• Clinical science

Malaria

Summary

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.

Epidemiology

  • 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.

Etiology

  • Pathogen: Plasmodia [1]
    • Eukaryotic parasites (belonging to the Sporozoa group)
    • For different species, see table below
  • Vector: the female Anopheles mosquito
  • Host: humans
  • Partial resistance against malaria [2]
    • Carriers of sickle‑cell mutation
    • Individuals with either certain Duffy antigens or no Duffy antigens are resistant to P. vivax and P. knowlesi [3]
    • Other hemoglobinopathies (e.g., thalassemia, HbC)
    • Infection with malaria subsequently leads to the development of specific Plasmodium antibodies that result in partial immunity for a limited amount of time (less than a year)
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

Pathophysiology

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.

Clinical features

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.

Diagnostics

General measures

Blood smear

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 [10][11][9]

  • 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

Treatment

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

Prevention

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 [21][22][14]

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.