anopheles mosquito. The clinical presentation and prognosis of the disease depend on the Plasmodium species. Malaria has an incubation period of 7–30 days and may present with relatively unspecific symptoms like fever, nausea, and vomiting. Therefore, it is often misdiagnosed. Clinically suspected cases are confirmed by direct parasite detection in a blood smear. Patients are treated with antimalarial drugs (e.g., chloroquine, quinine), some of which may also be used as prophylaxis during trips to endemic regions. However, the most important preventive measure is adequate protection against the Anopheles mosquito (e.g., mosquito nets, repellents, protective clothing, etc.). Malaria is a notifiable disease and should be suspected in all patients with fever and a history of travel to an endemic region.

  • Distribution [1]
    • Most cases of malaria occur in tropical Africa (West and Central Africa).
    • Transmission also occurs in other tropical and subtropical regions such as Asia (e.g., India, Thailand, Indonesia), and Latin America (e.g., Brazil, Colombia)

Epidemiological data refers to the US, unless otherwise specified.

Different species of plasmodium [4][5] Disease Fever spikes

Plasmodium vivax

Plasmodium ovale

  • Every 48 hours

Plasmodium malariae

  • Every 72 hours

Plasmodium falciparum

  • Irregular

Plasmodium knowlesi

  • Quotidian malaria
  • Irregular

Life cycle of Plasmodium (simplified) [6]

Asexual development in humans

  1. Transmission of Plasmodium sporozoites via Anopheles mosquito bite → sporozoites travel through the bloodstream to the liver of the host
  2. Liver: sporozoites enter hepatocytes sporozoites multiply asexually → schizonts are formed containing thousands of merozoites → release of merozoites into the bloodstream
  3. Circulatory system (two possible outcomes)

Sexual development in female Anopheles mosquito

  • A mosquito bites an infected human and ingests gametocytes → gametocytes mature within the mosquito intestines → sporozoites are formed and these migrate to the salivary glands → transmission of sporozoites to humans via mosquito bite
  • See “Developmental stages of Plasmodium in RBCs” in “Diagnostics” below.

Incubation period

  • 7–30 days [7]

The incubation period of malaria is a minimum of seven days; if fever occurs before the seventh day following exposure in an endemic region, it is most likely not due to malaria.

Course

  • Infection → asymptomatic parasitemia → uncomplicated illness → severe malaria → death
    • Asymptomatic parasitemia: Especially in endemic regions, cases of asymptomatic plasmodia carriers are reported. [8]
    • Tertian and quartan malaria are associated with less severe symptoms; , the involvement of fewer organs (rarely CNS or gastrointestinal symptoms), and a markedly lower risk of severe malaria.
    • Following the successful treatment of tertian malaria, dormant P. ovale or P. vivax forms (hypnozoites) may persist within the liver and cause reinfection (relapse) after months or even years.

General symptoms [1][7]

Organ-specific symptoms [1][7]

Severe malaria [7]

Malaria can present in many different ways and is therefore often misdiagnosed. In patients with fever who have recently traveled to endemic regions, malaria must always be considered.

General measures

Blood smear

  • Description: confirms suspected cases by visualizing parasites within RBCs
  • Best initial test: thick blood smear
    • High sensitivity
    • Detects the presence of parasites
  • Confirmatory testing: thin blood smear
  • Evaluation of negative test results [9]
    • If parasite densities are very low, malaria may be initially undetectable.
    • If an initial test result is negative, blood smears should be repeated three times every 12–24 hours
    • If all three sets are negative, malaria can be ruled out.
Developmental stages of Plasmodium in RBCs [6]
All Plasmodium spp. Plasmodium falciparum
Immature trophozoite
  • Fine rings
Mature trophozoite
  • Ameboid rings
Immature schizont
  • Irregular round, ameboid
  • Almost filling the entire erythrocytes
  • Hardly detectable in the blood
Mature schizont
  • Conglomerate of 6–24 merozoites (round with central darkening)
  • Develop from an immature schizont
Gametocytes
  • Macrogamete
    • Mature female (sexual) form
    • Visible as a round structure filling almost the entire erythrocyte
  • Microgamete
    • Mature male (sexual) form
    • Visible as a round structure within the erythrocyte
    • Smaller and has a brighter nucleus than macrogametes

If symptoms persist despite negative microscopy and rapid testing, blood smears should be repeated 3 times every 12-24 hours.

Other tests [9][10][11]

  • Rapid diagnostic tests (RDTs)
    • Determination of specific malaria antigens, e.g., HRP2, pLDH, and aldolase
    • Benefits: quick determination of malaria infection in areas lacking high‑quality malaria microscopy
    • All RDT results should be confirmed via microscopy (if available).
  • Serological tests
    • Not appropriate for acute diagnosis of malaria because antibodies are undetectable for 1–2 weeks after primary infection
    • Positive serological results indicate prior exposure to Plasmodium

General considerations [12][13][14]

  • When choosing antimalarial drugs, age, side effects, cost, geographic region, and dosing schedule should all be taken into consideration.
  • The increasing resistance to chloroquine due to the development of efflux membrane pumps (especially in P. falciparum) should also be considered.

Specific treatment for tertian and quartan malaria

Plasmodium species Treatment
Tertian malaria
P. vivax, P. ovale Chloroquine-sensitive
Chloroquine-resistant
Quartan malaria
P. malariae, P. knowlesi

Specific treatment for falciparum malaria

Severity of disease Region Treatment
Uncomplicated falciparum malaria
  • Chloroquine‑sensitive
  • Chloroquine‑resistant
Severe falciparum malaria
  • All regions

Plasmodium falciparum and, more recently, Plasmodium vivax are becoming increasingly resistant to chloroquine.

Side effects of antimalarial medication [15][16][17]

Drug Most important side effects

Chloroquine

Hydroxychloroquine

  • Gastrointestinal discomfort
  • Irreversible retinopathy
  • Pruritus: most commonly seen in dark-skinned individuals [18]
  • CNS: agitation, anxiety, confusion
Primaquine
Mefloquine
Atovaquone-proguanil
  • Gastrointestinal discomfort
Quinine

Doxycycline

Tetracycline

Artemether-lumefantrine
Quinidine
Artesunate

Mosquito bite prevention [19]

  • Avoid exposure
    • Exercise particular caution during peak biting periods [20]
    • Mosquito nets
    • Protective clothing (covering most of the skin, light colors)
    • Mosquito repellent, such as DEET (N,N-diethyl-meta-toluamide)
  • Mosquito control
    • Reduce breeding sites (e.g., eliminate pools of water, optimize plant watering)
    • Insecticide spraying

Malaria prophylaxis [14][21][22]

Prophylactic medication cannot prevent infection but instead suppresses the course of the disease and its symptoms by killing the parasite within the host before it can cause severe disease. There is no prophylactic medication that provides protection against all species of the Plasmodium genus.

Standby emergency treatment [14]

Obligation to report

  • Report all laboratory‑confirmed cases of malaria to the local or state health department.
  1. Malaria. http://www.who.int/mediacentre/factsheets/fs094/en/. Updated: December 1, 2016. Accessed: March 20, 2017.
  2. Williams TN, Mwangi TW, Wambua S et al. Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J Infect Dis. 2005; 192 (1): p.178-186. doi: 10.1086/430744 . | Open in Read by QxMD
  3. Gledson Barbosa de Carvalho and Glauber Barbosa de Carvalho. Duffy Blood Group System and the malaria adaptation process in humans. Revista Brasileira de Hematologia e Hemoterapia. 2011 .
  4. Mvumbi DM, Bobanga TL, Melin P et al. High Prevalence of Plasmodium falciparum Infection in Asymptomatic Individuals from the Democratic Republic of the Congo. Malar Res Treat. 2016; 2016 (2016): p.5405802. doi: 10.1155/2016/5405802 . | Open in Read by QxMD
  5. Antinori S, Galimberti L, Milazzo L, Corbellino M. Biology of human malaria plasmodia including Plasmodium Knowlesi. Mediterr J Hematol Infect Dis. 2012; 4 (1): p.2012013. doi: 10.4084/mjhid.2012.013 . | Open in Read by QxMD
  6. Malaria - Biology. https://www.cdc.gov/malaria/about/biology/. Updated: March 1, 2017. Accessed: March 20, 2017.
  7. Malaria - Disease. https://www.cdc.gov/malaria/about/disease.html. Updated: October 7, 2015. Accessed: February 22, 2018.
  8. Cheaveau J, Mogollon DC, Mohon MAN, Golassa L, Yewhalaw D, Pillai DR. Asymptomatic malaria in the clinical and public health context. Expert Rev Anti Infect Ther. 2019; 17 (12): p.997-1010. doi: 10.1080/14787210.2019.1693259 . | Open in Read by QxMD
  9. Treatment of Malaria: Guidelines for Clinicians (United States). https://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html. Updated: May 20, 2020. Accessed: July 29, 2020.
  10. General Approach to the Returned Traveler. https://wwwnc.cdc.gov/travel/yellowbook/2016/post-travel-evaluation/general-approach-to-the-returned-traveler. Updated: July 10, 2015. Accessed: March 20, 2017.
  11. Malaria Diagnosis (U.S.) – Rapid Diagnostic Test. https://www.cdc.gov/malaria/diagnosis_treatment/rdt.html. Updated: July 14, 2014. Accessed: March 20, 2017.
  12. Guidelines for Treatment of Malaria in the United States (Based on drugs currently available for use in the United States – updated July 1, 2013). https://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf. Updated: July 1, 2013. Accessed: March 20, 2017.
  13. Overview of malaria treatment. http://www.who.int/malaria/areas/treatment/overview/en/. Updated: March 18, 2016. Accessed: March 20, 2017.
  14. Infectious Diseases Related to Travel - Malaria. https://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/malaria#4660. Updated: July 10, 2015. Accessed: March 20, 2017.
  15. Artemether / Lumefantrine Side Effects. https://www.drugs.com/sfx/artemether-lumefantrine-side-effects.html. Updated: February 2, 2018. Accessed: February 22, 2018.
  16. Quinine Side Effects. https://www.drugs.com/sfx/quinine-side-effects.html. Updated: February 2, 2018. Accessed: February 22, 2018.
  17. Quinidine Side Effects. https://www.drugs.com/sfx/quinidine-side-effects.html. Updated: February 2, 2018. Accessed: February 22, 2018.
  18. Aghahowa S, Obianwu H, Isah A, Arhewoh I. Chloroquine-induced Pruritus. Indian J Pharm Sci. 2010; 72 (3): p.283. doi: 10.4103/0250-474x.70471 . | Open in Read by QxMD
  19. Protection against Mosquitoes, Ticks, & Other Arthropods. https://wwwnc.cdc.gov/travel/yellowbook/2016/the-pre-travel-consultation/protection-against-mosquitoes-ticks-other-arthropods. Updated: July 10, 2015. Accessed: March 20, 2017.
  20. Anopheles Mosquitoes. https://www.cdc.gov/malaria/about/biology/mosquitoes/. Updated: October 21, 2015. Accessed: March 20, 2017.
  21. Arguin PM, Keystone JS. Prevention of malaria infection in travelers. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/prevention-of-malaria-infection-in-travelers?source=search_result&search=malaria&selectedTitle=3~150#H7.Last updated: September 14, 2016. Accessed: March 20, 2017.
  22. Nosten F, McGready R, d'Alessandro U et al. Antimalarial Drugs in Pregnancy: a Review. Curr Drug Saf. 2006; 1 (1): p.1 - 15. doi: 10.2174/157488606775252584 . | Open in Read by QxMD
  23. Malaria Resistance and Sickle Cell Trait. https://microbewiki.kenyon.edu/index.php/Malaria_Resistance_and_Sickle_Cell_Trait. Updated: December 6, 2013. Accessed: March 20, 2017.