Malaria

Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of an infected female Anopheles mosquito, malaria is caused by single-celled microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis after a history of exposure in an area endemic to malaria, which is often cyclical. Prophylaxis is of utmost importance. Treatment with oral medications is available, but malaria can be severe and fatal without a timely diagnosis, especially in young children.

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Overview

Definition

Malaria is a parasitic disease caused by unicellular parasites of the Plasmodium genus and transmitted by mosquitoes of the Anopheles genus.

Epidemiology

  • Malaria occurs throughout most of the tropical regions of Africa, Central and South America, parts of the Caribbean, Asia, Eastern Europe, and the South Pacific.
  • In 2019, the WHO reported 229 million cases and 409,000 deaths from malaria, which is a decrease from 239 million cases in 2010.
  • Children < 5 years old account for ⅔ of deaths from malaria.
  • Malaria is not endemic to the United States, but there are approximately 2,000 cases diagnosed each year (mostly travelers and immigrants from sub-Saharan Africa and South Asia).

Etiology

  • Carried by Anopheles mosquitoes and transmitted to humans through bites
  • Caused by species of the Plasmodium genus:
    • P. falciparum: 
      • Most common (approximately 70% of cases)
      • Most lethal
      • Predominates in sub-Saharan Africa, New Guinea, Haiti, and the Dominican Republic
    • P. vivax: causes approximately 20% of cases and more common in North and South America
    • P. ovale: comprises < 1% of isolates and relatively unusual outside of Africa
    • P. malariae: uncommon, found in most endemic areas (especially in sub-Saharan Africa)

Pathophysiology

Transmission

  • Transmitted by female mosquitoes of the Anopheles species through bites
  • Transmission intensity is defined by the entomologic inoculation rate (EIR).
  • Low transmission: EIR < 10/year
  • High transmission: EIR ≥ 50/year
  • Stable infection:
    • Defined as constant, year-round transmission with EIR ≥ 50/year
    • Usually asymptomatic in adults residing in stable areas due to immunity

Plasmodium life cycle

Plasmodium is a genus of unicellular eukaryotes, which are obligate parasites of vertebrates and insects.

  1. An infected female Anopheles mosquito (primary host) bites the human and injects sporozoites from its saliva into the blood of the human host.
  2. Sporozoites travel through the circulatory system, reach the liver within 30 minutes, then asexually divide thousands of times until mature schizonts (multinucleated cell stage in the asexual cycle of Plasmodium) undergo multiple fissions to form merozoites.
  3. In the liver, infected hepatocytes rupture and release thousands of merozoites into the blood of the host.
  4. In the liver, P. ovale and P. vivax can transform into a dormant stage called hypnozoites that may cause late relapse by reactivating after many months.
  5. Merozoites can infect new liver cells to transform into schizonts and release trophozoites, which infect red blood cells (RBCs).
  6. In RBCs, they multiply and transform into mature schizonts.
  7. Infected RBCs eventually rupture, releasing more merozoites into the bloodstream and causing symptoms and cyclical fever due to proinflammatory cytokines:
    • This process takes 48 hours for P. falciparum, P. vivax, and P. ovale.
    • 72 hours for P. malariae
    • 24 hours for P. knowlesi
  8. Merozoites continue asexual replication in the liver and RBCs (although a few undergo sexual reproduction) and transform into gametocytes within the RBCs.
  9. Gametocytes are ingested by a new mosquito during a blood meal from an infected human (male gametocytes are microcytes, female gametocytes are macrocytes).
    • Within the mosquito’s stomach, Plasmodium undergoes sexual reproduction (fertilization → zygote → ookinete → oocyst → sporoblast).
    • The resulting sporozoites accumulate in the salivary glands to start the cycle over when the mosquito bites the next human.

Plasmodium life cycle

Image by Lecturio.

Pathophysiology

  • Plasmodium alters erythrocytes in several ways:
    • Derives energy from anaerobic glycolysis → hypoglycemia, ↑ lactic acid
    • Reduces membrane deformability → hemolysis, anemia, splenomegaly
    • Digests hemoglobin → forms the toxic product hemozoin
  • RBC lysis causes a release of inflammatory cytokines.
  • Splenomegaly and endothelial damage lead to platelet consumption and thrombocytopenia.
  • Plasmodium is cytoadherent to the endothelium and other cells and can undergo sequestration in various human tissues:
    • Microvascular disease: occlusion of small vessels, capillary leakage, infarcts
    • Cerebral malaria: sequestration in the brain
    • Renal failure
  • Host factors play a significant role in susceptibility and disease severity:
    • RBC antigens: Absence of the Duffy antigen provides protection against P. vivax malaria.
    • Some RBC diseases confer partial protection against malaria:
      • Sickle cell anemia
      • Thalassemia (reduced parasite multiplication)
      • Ovalocytosis, hereditary elliptocytosis
      • Pyruvate kinase deficiency
    • Some polymorphisms of tumor necrosis factor-alpha (TNF-ɑ) may influence severity.
    • People living in endemic areas often develop partial immunity.

Clinical Presentation

Uncomplicated malaria

  • Incubation period: 7–30 days
  • Symptoms:
    • Initial presentation includes headache, malaise, and myalgia.
    • Paroxysmal chills, high fever (> 40℃), tachycardia, and diaphoresis coincide with cycles of RBC destruction:
      • Initially occurs daily at irregular intervals
      • Later occurs every 2nd day for P. vivax, P. ovale, and P. falciparum; every 3rd day for P. malariae
    • Hemolytic anemia causes:
      • Fatigue
      • Weakness
      • Dizziness
      • Jaundice
    • GI symptoms:
      • Diarrhea
      • Abdominal pain
      • Nausea
      • Vomiting
      • Anorexia

Severe malaria

  • Can occur with P. falciparum and P. knowlesi parasitemia
  • Multiple organ systems can be affected:
    • Decreased consciousness, seizures
    • Profound weakness
    • Respiratory distress
    • Circulatory collapse
    • Coagulopathy
    • Renal failure, hemoglobinuria (“blackwater fever”)
    • Hepatic failure
    • Metabolic acidosis
    • Severe anemia
    • Hypoglycemia

Diagnosis

History and physical exam

  • Residence or travel to an endemic region
  • Fever
  • Pallor (anemia)
  • Splenomegaly (appears around day 4)

Laboratory tests

  • CBC:
    • Anemia (decreased hemoglobin and hematocrit), increased reticulocyte counts
    • Thrombocytopenia
  • Metabolic panel:
    • Hypoglycemia
    • Renal abnormalities 
    • Elevated indirect bilirubin and transaminases 
  • Blood smear: 
    • Thick: Specificity may be difficult, but greater sensitivity.
    • Thin: Specificity is easier, but less sensitivity.
    • Findings:
      • Trophozoite ring within RBCs
      • Schizont containing merozoites
      • Red granules (Schüffner granules) are seen throughout the RBC cytoplasm with P. vivax and P. ovale.
      • Gametocytes in peripheral blood are only seen with P. falciparum.
    • Rapid diagnostic tests: > 90% specificity and sensitivity
    • PCR assay: specific and sensitive, but rarely available in endemic settings

Management and Prophylaxis

Management

  • All confirmed cases of malaria must be reported.
  • Indications for hospitalization:
    • Young children
    • Immunocompromised individuals
    • Individuals without acquired immunity
    • Hyperparasitemia of 4%–10% (risk of progression to severe disease)
  • Treat with antimalarial drugs: 
    • Avoid the same drug for treatment if it was already used for prophylaxis.
    • Chloroquine or hydroxychloroquine for sensitive species
    • Doxycycline or atovaquone/proguanil (Malarone) for areas resistant to Chloroquine
    • Mefloquine: Use in areas with chloroquine-resistant P. falciparum if above is not available.
    • Use primaquine for hypnozoites if P. vivax or P. ovale are identified.
    • If life-threatening, use IV quinidine or artesunate (monotherapy is usually inefficient for severe malaria due to P. falciparum).

Prophylaxis

  • Medications need to be initiated before traveling to endemic regions:
    • For areas with chloroquine-sensitive P. falciparum: Use chloroquine.
    • For areas with chloroquine-resistant P. falciparum: Use doxycycline, mefloquine, or atovaquone-proguanil (Malarone).
    • For areas without P. falciparum: Use primaquine.
    • For pregnant patients: Use chloroquine or mefloquine.
  • Mosquito nets
  • Long-sleeved clothes
  • Insect repellent
  • Window screens in homes

Differential Diagnosis

  • Dengue fever: a viral disease transmitted by mosquitoes. Presentation may include malaise, headache, fatigue, abdominal discomfort, and muscle aches in association with fever. Myalgia and bone pain from dengue fever are usually more severe than myalgia due to malaria. Dengue fever can be complicated by severe thrombocytopenia, bleeding, and shock. Diagnosis is established with antigen detection. Management is mostly supportive.
  • Chikungunya: a viral illness transmitted by mosquitoes. Presentation includes abrupt onset of fever and joint pain. Chikungunya resembles dengue fever, but is milder, self-limiting, and often with a rash. Treatment includes supportive care.
  • Zika: a virus causing conjunctivitis and headache. Zika is associated with Guillain-Barré syndrome and can cause infant microcephaly if infected during pregnancy. Diagnosis is established with serology and management is mostly supportive.
  • Leptospirosis: a bacterial disease associated with fever, rigors, myalgia, and headache. Myalgia is usually more severe than in malaria. Presentation may also include petechial hemorrhages in the skin or mucous membranes. Diagnosis is established with culture and treatment includes antibiotics.

References

  1. Breman, J.G. (2021). Malaria: Epidemiology, prevention, and control. UpToDate. Retrieved March 24, 2021, from https://www.uptodate.com/contents/malaria-epidemiology-prevention-and-control
  2. Le, T., Bhusan, V., et al. (Eds.). (2020). First Aid for the USMLE Step 1. 30th edition. pp. 242–243.
  3. Milner, D.A. (2021). Pathogenesis of malaria. UpToDate. Retrieved March 27, 2021, from https://www.uptodate.com/contents/pathogenesis-of-malaria
  4. CDC: Centers for Disease Control and Prevention. (2018). Choosing a Drug to Prevent Malaria. https://www.cdc.gov/malaria/travelers/drugs.html
  5. World Health Organization. (2020). World Malaria Report 2020. Retrieved March 24, 2021, from https://www.who.int/docs/default-source/malaria/world-malaria-reports/

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