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
Malaria in Children
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