Malaria

Malaria is a potentially life‑threatening tropical infectious disease caused by Plasmodium parasites, which are transmitted through the bite of an infected female Anopheles mosquito. The disease is endemic in tropical and subtropical areas of Africa, Asia, and the Americas. Malaria has an incubation period of 7–30 days and may manifest with nonspecific symptoms like fever, nausea, and vomiting. Diagnosis can therefore be challenging. The gold standard for diagnosing malaria is identification of parasites in RBCs on a blood smear, although rapid diagnostic tests to identify Plasmodium antigens are used with increasing frequency. Malaria is classified as either severe or uncomplicated. Severe malaria is characterized by severe organ dysfunction; affected individuals should be admitted to the ICU and receive IV antimalarials immediately. Uncomplicated malaria can be treated with oral antimalarials. Preventative measures for malaria in travelers to endemic areas include chemoprophylaxis with antimalarial medications and efforts to prevent the bite of the Anopheles mosquito (e.g., mosquito nets, repellents, protective clothing). Malaria is a reportable disease and should be suspected in all patients with fever and a history of travel to an endemic region.

• Distribution ^[1]
  • Most cases of malaria occur in tropical Africa (West and Central Africa).
  • Transmission also occurs in other tropical and subtropical regions such as South and Southeast Asia, and Central and South America

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen: Plasmodia
  • Eukaryotic parasites (belonging to the Sporozoa group)
  • Species that affect humans ^[2][3][4][5]
    • Plasmodium falciparum; : most virulent and causes the most severe disease, i.e., falciparum malaria; dominant in Africa
    • Plasmodium vivax: the most common of the less virulent species and causes milder disease; dominant in endemic areas outside Subsaharan Africa (e.g., Southeast Asia)
    • Plasmodium ovale; and Plasmodium malariae: less common and cause milder disease ^[4]
    • Plasmodium knowlesi: found in Southeast Asia and can cause severe malaria; possibly zoonotic and often misidentified as other species due to morphological similarities. ^[6]
• Vector: the female Anopheles mosquito
• Host: humans
• Partial resistance against malaria ^[7]
  • Carriers of sickle‑cell mutation
  • Individuals with either certain Duffy antigens or no Duffy antigens are resistant to P. vivax and P. knowlesi ^[8]
  • Other hemoglobinopathies (e.g., thalassemia, HbC)
  • Infection with malaria subsequently leads to the development of specific Plasmodium antibodies that result in partial immunity for a limited amount of time (less than a year)

Life cycle of Plasmodium (simplified) ^[13]

Asexual development in humans

1. Transmission of Plasmodium sporozoites via Anopheles mosquito bite → sporozoites travel through the bloodstream to the liver of the host
2. Liver: sporozoites enter hepatocytes → sporozoites multiply asexually → schizonts are formed containing thousands of merozoites → release of merozoites into the bloodstream
3. Circulatory system (two possible outcomes)
   • Merozoites enter erythrocytes → maturation to trophozoites → red cell schizonts are formed containing thousands of merozoites → release of merozoites into the bloodstream (which causes fever and other manifestations of malaria) → penetration of erythrocytes recurs
   • Merozoites enter erythrocytes → differentiation into gametocytes (male or female)

Sexual development in female Anopheles mosquito

• A mosquito bites an infected human and ingests gametocytes → gametocytes mature within the mosquito intestines → sporozoites are formed and these migrate to the salivary glands → transmission of sporozoites to humans via mosquito bite
• See also “Developmental stages of Plasmodium in RBCs.”

Incubation period

• 7–30 days ^[14]

The incubation period of malaria is a minimum of seven days; if fever occurs before the seventh day following exposure in an endemic region, it is most likely not due to malaria.

Course

• Infection → asymptomatic parasitemia → uncomplicated illness → severe malaria → death
  • Asymptomatic parasitemia: Especially in endemic regions, cases of asymptomatic plasmodia carriers are reported. ^[15]
  • Infections with P. vivax, P. ovale, and P. malariae typically have milder symptoms; , involve fewer organs (CNS or gastrointestinal symptoms are rare), and have a markedly lower risk of causing severe malaria. ^[16]
  • Following the successful treatment of tertian malaria, dormant P. ovale or P. vivax forms (hypnozoites) may remain in the liver and can cause relapse after months or even years. ^[16]

General symptoms ^[1][14]

• Flu‑like symptoms, headache
• Diaphoresis
• High fever: Fever spikes occurring at regular intervals are no longer commonly observed. ; ^[9][10]
  • Tertian malaria: periodic fever spikes every 48 hrs
  • Quartan malaria: periodic fever spikes every 72 hrs
  • Malignant tertian malaria (associated with falciparum malaria): irregular fever spikes without a noticeable rhythm

Organ-specific symptoms ^[1][14]

• Blood
  • Thrombocytopenia: increased bleeding risk
  • Hemolytic anemia: weakness, paleness, dizziness
• Gastrointestinal
  • Nausea, vomiting
  • Diarrhea, abdominal pain
• Liver: : hepatosplenomegaly, discrete jaundice
• CNS: hallucinations, confusion, impaired consciousness, seizures, coma

Impaired consciousness, shock, and abnormal bleeding are signs of severe malaria that requires immediate IV treatment. ^[17]

Approach

• Focused clinical evaluation ^{[18][19][20][21]}
  • Time of travel to regions where malaria is endemic and previous chemoprophylaxis
  • Evaluate for signs of severe malaria.
• Routine laboratory studies: CBC, CMP, LFTs, and coagulation panel to evaluate for organ dysfunction ^[17]
• Parasitological testing: confirms the presence and determines the species of Plasmodia
  • Microscopic examination of thick and thin blood smears (gold standard) ^[19]
  • Antigen detection test (more rapid but less sensitive) ^[19]

Malaria can present in many different ways and is therefore often misdiagnosed. In patients with fever who have recently traveled to endemic regions, malaria must always be considered. ^[22]

Routine laboratory studies ^[21]

Used to assess the severity of malaria and identify concurrent diseases, see also “Criteria for severe malaria.”

• CBC: Changes in multiple parameters may occur. ^[23]
  • Hemolytic anemia: ↓ Hb, ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes
  • Thrombocytopenia
  • Leukocytosis or leukopenia are uncommon except in severe disease.
• CMP: Hypoglycemia and AKI can occur in severe malaria. ^[17]
• Urinalysis: Hemoglobinuria may occur with intravascular hemolysis. ^[16][17]
• Other (as clinically indicated): ABG , type and screen , blood and urine cultures CSF analysis ^[19][24]

Parasitological testing ^[16][19][25]

False-negative test results can occur with RDTs and blood smears, especially when malaria parasitemia is low. Repeat parasitological testing when clinical suspicion is high. ^[21][25][26]

Rapid diagnostic tests (RDTs)

• Detects specific malaria antigens (e.g., HRP2, pLDH, aldolase) ^[19][25]
• Allows for quick diagnosis if high‑quality microscopy is unavailable or delayed. ^[25]
• Confirm all RDT results via microscopy when available. ^[22][25]

RDTs can detect P. falciparum but typically cannot distinguish between other species of Plasmodium. ^[22]

Blood smear

Gold standard test: allows for visualization of parasites within RBCs via microscopy to confirm malaria diagnosis ^[22]

• Thick blood smear: high sensitivity; best initial test ^[10][19]
• Thin blood smear: lower sensitivity, high specificity; confirmatory test ^[27]
  • Allows identification of Plasmodium species ^[19]
  • Enables calculation of malaria parasitemia: the percentage of RBCs containing a Plasmodium organism; used to classify severity and monitor response to therapy. ^[16][17]
  • Findings include:
    • Schuffner granules (fine, brick-red dots) within RBCs infected with P. vivax and P. ovale ^[10]
    • Crescent-shaped gametocytes in individuals infected with P. falciparum
• Evaluation of a negative blood smear ^[16]
  • Patients may become symptomatic before parasites can be seen on the blood smear.
  • If an initial test result is negative, blood smears should be repeated every 12–24 hours for a total of 3 tests.
  • If all three sets are negative, malaria can be excluded as the diagnosis.

A single negative blood smear does not rule out malaria. Repeat three sets of blood smears (one set every 12–24 hours) before ruling out the diagnosis. ^[16][22]

Other studies

• PCR ^[25][28]
  • Identifies species of Plasmodium; useful for suspected P. knowlesi infection
  • High sensitivity but expensive and usually only available at reference laboratories
• Serological testing
  • Positive serological results indicate prior exposure to Plasmodium. ^[16]
  • Not recommended in acute malaria due to length of time for antibodies to reach detectable levels ^[25]

Uncomplicated malaria

• Definition: symptomatic, diagnostically proven malaria without features of severe malaria ^[21][22]
• Etiology: can be caused by all Plasmodium species
• Treatment: See “Treatment of uncomplicated malaria.”

Severe malaria ^[14][17][19]

• Description: potentially fatal manifestation or complication of malaria
• Etiology: most commonly a result of falciparum malaria
• Pathophysiology: Infected erythrocytes occlude capillaries, which can lead to severe organ dysfunction.
• Criteria for severe malaria: ≥ 1 of the following in a patient with proven malaria ^[16][19][21]
  • Clinical findings
    • General: prostration
    • CNS: hallucinations, confusion, impaired consciousness, seizures, coma
    • Cardiac: shock (e.g., hypotension, capillary refill time ≥ 3 seconds), heart failure
    • Pulmonary: respiratory distress, pulmonary edema, ARDS
    • Renal: flank pain, oliguria, hemoglobinuria, acute kidney injury
    • Gastrointestinal: jaundice
    • Hematopoietic: significant bleeding
  • Laboratory findings
    • Severe anemia: < 7 g/dL in adults, < 5 g/dL in children
    • Hypoglycemia: < 40 mg/dL
    • Acidosis (with or without lactemia): base deficit > 8 meq/L or bicarbonate < 15 meq/L
    • Hyperlactatemia: lactate > 5 meq/L
    • Acute kidney injury: creatinine > 3 mg/dL or urea > 20 mmol/L
    • Hyperbilirubinemia: bilirubin > 3 mg/dL
    • High malaria parasitemia ^[16][21]
• Treatment: See “Treatment of severe malaria.”

Approach ^{[16][19][21][22]}

• Consult infectious disease service early.
• Check for criteria for severe malaria.
• Treat severe malaria immediately with IV artesunate, following ABCDE approach.
• Treat uncomplicated malaria based on species, resistance patterns, and degree of chemoprophylaxis.
• Determine disposition
  • Severe malaria: ICU admission and supportive care
  • Uncomplicated malaria: Consider admission for observation and serial monitoring of parasite count.
• Report all confirmed malaria to public health authorities.

Treatment of severe malaria ^[16][19][21]

• Pharmacotherapy
  • Start IV artesunate immediately. ^[10][16][21]
  • Repeat malaria parasite density after 3^rd dose of artesunate.
    • > 1%: Continue IV artesunate
    • ≤ 1%: Switch to oral antimalarials under specialist guidance
      • Artemether-lumefantrine (preferred)
      • OR atovaquone-proguanil
      • OR quinidine (in the US; quinine elsewhere)
• Supportive care and monitoring
  • Manage fever with acetaminophen, tepid sponging, and/or cooling blankets.
  • Treat acute seizures, e.g., with IV or rectal diazepam
  • Avoid aggressive fluid replacement and rapid fluid boluses.
  • Rule out superadded bacterial infection: Perform fever workup, e.g., blood cultures. ^[21]
  • Prevent hypoglycemia: Check blood glucose every 4 hours. ^[21]
  • Monitor Hb every 6–12 hours and renal function daily. ^[9]
  • Measure malaria parasitemia on days 7 and 28 to monitor response to therapy. ^[25]
• Disposition: Admit to ICU.

The CDC recommends contacting their Malaria Hotline for all patients with severe malaria. ^[16]

Severe malaria is a medical emergency; without appropriate treatment, mortality is nearly 100%. ^[21]

Treatment of uncomplicated malaria ^[16][19][21]

• Agent selection based on: ^[16]
  • Infecting Plasmodium species
  • Prior use of chemoprophylaxis
  • Likelihood of chloroquine-resistance
  • See “Overview of treatment of uncomplicated malaria.”
• Additional considerations in P. vivax and P. ovale ^[16]
  • Check G6PD activity levels.
  • Give primaquine or tafenoquine to eradicate hypnozoites dormant in hepatocytes.
• Disposition: Consider admission for observation and serial monitoring of parasite concentration. ^[16][19]
  • P. falciparum or P. knowlesi infections: Patients are typically hospitalized.
  • P. vivax, P.ovale, P. malariae infections: Patients who tolerate PO medicine may receive outpatient treatment. ^[22]

Do not use medications that the patient has already used for chemoprophylaxis. ^[16]

Plasmodium falciparum and, more recently, Plasmodium vivax are becoming increasingly resistant to chloroquine.

Overview of antimalarial drugs

Mosquito bite prevention ^[41]

• Avoid exposure
  • Exercise particular caution during peak biting periods ^[42]
  • Mosquito nets
  • Protective clothing (covering most of the skin, light colors)
  • Mosquito repellent, such as DEET (N,N-diethyl-meta-toluamide)
• Mosquito control
  • Reduce breeding sites (e.g., eliminate pools of water, optimize plant watering)
  • Insecticide spraying

Malaria prophylaxis ^[43][44][45]

• Should be initiated before traveling to regions with a high risk of malaria, e.g., tropical Africa, Asia, and Central/South America
• Drug of choice is based on the region traveled and Plasmodium species
  • Areas with P. falciparum
    • If chloroquine-resistant P. falciparum (most malaria endemic regions): atovaquone-proguanil, doxycycline, mefloquine
    • If chloroquine-sensitive P. falciparum: chloroquine
  • Areas without P. falciparum; (some areas of Central/South America, Mexico, China, South Korea): primaquine
• Agents that are safe during pregnancy: chloroquine, mefloquine
• See “Tips & Links” for information from the 2020 CDC Yellow Book about malaria travel advisories and prophylaxis agents.

Prophylactic medication cannot prevent infection but instead suppresses the course of the disease and its symptoms by killing the parasite within the host before it can cause severe disease. There is no prophylactic medication that provides protection against all species of the Plasmodium genus.

Standby emergency treatment ^[45]

• Indication
  • Traveling to endemic regions with a medium to high risk of malaria
  • Depending on the risk, either prophylactic or standby emergency treatment may be recommended (when in doubt: prophylactic medication).
• Drugs
  • Atovaquone-proguanil
  • Artemether-lumefantrine
  • Chloroquine with limitations: there are now many chloroquine-resistant Plasmodium strains with membrane pumps that lower intracellular chloroquine concentrations

Public health surveillance

• Malaria is a reportable disease in the U.S. and is subject to active surveillance globally.
• Transmission and treatment resistance data informs travel advisories and chemoprophylaxis recommendations.

All patients

• Order thick and thin blood smear on all patients to confirm the diagnosis and determine malaria parasitemia.
• Consider rapid diagnostic tests initially if blood smear microscopy is delayed or unavailable.
• Order additional tests: CBC, CMP, coagulation panel, type and screen, urinalysis, and blood culture
• Identify criteria of severe malaria.
• Consult infectious disease service.

Severe malaria

• Admit to ICU.
• Begin IV artesunate.
• Check glucose every 4 hours.
• Check CBC every 6–12 hours.
• Check renal function every 24 hours.
• Treat fever with acetaminophen, tepid sponging, cooling blanket.
• Rule out bacterial coinfection.
• Avoid excessive fluid administration.
• Repeat malaria parasitemia every 12–24 hours.

Uncomplicated malaria

• Determine species of Plasmodium.
• Review patient travel history.
• Inquire about patient malaria chemoprophylaxis use.
• Begin appropriate antimalarial medication under specialist guidance.
• Admit the patient to hospital for observation.
• Obtain serial measurements of malaria parasitemia.

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