Malaria

Epidemiology

  • Causes about 500 million cases and 2 million deaths annually worldwide
  • Malaria is common in sub-Saharan Africa, Asia, Latin America, the Middle East, and parts of Greece and Turkey
  • Micro-epidemics have been reported in the United States where infected immigrants from these regions are believed to be the reservoir
  • Most common infectious disease causing severe illness in international travelers returning to the US
  • Approximately 1000 cases of malaria are diagnosed annually in the US

Teleology

  • Beta Thalassemia Trait (see Thalassemia, [[Thalassemia]]): believed confer a survival advantage against malaria
    • This explains the concentration of beta thalassemia trait in geographic areas affected by malaria (Middle East, Mediteranean, Africa, etc)

Etiology

  • Plasmodium Falciparum
    • Fatal illness occurs mainly with Plasmodium Falciparum
    • Infects red blood cells of all ages (not just young ones) -> leads to higher levels of parasitemia
    • Generates electron-dense knob-like excrescences on RBC surface, mediating cytoadherence and microvascular obstruction
  • Plasmodium Knowlesi
    • Can result in rapidly progressive severe illness/death
  • Plasmodium Malariae
    • Less likely to result in severe clinical manifestations
  • Plasmodium Ovale
    • Less likely to result in severe clinical manifestations
    • Requires treatment of hypnozoite (dormant) forms in the liver, which may result in relapsing infection
  • Plasmodium Vivax
    • Less likely to result in severe clinical manifestations
    • Requires treatment of hypnozoite (dormant) forms in the liver, which may result in relapsing infection

Physiology

  • Route of Transmission
    • Bite from Female Anopheles Mosquito (most bites occur between dusk and dawn, as mosquitoes are nocturnal)
    • Contaminated Blood Product
    • Maternal-Fetal Transmission
    • Organ Transplant
  • Course: parasite invades RBC

Diagnosis

Peripheral Blood Smears

  • General Comments
    • Necessity for Serial Blood Smears: blood smears should be repeated every 12-24 hrs for a total of 3 sets (since non-immune patients may be symptomatic at very low parasite densities that may be undetectable by a single smear): 3 sets at intervals are adequate to rule out malaria
  • Thin Smear: observation for organisms in standard peripheral blood smear
    • Technique: performed with monolayer of red blood cells (with red blood cells just touching, approximately 400 red blood cells per field) under oil immersion at 100x magnification -> count 500-2000 red blood cells to determine percentage of infected cells
  • Thick Smear: observation for organisms in thick smear
    • Technique: thick smear is prepared by drop of blood -> drying -> drop of blood -> drying -> drop of blood -> drying -> addition of water to lyse red blood cells
    • Although this technique concentrates organisms (and therefore, is more sensitive), it may be difficult to detect organisms due to the presence of cellular debris

Rapid Diagnostic Tests

  • Available: dipstick/cassette format

Lumbar Puncture (LP)

  • Decreased Glucose
  • Increased Opening Pressure: mean of 16 cm H2O in the setting of cerebral malaria
  • Slight Pleocytosis: may be observed
  • Slightly Elevated Total Protein: may be observed

Clinical Presentations

Clinical Classification

  • Uncomplicated Malaria: absence of below criteria
  • Severe Malaria: characterized by at least one of the following criteria
    • Acidosis
    • Acute Kidney Injury (AKI)
    • Acute Respiratory Distress Syndrome (ARDS)
    • Disseminated Intravascular Coagulation (DIC)
    • Encephalopathy
    • Hemoglobinuria
    • Hypotension
    • Jaundice
    • Parasitemia >5%
    • Repeated Seizures
    • Severe Normocytic Anemia (Hemoglobin <7 mg/dL)
    • Spontaneous Hemorrhage

Severe Falciparum Malaria

Cardiovascular Manifestations

Dermatologic Manifestations

Endocrinologic Manifestations

  • Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]]): may be severe
    • Mechanisms
      • Decreased Hepatic Gluconeogenesis
      • Depletion of Hepatic Glycogen Stores
      • Increased Host Consumption of Glucose
      • Quinine-Induced Hyperinsulinemia

Gastrointestinal Manifestations

  • Hepatic Failure (see xxxx, [[xxxx]])
  • Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])
  • Jaundice/Hyperbilirubinemia (see Hyperbilirubinemia, [[Hyperbilirubinemia]]): due to hemolytic anemia

Hematologic Manifestations

  • Absence of Eosinophilia
  • Coagulopathy with/without Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation, [[Disseminated Intravascular Coagulation]]): may lead to gingival, nasal-oral, or gastrointestinal hemorrhage
  • Anemia with Hemolysis (see Hemolytic Anemia, [[Hemolytic Anemia]]): Hct <15% (with parasitemia >5%)
    • Mechanisms of Anemia
      • Cytokine Suppression of Hematopoesis
      • Hemolysis of Parasitized Red Blood Cells
      • Recurrent Infection
      • Shortened Red Blood Cell Survival
      • Splenic Sequestration and Clearance of Red Blood Cells with Diminished Deformability
  • Splenomegaly (see Splenomegaly, [[Splenomegaly]])
  • Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): may lead to gingival, nasal-oral, or gastrointestinal hemorrhage

Neurologic Manifestations (Cerebral Malaria)

  • General Comments
    • Focal neurologic findings are uncommon
    • Onset may be gradual or abrupt (for example, following a seizure)
  • Altered Mental Status: due to adherence of red blood cells (“cytoadherence”) within the microcirculation, resulting in ischemia and/or micro-infarcts
  • Increased Intracranial Pressure/Cerebral Edema (see Increased Intracranial Pressure, [[Increased Intracranial Pressure]])
  • Seizures (see Seizures, [[Seizures]]): due to adherence of red blood cells (“cytoadherence”) within the microcirculation, resulting in ischemia and/or micro-infarcts
  • Extreme Weakness (see xxxx, [[xxxx]])

Pulmonary Manifestations

  • Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])
    • Physiology: sequestration of parasitized red blood cells in the lung microvasculature and/or capillary leak
  • Secondary Bacterial Pneumonia: may occur

Renal Manifestations

  • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Common in adults with severe Plasmodium Falciparum malaria (however, it is relatively rare in children)
  • Hemoglobinuria (see Hemoglobinuria, [[Hemoglobinuria]]): black/brown/red urine due to hemolytic anemia
    • “Blackwater Fever” (rare): black urine (due to large amounts of hemoglobin and malarial pigments in urine) occurring after repeated attacks of Plasmodium Falciparum malaria
  • Lactic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
    • Mechanisms
      • Decreased Hepatic/Renal Lactate Clearance
      • Hypovolemia
      • Increased Anaerobic Glycolysis (Due to Parasite Impairment of Micro-Circulatory Flow)
      • Lactate Production by Parasite
    • Prognosis: severe acidosis portends a poor prognosis
  • Hyponatremia (see Hyponatremia, [[Hyponatremia]])

Other Manifestations

  • Sepsis (see Sepsis, [[Sepsis]])
    • Epidemiology: Salmonella bacteremia has been associated with Plasmodium Falciparum malaria
  • Fever (see Fever, [[Fever]]): >40 °C
  • Rigors (see Rigors, [[Rigors]])

Malaria in Pregnancy

  • xxx

Malaria in Children

  • xxx

Treatment

Prevention and Monitoring

  • Prevention of Exposure to Mosquito Bites
    • Netting
    • DEET Repellants
    • Permethrins for Clothing
  • Monitor for Febrile Illnesses: malaria can be acquired despite protective measures and prophylaxis

Pre-Exposure Prophylaxis

  • General Comments: begin medication before departure and continue until a certain time after leaving the malaria risk area
  • Chloroquine (see Chloroquine, [[Chloroquine]]): for areas without chloroquine resistance (Mexico, Central America, Caribbean islands, North Africa, portions of Middle East, China)
  • Mefloquine (Lariam) (see Mefloquine, [[Mefloquine]]): for areas with chloroquine resistance
  • Alternatives
    • Atovaquone + Proguanil (Malarone) (see Atovaquone, [[Atovaquone]])
    • Doxycycline (see Doxycycline, [[Doxycycline]])

Antibiotics

  • General Comments
    • Uncomplicated Malaria: can generally be treated with oral anti-malarials
    • Severe Malaria: generally require intravenous anti-malarials
  • Artemether + Lumefantrine (Coartem)
  • Artemisinin Derivatives
    • Artesunate (see Artesunate, [[Artesunate]])
      • Available on compassionate use from the CDC (as is currently not licensed for use in the US)
      • Intravenous administration
  • Atovaquone + Proguanil (Malarone) (see Atovaquone, [[Atovaquone]])
  • Chloroquine (see Chloroquine, [[Chloroquine]]): active against parasite forms in the blood
  • Clindamycin (see Clindamycin, [[Clindamycin]]): used in combination with quinine
  • Mefloquine (Lariam) (see Mefloquine, [[Mefloquine]])
  • Primaquine (see Primaquine, [[Primaquine]]): active against dormant parasite forms (hypnozoites) and effective to prevent relapses
  • Quinine Sulfate IV (see Quinine, [[Quinine]]): not available in US
  • Quinidine Gluconate IV (see Quinidine, [[Quinidine]])
  • Tetracyclines (see Tetracyclines, [[Tetracyclines]])
    • Doxycycline (see Doxycycline, [[Doxycycline]]): used in combination with quinine
    • Tetracycline (see Tetracycline, [[Tetracycline]]): used in combination with quinine

Exchange Transfusion (see xxxx, [[xxxx]])

  • History: first used in 1974
  • Indications: parasitemia >5% (high level) or clinical signs of poor prognosis
  • Efficacy: an 8-10 unit exchange decreases level of parasitemia to <1%
  • Trial Data: exchange transfusion has not been demonstrated to have clinical benefit in randomized, controlled trials -> no longer recommended by the CDC

References

  • Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion. N Engl J Med 1989; 321:65-70
  • Malaria: overview and update. Clin Infect Dis 1993; 16:449-458
  • The treatment of malaria. N Engl J Med 1996; 335:800-806
  • Malaria: the global resurgence of disease. Emerg Med Clin North Am 1997; 1:113-155