• Clinical science

Malaria

Abstract

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 7–42 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 a 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
    • 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)

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Pathogen: Plasmodia
    • Eukaryotic parasites belonging to the Sporozoa group
    • For different species, see the table below.
  • Vector: : the female Anopheles mosquito
  • Host: humans
  • Partial resistance against malaria
    • Carriers of sickle‑cell mutation
    • Other hemoglobinopathies (e.g., thalassemia, Hb C)
    • 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 Disease Fever spikes
Every 48 hours
Every 72 hours
Irregular
  • Quotidian malaria
Irregular

References:[2][1][3][4][5][6][7]

Pathophysiology

Life cycle of Plasmodium (simplified)

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:
  • Merozoites enter erythrocytes → maturation to trophozoites → red cell schizonts are formed containing thousands of merozoites → release of merozoites into the bloodstream (which causes fever and other manifestations of malaria) → penetration of erythrocytes recurs
  • Merozoites enter erythrocytes → differentiation into gametocytes (male of female) → a mosquito bites an infected human and ingests gametocytes

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

Developmental stages of Plasmodium in RBCs

  • Immature trophozoite: thick, dark purple ring‑shaped inclusions (similar to signet ring cell carcinoma)
  • Mature trophozoite: ameboid rings
  • Immature schizont: irregular round, ameboid, almost filling the entire erythrocyte
  • Mature schizont: conglomerate of 6–24 merozoites (round with central darkening), which develops 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. In comparison to macrogametes, it is smaller and has a brighter nucleus.

References:[8][9]

Clinical features

  • Incubation: 7–42 days
    • Relapse in P. ovale or P. vivax infection
    • Following the successful treatment of tertian malaria, some Plasmodium forms (hypnozoites) may persist within the liver and cause reinfection after lying dormant for months or even years.
    • Asymptomatic parasitemia: Especially in endemic regions, cases of asymptomatic plasmodia carriers are reported.
    • Recurrence in P. malariae infection: Following the treatment of quartan malaria, parasitemia can recur after several days or weeks, even if no parasites are detectable.

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

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!

References:[1][10][11]

Diagnostics

  • History: recent or distant travel to regions where malaria is endemic
  • CBC
  • Blood smear: confirms suspected cases by visualizing parasites within RBCs
  • 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 always be confirmed via microscopy (if available).
  • PCR
    • High sensitivity
    • Expensive and unavailable in regions with limited resources
  • Serological tests
    • Not appropriate for acute diagnosis of malaria because antibodies are undetectable for 1–2 weeks
    • Positive serological results indicate past contact with Plasmodium

If symptoms persist despite negative microscopy and rapid testing, diagnostics should be repeated every eight hours for several days!

References:[12][13][14][15]

Treatment

When choosing antimalarial drugs, age, side effects, cost, geographic region, and dosing schedule should all be taken into consideration.

Tertian malaria

Plasmodium species Treatment

P. vivax, P. ovale (chloroquine‑sensitive)

P. vivax (chloroquine‑resistant)

Quartan malaria

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 increasingly resistant to chloroquine.

Side effects of antimalarial medication

Drug Most important side effects

Chloroquine or hydroxychloroquine

  • Irreversible retinopathy!
  • CNS: agitation, anxiety, confusion
  • Gastrointestinal discomfort
Primaquine
Mefloquine
Atovaquone-proguanil
  • Gastrointestinal discomfort
Quinine
  • CNS: headache, mental status altered
  • Gastrointestinal discomfort
  • Fever, flushing
Doxycycline or tetracycline
  • Photosensitivity
  • Nephro- and hepatotoxicity
  • Damage to mucous membranes (these antibiotics should be taken with a lot of water)
Artemether-lumefantrine
Quinidine
Artesunate

References:[16][17][18][19][20][21]

Prevention

Mosquito bite prevention

  • Avoid exposure
    • Exercise particular caution during peak biting periods
    • 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

Prophylactic medication cannot prevent infection but suppresses the clinical course and symptoms by killing the parasite before it can cause a severe infection. There is no prophylactic medication that provides protection against all potential parasites.

Standby emergency treatment

Obligation to report

Report all laboratory‑confirmed cases of malaria to the local or state health department.

References:[22][23][24][25][26][27][18][28][29][30][31]