Malaria

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.

• 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)

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)
   • 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 or female)

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]

• Flu‑like symptoms, headache
• Diaphoresis
• High fever
  • Tertian malaria: periodic fever spikes every 48 hrs
  • Quartan malaria: periodic fever spikes every 72 hrs
  • Falciparum malaria (malignant tertian malaria): irregular fever spikes without a noticeable rhythm

Organ-specific symptoms ^[1][7]

• Blood
  • Thrombocytopenia: increased bleeding risk
  • Hemolytic anemia: weakness, paleness, dizziness
• Gastrointestinal
  • Nausea, vomiting
  • Diarrhea, abdominal pain
• Liver: : hepatosplenomegaly, discrete jaundice

Severe malaria ^[7]

• Description: potentially fatal manifestation or complication of malaria
• Etiology: most commonly a result of falciparum malaria
• Pathophysiology: infected erythrocytes occlude capillaries, which can lead to severe organ dysfunction
• Manifestations
  • Kidneys: flank pain, oliguria, hemoglobinuria, acute kidney injury
  • Cerebral: hallucinations, confusion, impaired consciousness, seizures, or even coma
  • Cardiopulmonary: heart failure, pulmonary edema, ARDS, shock
  • Hematologic: severe anemia, coagulation disorders
  • Metabolic: hypoglycemia, metabolic acidosis
  • Hyperparasitemia: > 5% of RBC are infected with plasmodia

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

• History: recent or distant travel to regions where malaria is endemic
• CBC
  • Hemolytic anemia: ↓ Hb, ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes
  • Thrombocytopenia
  • Possibly leukocytopenia

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
  • Lower sensitivity than thick blood smear, but higher specificity
  • Parasites are visible within red blood cells since the morphology of erythrocytes is preserved
  • Allows determination of Plasmodium species
  • Schuffner granules (fine, brick-red dots) within the cytoplasm of P. vivax and P. ovale
• 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.

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.

Overview of antimalarial drugs

Treatment regimens

Tertian and quartan malaria

Falciparum malaria

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

Side effects of antimalarial medication ^[21][22][23]

Mosquito bite prevention ^[25]

• Avoid exposure
  • Exercise particular caution during peak biting periods ^[26]
  • 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][27][28]

• Should be initiated before traveling to regions with a high risk of malaria, e.g., tropical Africa, Asia, and Latin America
• Drug of choice is based on the region travelled
  • Areas with P. falciparum
    • If chloroquine-resistant P. falciparum (most malaria endemic regions): atovaquone-proguanil, doxycycline, mefloquine
    • If chloroquine-sensitive P. falciparum: chloroquine
  • Areas without P. falciparum; (some areas of Central/South America, Mexico, China, South Korea): primaquine
• Agents that are safe during pregnancy: chloroquine, mefloquine

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]

• Indication
  • Traveling to endemic regions with a medium to high risk of malaria
  • Depending on the risk, either prophylactic or standby emergency treatment may be recommended (when in doubt: prophylactic medication).
• Drugs
  • Atovaquone-proguanil
  • Artemether-lumefantrine
  • Chloroquine with limitations: there are now many chloroquine-resistant Plasmodium strains with membrane pumps that lower intracellular chloroquine concentrations

Obligation to report

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