DESCRIPTION

• Malaria is a febrile illness caused by the Plasmodium species of protozoan parasites, transmitted by the Anopheles mosquito vector.
• Five Plasmodium strains infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. P. falciparum and P. vivax cause the majority of disease.
• Classic symptoms include stages of chills, followed by high fevers, and then sweating. However, this classic symptom pattern is less likely to be seen in children. Children may manifest initially with only fever.

EPIDEMIOLOGY

• High-risk areas of endemic malaria include Africa, parts of Central and South America, Oceania, and tropical regions of Asia.
• P. falciparum is the major species in sub-Saharan Africa. Both P. falciparum and P. vivax are found in India, Southeast Asia, Oceania, and Central and South America, and P. vivax is present in some areas of Africa. P. ovale is usually found in West Africa. P. malariae is present at low prevalence in Africa, South America, Southeast Asia and Oceania.
• P. falciparum causes more deaths in children <5 years of age than any other organism.
• The World Health Organization (WHO) reports that 96% of malaria deaths occur in the African region and 80% these deaths occur in children <5 years of age. Pregnant women are also at high risk.
• Mortality has decreased from 30.1 per 100,000 population at risk in 2000 to 13.8 in 2019 before rising to 15.3 in 2020 in association with the SARS-CoV-2 pandemic.

ETIOLOGY

• Infection is typically transmitted by the bite of the female Anopheles mosquito, but it can also be transmitted through contaminated blood transfusions or acquired congenitally.
• The majority of human disease is caused by P. falciparum and P. vivax.
  • P. vivax and P. ovale can cause relapsing disease because of the persistent hepatic (hypnozoite) stage of the infection.
  • Asymptomatic carriage for years may occur with P. malariae.
  • P. knowlesi is a primate parasite that can cause severe disease in humans. To date, it has occurred in humans only in Southeast Asia.

RISK FACTORS

GENERAL PREVENTION

• Personal protective measures against mosquito bites are extremely important.
  • Remain in well-screened areas.
  • Wear protective clothing, including pants and long-sleeved shirts.
  • Use insect repellents containing N,N-diethyl-meta-toluamide (DEET).
  • Use insecticide-treated bed nets.
• Chemoprophylaxis is strongly advised for travelers to endemic areas.
• In areas with chloroquine-sensitive parasites only, chloroquine may be used (5 mg/kg base [8.3 mg/kg salt] PO once a week—max 300 mg base/500 mg salt).
• In chloroquine-resistant areas, effective options are atovaquone-proguanil (Malarone^®), mefloquine, doxycycline, or tafenoquine. In areas with >90% P. vivax, primaquine is an alternative option.
  • Atovaquone-proguanil (Malarone^®) can be used in all areas but is contraindicated in severe renal impairment (creatinine clearance [Cr Cl] <30 mL/min), pregnancy, infants <5 kg body weight, or mothers breastfeeding infants <5 kg. Dosing (PO): 5 to 8 kg: 1/2 pediatric tab once daily; >8 to 10 kg: 3/4 pediatric tab once daily; >10 to 20 kg: 1 pediatric tab (62.5 mg atovaquone/25 mg proguanil) once daily; >20 to 30 kg: 2 pediatric tabs once daily; >30 to 40 kg: 3 pediatric tabs once daily; >40 kg: 1 adult tab (250 mg atovaquone/100 mg proguanil) once daily
  • Mefloquine resistance is present in parts of Asia. Contraindications to mefloquine include seizure disorder, major psychiatric illness, or cardiac disease. It is safe in pregnancy and for young infants; dosing (PO): ≤9 kg: 5 mg/kg weekly; >9 to 19 kg: 1/4 tablet (62.5 mg) once weekly; >19 to 30 kg: 1/2 tab (125 mg) once weekly; >30 to 45 kg: 3/4 tab (187.5 mg) once weekly; >45 kg: 1 tab (250 mg) once weekly
  • Doxycycline is contraindicated if <8 years of age and in pregnancy; dosing: 2.2 mg/kg PO once daily (max 100 mg/24 h)
  • Tafenoquine is approved for children aged ≥16 years at adult dosing of 200 mg/dose PO once daily for 3 days followed by 200 mg once weekly starting 7 days after the last dose of the initial 3-day course. IIt is contraindicated in patients with G6PD deficiency and in patients who are pregnant or breastfeeding and is not recommended in patients with psychotic disorders.
  • Primaquine is dosed at 0.5 mg/kg base PO once daily (max 30 mg base/24 h). It is contraindicated in G6PD deficiency, pregnancy, breastfeeding (unless infant has been tested for G6PD deficiency and is >6 months old), and infants <6 months of age.
• Chloroquine and mefloquine are started 1 and 2 weeks respectively before travel, continued during the period of exposure and for 4 weeks after leaving the endemic region. Atovaquone-proguanil (Malarone^®) and primaquine are started 2 days prior to travel and continued 1 week after return. Doxycycline is started 2 days before travel and continued for 4 weeks after return. Tafenoquine is taken daily for 3 days prior to travel, weekly during travel, and for 1 week after leaving.
• The RTS,S/AS01 malaria vaccine is the first and presently only vaccine to be recommended by the World Health Organization (WHO for routine immunization in sub-Saharan Africa and other areas of high transmission for children ≥5 months of age. Vaccine efficacy is improved when combined with seasonal malaria chemoprevention.

COMMONLY ASSOCIATED CONDITIONS

• Severe malaria is most commonly caused by P. falciparum; however, severe cases caused by P. vivax, and, rarely, P. ovale and P. knowlesi, have been reported.
• Severe malaria is defined as parasitemia >5%, shock, acidosis, severe anemia, or signs of CNS or other end-organ involvement such as renal injury or failure, pulmonary edema, respiratory distress (acidotic/irregular breathing), impaired consciousness, seizures, prostration, hemoglobinuria, jaundice (with elevated parasite count), significant bleeding, disseminated intravascular coagulation, or hypoglycemia. Parasite density threshold is limited to P. falciparum.
• Cerebral malaria is a serious consequence of malaria infection, defined as coma in conjunction with P. falciparum parasitemia; occurs most often in children aged 1 to 6 years in Africa but often occurs in adolescents and adults in Southeast Asia
• Severe anemia is common and can be severe, especially with P. falciparum. This is due to high parasitemia, hemolysis, sequestration, and bone marrow suppression.
• Respiratory distress has high mortality, particularly if combined with impaired consciousness.
• Blackwater fever is a complication associated with falciparum malaria. It occurs due to massive hemolysis with resulting hemoglobinuria and acute renal failure.
• Pulmonary edema, renal failure, distributive shock, and progression to coma or death can occur.
• Acute kidney injury (AKI) is common in children with severe malaria and is associated with increased mortality proportional to AKI stage and with long-term neurocognitive impairment.
• Hyperreactive malarial splenomegaly is seen with chronic exposure to malaria in endemic areas, most commonly Indonesia and Papua New Guinea. High levels of malaria immunoglobulin M (IgM) are present, and massive hepatosplenomegaly is seen. Blood smear is usually negative for parasites, but PCR may be positive.
• Splenic rupture may occur due to splenomegaly.
• P. malariae can cause nephrotic syndrome.