Malaria

Last updated: October 12, 2022

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Malaria is a potentially life‑threatening tropical infectious disease caused by Plasmodium parasites, which are transmitted through the bite of an infected female Anopheles mosquito. The disease is endemic in tropical and subtropical areas of Africa, Asia, and the Americas. Malaria has an incubation period of 7–30 days and may manifest with nonspecific symptoms like fever, nausea, and vomiting. Diagnosis can therefore be challenging. The gold standard for diagnosing malaria is identification of parasites in RBCs on a blood smear, although rapid diagnostic tests to identify Plasmodium antigens are used with increasing frequency. Malaria is classified as either severe or uncomplicated. Severe malaria is characterized by severe organ dysfunction; affected individuals should be admitted to the ICU and receive IV antimalarials immediately. Uncomplicated malaria can be treated with oral antimalarials. Preventative measures for malaria in travelers to endemic areas include chemoprophylaxis with antimalarial medications and efforts to prevent the bite of the Anopheles mosquito (e.g., mosquito nets, repellents, protective clothing). Malaria is a reportable 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 South and Southeast Asia, and Central and South America

Epidemiological data refers to the US, unless otherwise specified.

  • Pathogen: Plasmodia
    • Eukaryotic parasites (belonging to the Sporozoa group)
    • Species that affect humans [2][3][4][5]
      • Plasmodium falciparum; : most virulent and causes the most severe disease, i.e., falciparum malaria; dominant in Africa
      • Plasmodium vivax: the most common of the less virulent species and causes milder disease; dominant in endemic areas outside Subsaharan Africa (e.g., Southeast Asia)
      • Plasmodium ovale; and Plasmodium malariae: less common and cause milder disease [4]
      • Plasmodium knowlesi: found in Southeast Asia and can cause severe malaria; possibly zoonotic and often misidentified as other species due to morphological similarities. [6]
  • Vector: the female Anopheles mosquito
  • Host: humans
  • Partial resistance against malaria [7]

Classic disease and fever patterns of different plasmodium species [9][10].

Different species of plasmodium [11][12] Disease Fever spikes

P. vivax

P. ovale

  • Every 48 hours

P. malariae

  • Every 72 hours

P. falciparum

  • Irregular

P. knowlesi

  • Quotidian malaria
  • Every 24 hours

Life cycle of Plasmodium (simplified) [13]

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

Incubation period

  • 7–30 days [14]

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. [15]
    • Infections with P. vivax, P. ovale, and P. malariae typically have milder symptoms; , involve fewer organs (CNS or gastrointestinal symptoms are rare), and have a markedly lower risk of causing severe malaria. [16]
    • Following the successful treatment of tertian malaria, dormant P. ovale or P. vivax forms (hypnozoites) may remain in the liver and can cause relapse after months or even years. [16]

General symptoms [1][14]

Organ-specific symptoms [1][14]

Impaired consciousness, shock, and abnormal bleeding are signs of severe malaria that requires immediate IV treatment. [17]

Approach

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. [22]

Routine laboratory studies [21]

Used to assess the severity of malaria and identify concurrent diseases, see also “Criteria for severe malaria.”

Parasitological testing [16][19][25]

False-negative test results can occur with RDTs and blood smears, especially when malaria parasitemia is low. Repeat parasitological testing when clinical suspicion is high. [21][25][26]

Rapid diagnostic tests (RDTs)

  • Detects specific malaria antigens (e.g., HRP2, pLDH, aldolase) [19][25]
  • Allows for quick diagnosis if high‑quality microscopy is unavailable or delayed. [25]
  • Confirm all RDT results via microscopy when available. [22][25]

RDTs can detect P. falciparum but typically cannot distinguish between other species of Plasmodium. [22]

Blood smear

Gold standard test: allows for visualization of parasites within RBCs via microscopy to confirm malaria diagnosis [22]

A single negative blood smear does not rule out malaria. Repeat three sets of blood smears (one set every 12–24 hours) before ruling out the diagnosis. [16][22]

Developmental stages of Plasmodium in RBCs [13]
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

Other studies

  • PCR [25][28]
    • Identifies species of Plasmodium; useful for suspected P. knowlesi infection
    • High sensitivity but expensive and usually only available at reference laboratories
  • Serological testing
    • Positive serological results indicate prior exposure to Plasmodium. [16]
    • Not recommended in acute malaria due to length of time for antibodies to reach detectable levels [25]

Uncomplicated malaria

Severe malaria [14][17][19]

Approach [16][19][21][22]

Treatment of severe malaria [16][19][21]

The CDC recommends contacting their Malaria Hotline for all patients with severe malaria. [16]

Severe malaria is a medical emergency; without appropriate treatment, mortality is nearly 100%. [21]

Treatment of uncomplicated malaria [16][19][21]

Overview of treatment of uncomplicated malaria in adults [29]
Plasmodium species Acquired area

Treatment

P. vivax, P. ovale

(tertian malaria)

No chloroquine resistance

With chloroquine resistance
Uncomplicated falciparum malaria No chloroquine resistance
With chloroquine resistance

P. malariae, P. knowlesi

(quartan malaria) [16]

Do not use medications that the patient has already used for chemoprophylaxis. [16]

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

Overview of antimalarial drugs

Indications and pharmacology of antimalarial medication
Agents Indications Mechanism of action Most common adverse effects [30][31][32][33]
Chloroquine
  • Drug accumulation in the parasite's food vacuole → inhibition of heme polymerization → lysis of membranes
  • Interference with antigen processing → antirheumatic effects
Hydroxychloroquine
Doxycycline/ tetracycline
Mefloquine
Quinine
Artemether-lumefantrine
Atovaquone-proguanil
  • Gastrointestinal discomfort
  • Rarely: liver failure, anemia
Quinidine
  • Moderate blockade of Na+ channels
  • Weak blockade of the K+ channel

Artesunate

Primaquine

Mosquito bite prevention [41]

  • Avoid exposure
    • Exercise particular caution during peak biting periods [42]
    • 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 [43][44][45]

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 [45]

Public health surveillance

All patients

Severe malaria

Uncomplicated malaria

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