Malaria

Epidemiology

Demographics

  • Prevalence
    • Malaria Causes Approximately 500 Million Cases and 2 Million Deaths Annually Worldwide
  • Geography
    • Malaria is Common in Sub-Saharan Africa, Asia, Latin America, the Middle East, and Parts of Greece and Turkey
    • Micro-Epidemics of Malaria in the United States: have been reported where infected immigrants from these regions are believed to be the reservoir
    • Malaria is the Most Common infectious Disease Causing Severe Illness in International Travelers Returning to the United States
    • Approximately 1000 Cases of Malaria are Diagnosed Annually in the United States

Teleology

  • Beta Thalassemia Trait (see Thalassemias)
    • Believed to 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
    • Physiology
      • Infects Red Blood Cells of All Ages (Not Just Young Ones), Resulting in Higher Levels of Parasitemia
      • Generates Electron-Dense Knob-Like Excrescences on RBC Surface, Mediating Cytoadherence and Microvascular Obstruction
    • Clinical
      • Fatal Illness Occurs Mainly with Plasmodium Falciparum
  • Plasmodium Knowlesi
    • Clinical
      • Can Result in Rapidly Progressive Severe Illness/Death
  • Plasmodium Malariae
    • Clinical
      • Less Likely to Result in Severe Clinical Manifestations
  • Plasmodium Ovale
    • Clinical
      • Less Likely to Result in Severe Clinical Manifestations
    • Treatment
      • Requires Treatment of Hypnozoite (Dormant) Forms in the Liver, Which May Result in Relapsing Infection
  • Plasmodium Vivax
    • Clinical
      • Less Likely to Result in Severe Clinical Manifestations
    • Treatment
      • Requires Treatment of Hypnozoite (Dormant) Forms in the Liver, Which May Result in Relapsing Infection

Physiology

  • Routes of Transmission
    • Bite from Female Anopheles Mosquito (see Mosquito Bite): most bites occur between dusk and dawn, as mosquitoes are nocturnal
    • Contaminated Blood Product
    • Maternal-Fetal Transmission
    • Organ Transplant
  • Course
    • Parasite Invades the Red Blood Cell

Diagnosis

Peripheral Blood Smear (see Peripheral Blood Smear)

  • General Comments
    • 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 Which May be Undetectable by a Single Smear
    • Three Sets of Smears at Intervals are Adequate to Rule Out Malaria
  • Thin Smear (Standard Peripheral Blood Smear)
    • Preparation of Thin Smear
      • Performed with Monolayer of Red Blood Cells (with Red Blood Cells Just Touching Each Other, at Approximately 400 Red Blood Cells Per Field)
    • Interpretation
      • Examine Under Oil Immersion at 100x Magnification and Count 500-2000 Red Blood Cells to Determine the Percentage of Infected Cells (Containing Ring Forms, Gametocytes, etc)
  • Thick Smear
    • Preparation of Thick Smear
      • Apply Drop of Blood, Allow to Dry -> Apply Drop of Blood, Allow to Dry -> Apply Drop of Blood, Allow to Dry -> Add Water to Lyse Red Blood Cells
    • Interpretation
      • Examine for the Presence of Organisms (Ring Forms, Gametocytes, etc)
      • 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 in Dipstick/Cassette Format

Lumbar Puncture (LP) (see Lumbar Puncture)

  • Findings
    • 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

Severe Falciparum Malaria

Cardiovascular Manifestations

Dermatologic Manifestations

Endocrinologic Manifestations

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

Gastrointestinal Manifestations

  • Acute Liver Failure (Fulminant Hepatic Failure) (see Acute Liver Failure)
    • Epidemiology
      • May Occur in the Setting of Plasmodium Falciparum Infection (More Commonly in Adults than in Children)
    • Physiology
      • Due to Cholestasis and Hepatocyte Injury
    • Clinical
      • Presents with Severe Hyperbilirubinemia
    • Prognosis
      • Hepatic Dysfunction with Acute Kidney Injury Portends a Poor Prognosis
  • Hepatomegaly (see Hepatomegaly)
  • Jaundice/Hyperbilirubinemia (see Hyperbilirubinemia)

Hematologic Manifestations

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 (see Altered Mental Status)
    • Due to Adherence of Red Blood Cells (“Cytoadherence”) within the Microcirculation, Resulting in Ischemia and/or Micro-Infarcts
    • Delirium/Encephalopathy (see Delirium)
    • Obtundation/Coma (see Obtundation-Coma)
  • Increased Intracranial Pressure/Cerebral Edema (see Increased Intracranial Pressure)
  • Seizures (see Seizures)
    • Due to Adherence of Red Blood Cells (“Cytoadherence”) within the Microcirculation, Resulting in Ischemia and/or Micro-Infarcts
  • Extreme Weakness (see Weakness)

Pulmonary Manifestations

  • Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)
    • Physiology
      • Sequestration of Parasitized Red Blood Cells in the Lung Microvasculature and/or Capillary Leak
  • Secondary Bacterial Pneumonia
    • Epidemiology
      • May Occur

Renal Manifestations

  • Acute Kidney Injury (AKI) (see Acute Kidney Injury)
    • Epidemiology
      • Common in Adults with Severe Plasmodium Falciparum Malaria (However, it is Relatively Rare in Children)
  • Hemoglobinuria (see Hemoglobinuria)
    • Black/Brown/Red Urine Due to Hemolytic Anemia (see 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)
    • 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)

Other Manifestations

  • Sepsis (see Sepsis)
    • Epidemiology
      • Salmonella Bacteremia Has Been Associated with Plasmodium Falciparum Malaria
  • Fever (see Fever): >40 °C
  • Rigors (see Rigors)

Malaria in Pregnancy (see Pregnancy)

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Malaria in Children

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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)
  • Mefloquine (Lariam) (see Mefloquine)
    • For Areas with Chloroquine Resistance (Mexico, Central America, Caribbean islands, North Africa, Portions of Middle East, China)
  • Alternatives

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)
      • Availability: available on compassionate use from the CDC (as is currently not licensed for use in the US)
      • Administration: IV
  • Atovaquone + Proguanil (Malarone) (see Atovaquone)
  • Chloroquine (see Chloroquine): active against parasite forms in the blood
  • Clindamycin (see Clindamycin): used in combination with quinine
  • Mefloquine (Lariam) (see Mefloquine)
  • Primaquine (see Primaquine): active against dormant parasite forms (hypnozoites) and effective to prevent relapses
  • Quinine Sulfate IV (see Quinine): not available in US
  • Quinidine Gluconate IV (see Quinidine)
  • Tetracyclines (see Tetracyclines)
    • Doxycycline (see Doxycycline): used in combination with quinine
    • Tetracycline (see Tetracycline): used in combination with quinine

Exchange Transfusion

  • 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 and is 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