Epidemiology

Etiology

• Pathogen: Plasmodia
  • Plasmodium falciparum: most virulent and causes the most severe disease, i.e., falciparum malaria; dominant in Africa
    • Plasmodium vivax and Plasmodium ovale primarily infect very young, large erythrocytes recently released from the bone marrow (ie, reticulocytes), whereas Plasmodium malariae primarily infects old erythrocytes that have been in the bloodstream for months. In contrast, Plasmodium falciparum has the unique ability to infect erythrocytes of all ages.
    • No hypnozoites; recrudescence may occur due to treatment failure, not true relapse.
  • 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

Pathophysiology

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)
4. 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.

Clinical features

Diagnostics

Treatment

Antimalarial drugs

• Primaquine is the only antimalarial that attacks the hypnozoites, preventing relapse

• Chloroquine:

  • MOA: Blocks heme detoxification.
  • Use: Tx of sensitive malaria; Prophylaxis in sensitive areas.
  • SE/CI: Pruritus, retinopathy (chronic use). Widespread P. falciparum resistance. Safe in pregnancy.

• Primaquine / Tafenoquine:

  • MOA: Kills liver hypnozoites (disrupts mitochondrial e- transport).
  • Use: Radical cure for P. vivax & P. ovale. Terminal prophylaxis (P. vivax).
  • SE/CI: Hemolytic anemia in G6PD deficiency (MUST TEST!). Contraindicated in pregnancy, G6PD deficiency.

• Artemisinins (IV Artesunate, Artemether-Lumefantrine):

  • MOA: Free radical damage (via endoperoxide bridge activation by heme). Rapid acting.
  • Use: IV Artesunate = 1st line for SEVERE P. falciparum. Artemisinin Combination Therapies (ACTs) = 1st line for uncomplicated chloroquine-resistant P. falciparum.
  • SE/CI: Generally well-tolerated. ACTs preferred. Artemether-lumefantrine often used in pregnancy.

• Atovaquone-Proguanil (Malarone):

  • MOA: Atovaquone (mito e- transport inhibitor) + Proguanil (DHFR inhibitor).
  • Use: Prophylaxis & Tx of chloroquine-resistant P. falciparum.
  • SE/CI: GI upset (take with food). Contraindicated: severe renal impairment, pregnancy (generally).

• Mefloquine:

  • MOA: Unclear (likely heme polymerization inhibitor).
  • Use: Prophylaxis (weekly) & Tx of chloroquine-resistant P. falciparum.
  • SE/CI: Neuropsychiatric effects (BLACK BOX WARNING!) - vivid dreams, psychosis, seizures. Contraindicated: psychiatric disorders, seizures. Use with caution in pregnancy.

• Quinine / Quinidine (IV):

  • MOA: Unclear (likely heme polymerization inhibitor).
  • Use: Tx chloroquine-resistant P. falciparum (often + doxycycline/clindamycin). IV Quinidine for severe malaria if artesunate unavailable.
  • SE/CI: Cinchonism (tinnitus, headache, dizziness), hypoglycemia, QTc prolongation.

• Doxycycline:

  • MOA: 30S ribosomal inhibitor.
  • Use: Prophylaxis (daily) for resistant malaria. Tx (with quinine) for resistant P. falciparum.
  • SE/CI: Photosensitivity, GI upset (esophagitis). Contraindicated: pregnancy, children <8 years.

• Clindamycin:

  • MOA: 50S ribosomal inhibitor.
  • Use: With quinine for resistant P. falciparum (esp. pregnancy 1st trimester as alternative).
  • SE/CI: Diarrhea, C. difficile colitis.

Plans

• Chloroquine-Resistant P. falciparum:
  • Uncomplicated: ACTs (e.g., Artemether-Lumefantrine) = First line.
  • Severe: IV Artesunate = First line. (IV Quinidine + Doxycycline if artesunate unavailable).
• P. vivax / P. ovale (Relapsing Malaria): Treat blood stages (e.g., chloroquine if sensitive, or ACT) PLUS Primaquine or Tafenoquine for liver hypnozoites (radical cure �?check G6PD status!).
• Prophylaxis (Chloroquine-Resistant Areas): Atovaquone-Proguanil, Doxycycline, or Mefloquine.
• Pregnancy:
  • Uncomplicated P. falciparum: Artemether-lumefantrine preferred. Quinine + Clindamycin (esp. 1st trimester).
  • Severe: IV Artesunate.
  • Contraindicated: Doxycycline, Primaquine, Tafenoquine. Atovaquone-Proguanil generally avoided.
• G6PD Deficiency: NO Primaquine or Tafenoquine. Use Quinine with caution.

Prevention

• Should be initiated before traveling to regions with a high risk of malaria, e.g., tropical Africa, Asia, and Central/South America
• Drug of choice is based on the region traveled and Plasmodium species
  • 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