Malaria, Plasmodium Falciparum, Plasmodium Malariae, Plasmodium Vivax, Plasmodium Ovale, Plasmodium Falciparum Infection, Plasmodium Malariae Infection, Plasmodium Vivax Infection, Plasmodium Ovale Infection, Ovale Malaria, Falciparum Malaria, Vivax Malaria, Quartan Malaria, Tertian Fever, Quartan Fever

  • Etiology
  • Malaria Species
  1. Plasmodium Vivax
  2. Plasmodium Ovale
  3. Plasmodium Falciparum
  4. Plasmodium Malariae (Quartan Malaria)
  • Pathophysiology
  1. See Vector-Borne Infection
  2. Transmitted by bite of anopheline (or anopheles) Mosquito
    1. Usually bites between dusk and dawn
    2. Injects Malaria protozoa from Salivary Glands
  3. Species of Malaria
    1. Plasmodium Falciparum (most common and most life threatening)
      1. Fulminant Malaria associated with high Parasitemia and intravascular congestion
      2. Incubation Period: Typically 12-14 days (ranges from 7 to 30 days)
    2. Plasmodium Vivax
      1. Incubation Period: Months to years
    3. Plasmodium Malariae (Quartan Malaria)
      1. Fever recurs every 3 days (Quartan Fever), instead of the 2 day intervals of other Plasmodium
    4. Plasmodium Ovale
      1. Incubation Period: Months to years
    5. Plasmodium knowlesi
      1. Emerging pathogen in those exposed to macque monkeys
      2. Similar in appearance to p. Malariae
  4. Life cycle of Malaria
    1. Injected from Mosquito as sporozoite
    2. Sporozoites invade hepatocytes in human liver
      1. Develop into merozoites after weeks to months of development within hepatocytes
      2. Merozoites released into blood stream
      3. Sporozoites may lie dormant in liver (hypnozoites)
        1. Occurs with Plasmodium Vivax and Plasmodium Ovale
        2. Symptoms recur when reactivates in months to years
    3. Merozoites invade erythrocytes and circulate freely
      1. P. Malariae may remain in Red Blood Cells without lysis, latent for months to years
      2. Typically results in Red Blood Cell lysis within 48-72 hours of erythrocyte invasion
      3. Hemolysis is associated with fever spikes
        1. Fever spikes typically occur randomly, but may occur with RBC lysis in a pattern
        2. May cause Tertian Fever (recurring every third day)
        3. May cause Quartan Fever (recurring every fourth day)
    4. Circulating merozoites differentiate into Gametocytes
      1. Gametocytes are the sexual form of plasmodium
      2. Mosquito ingests gametocytes from infected host
      3. Protozoa develop within the Mosquito over a 10-21 day course
      4. Mosquito infects next human host with bite
  • Epidemiology
  1. Incidence
    1. Most common life threatening disease for travelers
    2. Mosquito population is expected to as much as double with global warming (0.4 C) by 2020
    3. European, North American traveler cases: 30,000/year
    4. Cases reported to CDC per year: 1500 (out of 18 million U.S. travelers to Malaria endemic areas)
    5. Worldwide Infections: 300 million per year
    6. Worldwide Mortality: 1-3 million deaths per year
      1. Malaria is among the top three infectious causes of death in the world
      2. Other high mortality infectious causes include HIV Infection and Tuberculosis)
  2. Timing
    1. Majority of Malaria outbreaks occur between May and December
    2. Highest risk is during and after the rainy season
      1. River beds and stagnant pools of water are most common breading grounds
  3. Regions
    1. Endemic to tropical and subtropical world around the equator (106 countries as of 2010)
    2. Highest Risk
      1. Sub-Saharan Africa
      2. Papua New Guinea
      3. Solomon Islands
      4. Vanuatu
    3. Intermediate Risk
      1. Haiti
      2. Indian subcontinent
    4. Low Risk
      1. Southeast Asia
      2. Latin America
  • Symptoms
  1. Timing
    1. Presentation within the first month of return from travel to endemic region
    2. Delayed presentation beyond 2 months may occur with the use of chemoprophylaxis
  2. Initial prodrome
    1. Headache
    2. Malaise
  3. Next
    1. Fever (>50% of patients)
    2. Shaking chills
  4. Next
    1. Drowsiness
    2. Lethargy
    3. Fatigue
  5. Other symptoms
    1. Myalgias
      1. More severe in Dengue Fever
    2. Muscle tenderness
      1. More severe in Leptospirosis and Typhus
    3. Arthralgias
    4. Back pain
    5. Nausea
    6. Vomiting
    7. Diarrhea
    8. Abdominal Pain
  • Signs
  1. Fever for 1-8 hours
  2. Fever recurs
    1. Plasmodium Vivax: 48 hour intervals (Tertian Fever)
    2. Plasmodium Malariae: 72 hour intervals (Quartan Fever)
    3. Plasmodium Falciparum: Variable
  3. Gastrointestinal findings (in <35-40% of cases)
    1. Tender Splenomegaly
  4. Severe Falciparum Malaria
    1. Hypotension and shock
    2. Multisystem failure
      1. Pulmonary Edema
      2. Acute Respiratory Distress Syndrome
      3. Renal Failure (1% of cases)
      4. Jaundice and liver failure (associated with poor prognosis)
    3. Cerebral Malaria
      1. Altered Mental Status to unresponsive
      2. Seizures
      3. Meningism
  • Differential Diagnosis
  1. See Fever in the Returning Traveler
  2. See Vector-Borne Infection
  3. Other Arboviruses that are Vector-Borne Infections (Aedes aegypti Mosquito-Borne Disease)
    1. Typhoid Fever
    2. Dengue Fever
    3. Chikungunya
    4. Zika Virus
    5. Yellow Fever
  4. Other causes in the differential diagnosis of Malaria
    1. Viral Hepatitis
    2. Acute HIV Infection
  5. Rash is uncommon in Malaria (aside from Petechiae in severe Falciparum Malaria with DIC) and suggests other diagnosis
    1. See Febrile Traveler with Rash
    2. Dengue Fever
    3. Chikungunya
    4. Zika Virus
    5. Typhus
    6. Enteric Fever
    7. Meningococcus
  • Labs
  1. Blood Glucose
    1. Hypoglycemia may occur (esp. children)
  2. Complete Blood Count (CBC) with differential
    1. Especially consider Malaria with Leukopenia and Left Shift, Thrombocytopenia
    2. Hemoglobin or Hematocrit consistent with Anemia (29%)
    3. Leukopenia with White Blood Cell Count <5000/mm3 (26%)
    4. Thrombocytopenia (45%)
    5. Bandemia (85%)
  3. Urinalysis
    1. Urobilinogen positive
    2. Hemoglobinuria (rare, may occur with Plasmodium Falciparum)
  4. Cerebrospinal Fluid Examination
    1. Indicated in Altered Mental Status and fever
    2. Exclude Meningitis and Encephalitis (esp. if Malaria diagnosis is unclear)
    3. Malaria CSF is typically normal (aside from mild Pleocytosis, mild increased protein)
  • Diagnosis
  1. Peripheral Blood Smear
    1. Gold standard for diagnosis
    2. Stains
      1. Giemsa stain (standard stain for Malaria evaluation with thick and thin smears)
        1. Thin blood smear (first-line Malaria evaluation)
          1. Giemsa stain of blood fixed with Alcohol to prevent Red Blood Cell lysis
          2. High Test Sensitivity
        2. Thick blood smear (perform if thin blood smear negative)
          1. Giemsa stain of blood allowed to dry on slide (allowing cell lysis)
      2. Wright stain (standard stain for most Complete Blood Count associated manual differentials)
        1. Test Sensitivity approaches that of Giemsa stain
    3. Protocol
      1. Stat blood smear with direct communication with reading pathologist (alert for Malaria concern)
      2. Examine new smear every 12-24 hours for 2-3 days (low Parasitemia may require additional smears)
      3. Sample is best obtained when patient is febrile
    4. Image
      1. HemeoncFalciparum.jpg
  2. Rapid blood dipstick testing (when smear not available)
    1. Tests
      1. HRP-2 detection (only detects P. falciparum)
      2. LDH detection (detects all 4 Malaria types)
    2. Precautions
      1. Decreased Test Sensitivity with low levels of Parasitemia
        1. Examples: Patients who took chemoprophylaxis, or prior exposure
      2. Negative rapid tests should be confirmed with blood smears
  3. Malaria PCR
    1. Detects low levels of parsites in blood (<5 Parasites/ul)
    2. Distinguishes between plasmodium species
    3. May be used to monitor response to treatment at 5-8 days (however False Positives may occur)
  • Management
  • Chemoprophylaxis
  • Precautions
  1. Fever in a returning traveler from Malaria endemic area is Malaria until proven otherwise
  2. Up to 50% of Malaria cases are misdiagnosed on the first visit
  3. Initial presentations are often mild and non-specific (fever, chills, malaise, myalgia, Headache)
  4. Malaria is an emergent evaluation
  • Management
  • Non-Falciparum Malaria treatment
  1. Uncomplicated non-Falciparum Malaria
    1. Step 1: Chloroquine
      1. Dose: 600 mg load, then 300 mg in 6-8 hours, then 300 mg daily for 2 days
      2. Obtain baseline EKG for QT Prolongation and monitor as needed
    2. Step 2: Primaquine (if G6PD Deficiency negative)
      1. Used to eliminate hypnozoites (liver stage) of vivax and ovale species
      2. Dose: 30 mg daily for 2 weeks after Chloroquine course
      3. Decrease dose if Tinnitus or hyperexcitability occur
      4. Use Chloroquine weekly for 6 months if patient G6PD Deficiency positive
  2. Severe Non-Falciparum Malaria
    1. Replace Chloroquine with Quinine, Quinidine or Artesunate
    2. Follow course with Primaquine if without G6PD Deficiency (as above)
  • Management
  • Falciparum Malaria treatment
  1. Admit all cases to hospital (high mortality in first 48 hours)
    1. Also admit all undiferentiated cases where species of Malaria cannot be discerned
  2. Combination antiparasitic agents (2 agents)
    1. Intravenous antimalarial agents for severe disease or Parasite load >5%
    2. Agent 1: IV Artemisinin (or dihydroartemisinin, artemether, or Artesunate) - first-line agent
      1. See Artesunate (preferred in U.S.)
      2. May use Lumefantrine/artemether twice daily for 3 days in less severe cases
    3. Agent 2: Chloroquine, Sulfadoxine-pyrimethamine (Fansidar) or Mefloquine
    4. Treat for 3 days (6 days if travel to areas with high Malaria resistance)
  3. Specific complication management
    1. Shock
      1. Intravenous hydration (including fluid boluses)
      2. Obtain Blood Cultures and add third generation Cephalosporin to regimen
        1. Continue until cultures back (risk of comorbid Bacterial Sepsis)
    2. Cerebral Malaria (18% of cases)
      1. Seizures
      2. Supportive care including intubation may be needed
      3. Meningism (uncommon but carries 23% mortality)
    3. Bleeding
      1. Coagulopathy reversal
      2. Blood Transfusion
  • Prevention
  1. See Malaria Chemoprophylaxis
    1. Critical and not taken adequately in as much as 75% of U.S. travelers
  2. See Prevention of Vector-borne Infection
  3. Malaria Vaccine (investigational in 2012)
  4. Stay in air conditioned or well screened rooms
  5. Reduce nighttime outdoor activity (Dusk until dawn)
  6. Apply an effective Insect repellent
    1. DEET 30% to skin every 3-4 hours or
    2. p-Menthane-3,8-diol (PMD)
  7. Spray clothing and bed nets with Permethrin
  8. Wear long sleeve shirt and pants
  9. Use Insecticide aerosols at dusk in living areas
  10. Use a strong fan at bedside
  11. Use Mosquito bed netting even in hotel rooms
    1. Mosquito net pre-treated with Permethrin
    2. Reapply Permethrin every 6 months
  • Prognosis
  1. Plasmodium Falciparum Mortality: 4% (20% severe cases)
  2. More severe cases in pregnant women and children
  • Resources
  1. See Travel Resources
  2. CDC Malaria hotline (physicians)
    1. Phone: 855-856-4713 (daytime)
    2. Phone: 770-488-7100 (after hours, emergency operations center)
  3. CDC Malaria
  4. Malaria Foundation International
  • References