Key Points
Disease summary:
Malaria is a major parasitic infection in humans with significant global health impact. The pathogen Plasmodium completes its sexual maturation in mosquitoes, which in turn transmit sporozoites to humans while feeding on their blood. In humans, the liver incubates sporozoites allowing for their asexual reproduction before their release into the blood stream where they continue their reproduction in red blood cells (RBCs), altering their properties, and causing the various symptoms of malaria.
Differential diagnosis:
Consider viral infections such as HIV seroconversion, dengue fever, hepatitis A, B, and E, influenza and viral hemorrhagic fevers. Bacterial infections with a similar presentation include typhoid, pneumonias, and leptospirosis.
Monogenic forms:
Genetic host and pathogen factors are known to influence the disease risk. The best known host genetic factor is sickle cell hemoglobinopathy where carriers of this disease have an approximately 10-fold increase in protection against severe and complicated malaria.
Genome-wide associations:
A number of genetic variants in the pathogen genome have been identified, some of which may serve as candidates for the development of more effective antimalarial therapies and vaccines.
Pharmacogenomics:
Some antimalarial drugs can cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency so measurement of G6PD activity is indicated.
Diagnostic Criteria and Clinical Characteristics
Malaria should be suspected in anyone who has previously visited a malaria-endemic area, including those that took prophylaxis. Human malaria can be caused by five species of Plasmodium (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and the simian parasite Plasmodium knowlesi) out of which infections by P falciparum and P vivax are most common. Human infection with P knowlesi is thought to be a zoonosis and has only been reported in Southeast Asia.
Incubation period can be as short as 6 days for naturally acquired infection. Most patients who have a P falciparum infection will present within 6 months of exposure. P vivax and P ovale may enter a hypnozoite stage in the liver with infections usually presenting more than 6 months, and occasionally years, after exposure. There is a risk of relapse if only the blood phase of the disease is treated and the hypnozoites are not cleared.
Symptoms are nonspecific and there are no pathognomonic features. Most patients complain of fever or sweats or rigors, myalgia, headache, and general malaise. Malaria may be misdiagnosed as influenza or another respiratory viral infection, or as gastroenteritis due to gastrointestinal symptoms and jaundice. The fever typically does not follow the classically described quotidian, tertian, or quartan patterns.
Signs are also nonspecific and reminiscent of many other conditions. A fever is not invariably present and hepatomegaly is uncommon in acute malaria. Children are more likely to have hepatosplenomegaly than adults.
Severe or complicated falciparum malaria may present with
Metabolic acidosis (pH <7.35)
Hypoglycemia (blood glucose <2.2 mmol/L)
Shock
Anemia (Hb <8 g/dL)
Disseminated intravascular coagulopathy
Pulmonary edema leading to acute respiratory distress syndrome
Renal impairment or failure
Impaired consciousness and/or seizures
Jaundice
A detailed exposure history is essential. Obtain details of countries visited and regions within each country, including stopovers. Ask about accommodation, use of bed nets, mosquito repellent chemicals, and chemoprophylaxis. Ask about prophylactic drug combination, duration, side effects, adherence, and premature cessation.
Consider viral infections such as HIV seroconversion, dengue fever, hepatitis A, B, and E, influenza, and viral hemorrhagic fevers. Bacterial infections with a similar presentation include typhoid, pneumonias, and leptospirosis.
Timing of investigations is important. In suspected malaria cases blood should be taken for testing immediately. All tests should be communicated back to the clinician as positive or negative for malaria within 1 to 2 hours. Speciation should then be available within 12 hours, if not possible at the time of initial diagnosis. Ensure to stop chemoprophylaxis upon admission to hospital as this may interfere with parasite detection in the blood.
Thick and thin blood films are sensitive and specific for all Plasmodium species in the hands of an experienced light microscopist. A thin smear should be examined under oil emersion for 15 to 20 minutes and a thick smear for 5 to 10 minutes before being declared negative. If there is clinical suspicion of malaria but initial films are negative, then repeat films should be carried out after 12 to 24 hours and again after a further 24 hours. In pregnancy thick films can still be negative in severe infections due to the sequestration of parasites in the placenta.
Percentage of infected RBCs should be estimated if falciparum malaria is diagnosed as this has implications for the choice of treatment to be used.
Rapid diagnostic tests (RDTs) are not as sensitive or specific for the detection of nonfalciparum infections. However, due to the lack of expertise in many Western laboratories they are particularly useful for suspected cases of malaria presenting out of hours. These tests require small volumes of blood (2-50 μL) and therefore can be done on finger-prick samples. Targets vary but include histidine-rich protein-2 of P falciparum (PfHRP-2), parasite-specific (P falciparum, P vivax, or both) lactate dehydrogenase, or the pan-malarial Plasmodium aldolase. However, there are currently no specific tests available for P malariae, P ovale, or P knowlesi. They require higher parasite densities than a good light microscopist for detection and cannot be used for assessing response to therapy. Autoantibodies such as rheumatoid factor or heterophile antibodies may lead to false-positive results and false-negative results have been reported in high-grade parasitemias due to the prozone phenomenon.
Polymerase chain reaction is emerging but still of limited availability. It should be considered as the new gold standard as it is highly sensitive and specific and allows for speciation.
Additional blood tests
Routine
Full blood count (anemia and thrombocytopenia)
Urea and electrolytes (renal failure and metabolic disturbance)
Liver function tests (hepatitis)
Blood glucose (hypoglycemia due to disease, or baseline before treatment)
Sick patients
Blood gases (metabolic acidosis)
Blood culture (superinfections)
Lactate (hyperlactatemia)
Clotting studies (disseminated intravascular coagulopathy)
Consider for differential diagnosis
Chest x-ray
Computed tomography (CT) head and lumbar puncture
Other infection screening samples, for example, urine, stool
Notification of cases: Your health authority is likely to require you to refer all cases of malaria to a central public health notification unit.
Management and Treatment
Malaria caused by P ovale, P vivax, or P malariae are rarely life threatening but severe or complicated cases (as defined in Signs and Symptoms) should be treated the same as falciparum malaria. P knowlesi can be confused by microscopists as P malariae but usually has high parasitemias (>1%) and should be treated as falciparum malaria.
Can usually be managed on an outpatient basis.
G6PD activity will need to be measured before discharge.
