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Editors

HeliSiikamäki
NathalieFriberg
VilleHolmberg

Diagnosis and Treatment of Malaria

Essentials

  • Travel to endemic areas necessitates the use of malaria chemoprophylaxis and protection against mosquito bites.
  • For prevention and prophylactic medication, see Traveller's infection prophylaxis Traveller's Infection Prophylaxis.
  • Malaria must be excluded in all ill patients, particularly in those with fever, who present with a history of travel to malaria-endemic areas, even if appropriate malaria chemoprophylaxis has been used. Other possible aetiologies of fever must also be considered.
  • The risk of malaria is highest in tropical Africa.
  • Making the diagnosis of and starting treatment for malaria must be carried out as an emergency case.
  • Official guidelines must be followed in all cases of suspected malaria and an infectious disease physician should be contacted for advice. Local laboratory personnel will give advice as regards the samples and investigations required.
  • Malaria is a notifiable infectious disease, and the treating physician is required to report cases in accordance with official guidelines and local practices.

Causative agent

  • Malaria is caused by the Plasmodium protozoa, which infects red blood cells.
  • Five Plasmodium species are capable of causing malaria in humans: P. falciparum, P. vivax, P. ovale, P. malariae and the primate malaria parasite P. knowlesi.

Transmission

  • Malaria is transmitted between humans by an Anopheles mosquito bite.
  • Rare routes of transmission are contaminated needles, blood transfusions and from a mother to her foetus via the placenta.

Prevalence and significance

  • Globally, malaria is one of the most important infections. Over 200 million cases occur annually, and malaria causes over half a million deaths every year, mainly African children.
  • The majority of malaria cases and deaths occur in tropical Africa.
  • P. falciparum is the most common malaria parasite, and it causes the most severe clinical picture. It is responsible for about 90% of all cases worldwide.
  • The increasing drug resistance of the malaria parasite renders prophylaxis and treatment problematic.
  • For countries and areas at risk of malaria transmission, see the relevant maps in http://wwwnc.cdc.gov/travel/diseases/malaria.

Incubation period

  • P. falciparum malaria: at least one week, usually 2-4 weeks, very rarely several months
  • Other malaria types: at least 2-4 weeks, often several months
  • The latent liver forms of P. vivax and P. ovale (hypnozoites) may cause the emergence of symptoms several months, even a few years, after the initial infection, even if appropriate malaria chemoprophylaxis had been used.

Symptoms

  • Fever
    • Often with chills
    • Intermittent
      • P. vivax, P. ovale: every 2 days
      • P. malariae: every 3 days
      • P. knowlesi: daily
    • The fever in P. falciparum malaria lacks a regular pattern.
  • Headache, myalgia
  • Abdominal pain, diarrhoea, any other symptoms
  • Small children may, in addition to fever, present with non-specific general symptoms, such as anorexia, restlessness and irritability.
  • Fever may be totally absent in infants, and only general and CNS symptoms may emerge.
  • A person who originates from an endemic area may have residual partial immunity against malaria possibly resulting in disease with mild symptoms or no symptoms at all. The only clinical sign of malaria in a pregnant immigrant woman might be anaemia.
  • Acquired partial immunity usually disappears gradually after the person moves away from the malaria area and regular exposure ceases.

Complications

  • P. falciparum is capable of infecting red blood cells of all ages leading to parasitaemia exceeding 2% and complications.
  • P. knowlesi infection may lead to a high parasitaemia level and complications.
  • P. vivax and P. ovale infect only young red blood cells and P. malariae only the old ones, and they do not usually lead to parasitaemia exceeding 2% and to complications; P. vivax infection may, however, occasionally be associated with complications.
  • Even one of the following symptoms or signs is enough to suggest serious or complicated malaria in adults:
    • neurological symptoms, somnolence, seizures (cerebral malaria)
    • respiratory difficulties, pulmonary oedema, ARDS
    • oliguria, renal insufficiency
    • shock (systolic BP < 80 mmHg)
    • DIC, haemorrhagic diathesis, jaundice
    • severe anaemia (Hb < 70 g/l)
    • hypoglycaemia, acidosis, high plasma lactate concentration, severe haemolysis.

Laboratory findings

  • Malaria is often associated with leucocytopenia and thrombocytopenia and later anaemia.
  • Haemolysis
  • CRP is often moderately elevated (40-100 mg/l).
  • Plasma ALT and creatinine concentrations are often elevated.

Diagnosis

  • Must be considered an emergency!
  • The diagnosis of malaria can in principle be carried out in any emergency hospital with a laboratory that offers on-call services. National guidelines apply as to the procedures of when and how to contact the local malaria reference laboratory.
  • One negative sample does not exclude malaria. Sampling should be repeated after 3-4 hours and during a fever spike.
  • The aim is to obtain at least 3 to 4 samples within 48 to 72 hours.
  • Should preferably be taken during a fever spike for the identification of malaria parasites.
    • 3-4 thin smear preparations. The usual May-Grünwald-Giemsa stain can be used, but plain Giemsa solution is better.
    • 3-4 thick smear preparations. Apply 2-3 drops of blood on a slide, spread it out to a 2 × 2 cm patch by rubbing with a glass rod for about 30 seconds, allow to dry thoroughly, do not fix.
  • At least one smear preparation must be examined immediately in the laboratory that took the sample, so that the physician on call has the preliminary result at hand as soon as possible.
  • The preparations are sent non-fixed and non-stained to a specialized parasitological laboratory according to the local guidelines for confirmation, species identification and definition of parasitaemia level.
  • The referral form should include the patient's travel history, information on chemoprophylaxis, possible earlier malaria treatment and the address and phone number of the referring unit.
  • Rapid diagnostic tests based on antigen detection can be used in emergency settings, but they are not recommended without at least a short microscopic examination of an accompanying smear sample. Thick and thin blood smear tests must be taken in any case and examined as soon as possible during office hours.
  • A nucleic acid detection test from EDTA-blood is used in some laboratories for emergency diagnostics. The nucleic acid test cannot determine the species or the level of parasitaemia. Even in these cases, a thick and thin blood smear tests must always be taken.
  • More detailed instructions regarding the diagnosis of malaria are available from local sources or from the WHO http://www.who.int/teams/global-malaria-programme/case-management/diagnosis.
  • Check local policies and practices concerning specialist advice and sending of duplicate samples of confirmed cases to a reference laboratory.

Treatment High First Dose Quinine Regimen for Treating Severe Malaria, Artesunate Plus Mefloquine Versus Mefloquine for Treating Uncomplicated Malaria, Routine Anticonvulsants for Treating Cerebral Malaria, Artemisinin-Based Combination Therapy for Treating Uncomplicated Malaria, Intramuscular Arteether for Treating Severe Malaria, Steroids for Treating Cerebral Malaria, Artemether for Severe Malaria, Pyronaridine-Artesunate for Treating Uncomplicated Plasmodium Falciparum Malaria

  • Antimalarial drug treatment must be started without delay.
  • Where feasible, a patient with malaria should be treated in hospital.
  • The management of serious or complicated malaria should be carried out in a high dependency or intensive care unit.
  • The on-call infectious disease physician should always be consulted.
  • More detailed instructions regarding the treatment of malaria are available from local sources or from the WHO http://www.who.int/teams/global-malaria-programme/case-management/treatment.

P. falciparum and P. knowlesi malaria

  1. An unwell patient or complicated malaria or parasitaemia > 2% (> 5% in a semi-immune patient, i.e. a patient who originates from an endemic area) or the patient is vomiting:
    • The first-line treatment is intravenous artesunate Artesunate Versus Quinine for Treating Severe Malaria (may require a special permit) 2.4 mg/kg. For children weighing less than 20 kg, the dose is 3 mg/kg. The dose is repeated after 12 hours and 24 hours, followed by a dose once daily until the patient can be switched over to oral treatment (a combination product of artemether and lumefantrine) of which a complete course should be given. The medication should be switched over to peroral administration as soon as possible after the third dose, since treatment with artesunate is associated with a risk of serious haemolysis developing at a later stage.
      • If the patient comes from the Thai-Cambodia or Thai-Myanmar borders, artesunate should be combined with intravenous doxycycline or, in the case of a pregnant woman, with clindamycin 5 mg/kg every 8 hours, starting dose 10 mg/kg.
  2. A patient who is not unwell, has no complications and parasitaemia < 2% (< 5% in a semi-immune patient, i.e. a patient who originates from an endemic area) and is able to take medicines by mouth:

P. vivax-, ovale- or malariae malaria Primaquine at Alternative Dosing Schedules for Preventing Relapse in People with Plasmodium Vivax Malaria., Tafenoquine for Preventing Relapse in People with Plasmodium Vivax Malaria

  • The antimalarial treatment used in P. falciparum malaria is also effective.
  • The specific treatment consists of oral chloroquine (may require special permit), total dose 40 mg chloroquine phosphate/kg. Adults: initially a single dose of four 250 mg tablets, followed by 2 tablets 6-8 hours later and then 2 tablets once daily during the next 2 days. The total dose for children is divided up in a similar manner.
  • In order to attain a radical cure in P. vivax and P. ovale malaria, chloroquine treatment must be followed by a course of primaquine (may require special permit). In P. vivax infection, the adult dose of primaquine base is 30 mg once daily and for children 0.5 mg/kg/day for 14 days. In P. ovale infection, the adult dose is 15 mg once daily and for children 0.25 mg/kg/day for 14 days.
  • Primaquine may cause severe haemolysis in patients with G6PD deficiency. Deficiency is encountered in Mediterranean countries, the Middle East, Asia and Africa. G6PD deficiency is rare in Caucasians. The erythrocyte G6PD activity must be determined from patients in risk groups before primaquine is administered.

Antimalarial drugs during pregnancy and for children Drugs for Malaria in Pregnant Women

  • Artemisin derivatives have not been reported to cause adverse effects when used during pregnancy. According to the WHO, intravenous artesunate and oral artemether-lumefantrine combination are safe during any trimester of pregnancy and for children.
  • Clindamycin and chloroquine are safe during pregnancy and for children.
  • Doxycycline should be used during pregnancy for compelling reasons only; it is contraindicated in children aged under 8 years.
  • The combination of atovaquone and proguanil should be used during pregnancy for compelling reasons only; it is contraindicated in children weighing less than 5 kg.
  • Mefloquine can be used during pregnancy; it is contraindicated in children weighing less than 5 kg.
  • Primaquine is contraindicated during pregnancy and breastfeeding. It may be used in children.

Prognosis

  • The mortality rate of untreated malaria is 20%. The mortality rate of treated malaria in the industrialised countries is approximately 1%.

    References

    • WHO Guidelines for malaria, 14 March 2023. Geneva: World Health Organization; 2023. http://www.mmv.org/malaria-guidelines?gclid=EAIaIQobChMI8v7by__d_gIVlaWyCh2r-AU1EAAYASAAEgKqWfD_BwE
    • Saito M, McGready R, Tinto H ym. Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis. Lancet 2023;401(10371):118-130. [PubMed]
    • Neumayr A. Antiparasitic Treatment Recommendations. A practical guide to clinical parasitology. 2nd edition. Swiss Tropical and Public Health Institute, December 2018.
    • Lalloo DG, Shingadia D, Bell DJ ym. UK malaria treatment guidelines 2016. J Infect 2016;72(6):635-649. [PubMed] http://doi.org/10.1016/j.jinf.2016.02.001
    • Askling HH, Bruneel F, Burchard G et al. Management of imported malaria in Europe. Malar J 2012;(11):328. [PubMed]