Malaria

Essentials of Diagnosis

• Exposure to anopheline mosquitoes in a malaria-endemic area

• Intermittent attacks of chills, fever, and sweating

• Headache, myalgia, vomiting, splenomegaly; anemia, thrombocytopenia

• Intraerythrocytic parasites identified in thick or thin blood smears or positive rapid diagnostic tests

• Complications of falciparum malaria, including

  • Cerebral malaria

  • Severe anemia

  • Hypotension

  • Noncardiogenic pulmonary edema

  • Acute kidney injury

  • Hypoglycemia

  • Acidosis

  • Hemolysis

General Considerations

• Five species of the genus Plasmodium are responsible for human malaria

  • P vivax

  • P malariae

  • P ovale

  • P falciparum

  • P knowlesi

• Mode of transmission

  • Bite of infected female anopheline mosquitoes

  • Can be transmitted congenitally and by blood transfusion (uncommon)

• P falciparum is responsible for nearly all severe disease because it

  • Uniquely infects erythrocytes of all ages

  • Mediates the sequestration of infected erythrocytes in small blood vessels, thereby evading clearance by the spleen

• P vivax seldom causes severe disease

• P ovale and P malariae generally do not cause severe illness

• For all plasmodial species, parasites may recrudesce following initial clinical improvement after suboptimal therapy

• Disease and response to therapy are dramatically affected by immune status

• P knowlesi, a parasite of macaque monkeys, causes illnesses in humans, including some severe disease, in Southeast Asia

Demographics

• Causes hundreds of millions of cases and hundreds of thousands of deaths each year

• Disease is endemic in most of the tropics, including

  • Central and South America

  • Africa

  • The Middle East

  • The Indian subcontinent

  • Southeast Asia

  • Oceania

• Transmission, morbidity, and mortality are greatest in Africa

• Disease also common in travelers from nonendemic areas

• Groups at particular risk for severe malaria

  • Children

  • Pregnant women

  • HIV-infected persons

  • Nonimmune travelers

Symptoms and Signs

ACUTE MALARIA

• Typically begins with a prodrome of headache and fatigue, followed by fever (usually irregular)

• Without therapy, however, fevers may become regular, especially with non-falciparum disease

  • 48-hour cycles (for P vivax and P ovale)

  • 72-hour cycles (for P malariae)

• Headache, malaise

• Myalgias, arthralgias

• Cough

• Chest pain, abdominal pain

• Anorexia, nausea, vomiting, and diarrhea

• Seizures may represent simple febrile convulsions or evidence of severe neurologic disease

• Physical findings may be absent or include signs of

  • Anemia

  • Jaundice

  • Splenomegaly

  • Mild hepatomegaly

SEVERE MALARIA

• Characterized by signs of severe illness, organ dysfunction, or a high parasite load (peripheral parasitemia > 5% or > 200,000 parasites/mcL)

• Principally a result of P falciparum infection

• Can include dysfunction of any system, including

  • Neurologic abnormalities progressing to alterations in consciousness, repeated seizures, and coma (cerebral malaria)

  • Severe anemia

  • Hypotension and shock

  • Noncardiogenic pulmonary edema and the acute respiratory distress syndrome

  • Acute kidney injury (due to acute tubular necrosis or, less commonly, severe hemolysis)

  • Hypoglycemia

  • Acidosis

  • Hemolysis with jaundice

  • Hepatic dysfunction

  • Retinal hemorrhages and other fundoscopic abnormalities

  • Bleeding abnormalities, including disseminated intravascular coagulation

  • Secondary bacterial infections, including pneumonia and Salmonella bacteremia

CHRONIC MALARIA

• Massive splenomegaly

• Immune complex glomerulopathy with nephrotic syndrome (with P malariae infection)

• Although both these disorders are uncommon, they result from immunologic responses to chronic infection

Differential Diagnosis

• Influenza

• Typhoid fever

• Viral hepatitis

• Dengue

• Visceral leishmaniasis (kala azar)

• Amebic liver abscess

• Babesiosis

• Leptospirosis

• Relapsing fever

Laboratory Tests

• Giemsa-stained blood smears

  • Mainstay of diagnosis, although other routine stains (eg, Wright stain) also demonstrate parasites

  • Thick smears provide efficient evaluation of large volumes of blood, but thin smears are simpler and better for discrimination of parasite species

  • Single smears are usually positive in infected individuals, although parasitemias may be very low in nonimmune individuals

  • If illness is suspected, repeating smears in 8- to 24-hour intervals is appropriate

• Rapid diagnostic tests

  • Can identify circulating plasmodial antigens with a simple "dipstick" format

  • Not well standardized but are widely available around the world

  • Offer sensitivity and specificity near that of high-quality blood smear analysis and are simpler to perform

• Serologic tests indicate history of disease but are not useful for diagnosis of acute infection

• Polymerase chain reaction (PCR) and related molecular tests (eg, loop-mediated isothermal amplification) are highly sensitive but not available for routine diagnosis

• Liver biochemical tests

• Complete blood count reveals thrombocytopenia, anemia, leukocytosis or leukopenia

• Table 35–2 lists major antimalarial drugs

• See Table 35–3 for treatment recommendations established by the World Health Organization

• Table 35–4 outlines treatment options

• Therapeutic decisions made based on infecting species and geography

• First-line drug for non-falciparum malaria is chloroquine

• For P vivax or P ovale, chloroquine accompanied by primaquine or tafenoquine are used to eradicate erythrocytic parasites (after evaluating for glucose-6-phosphate dehydrogenase [G6PD] deficiency)

• Artemisinin-based combinations are first-line therapy for uncomplicated falciparum malaria

• Intravenous artesunate

  • Standard of care for severe malaria

  • Has demonstrated superior efficacy and better tolerability than quinine

  • Dosage: four doses of 2.4 mg/kg over 3 days, every 12 hours on day 1, and then daily

• If artesunate cannot be obtained promptly, severe malaria should be treated with intravenous quinine (available in most countries, but not the United States) or intravenous quinidine (no longer available in the United States) or an oral agent until intravenous artesunate is available

  • Patients receiving intravenous quinine or quinidine should receive continuous cardiac monitoring

  • If QTc prolongation exceeds 25% of baseline, the infusion rate should be reduced

  • Blood glucose should be monitored every 4–6 hours, and 5–10% dextrose may be coadministered to decrease the likelihood of hypoglycemia

• In endemic regions, if parenteral therapy is not available, intrarectal administration of artemether or artesunate is also effective

• For severe malaria

  • Maintain fluids and electrolytes

  • Provide respiratory and hemodynamic support

  • Consider blood transfusions, anticonvulsants, antibiotics for bacterial infections, and hemofiltration or hemodialysis

  • Exchange transfusion is sometimes used for those with high parasitemia (>5–10%), but beneficial effects have not clearly been demonstrated

Prognosis

• When treated appropriately, uncomplicated malaria responds well, with a mortality rate of about 0.1%

• Severe malaria can commonly progress to death

• In the developed world, mortality from malaria is mostly in adults, and often follows extended illnesses and secondary complications long after eradication of the malarial infection

• Pregnant women are at particular risk during their first pregnancy, probably due to the selection of P falciparum strains that preferentially sequester in the placenta

• Malaria in pregnancy also increases the likelihood of poor pregnancy outcomes, with increased prematurity, low birth weight, and mortality

• In a large trial of African children, acidosis, impaired consciousness, convulsions, renal impairment, and underlying chronic illness were associated with poor outcome

Prevention

• Avoid mosquito bites (bed nets treated with permethrin insecticides, insect repellents)

• Chemoprophylaxis

  • Recommended for all travelers from nonendemic regions to endemic areas, although risks vary greatly for different locations, and some tropical areas entail no risk

  • See Table 35–5

  • Specific recommendations for travel to different locales are available from the CDC

• Amodiaquine and sulfadoxine-pyrimethamine are administered to children monthly during the transmission season in areas with seasonal malaria transmission and limited drug resistance, principally parts of West Africa

• RTS,S vaccine, which is based on a sporozoite antigen, is the most advanced vaccine candidate

When to Refer

• All patients should be referred to a provider with expertise in this area

When to Admit

• Admission for non-falciparum malaria is only warranted if a patient presents with specific problems that require hospital management

• Patients with falciparum malaria are generally admitted because the disease can progress rapidly to severe illness