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.
In non-endemic areas the diagnosis of malaria is a medical emergency and treatment must be initiated urgently.
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 prevalence of malaria has significantly decreased in recent years.
The increasing drug resistance of the malaria parasite renders prophylaxis and treatment problematic.
P. falciparum malaria: at least one week, usually 2-4 weeks, vary 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:
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 for expert advice. Reference laboratories also carry out surveillance of all malaria cases reported and may request, for example, duplicate samples of confirmed cases.
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 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 capillary 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-anticoagulated 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.
Antimalarial drug treatment should 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 WHO http://www.who.int/ith/en/index.html.
P. falciparum and P. knowlesi malaria
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 artesunateArtesunate Versus Quinine for Treating Severe Malaria (available on a named patient basis only) 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 must 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 must be combined with intravenous doxycycline.
If artesunate is not available, intravenous quinine hydrochloride (available on a named patient basis only) is used. The loading dose is 15-20 mg/kg in 500 ml of 5% glucose as an infusion over 4 hours, followed by 10 mg/kg as an infusion over 4 hours every 8 hours (the maximum single dose of 1 500 mg must not be exceeded). Quinine is combined with doxycycline at the dose of 3 mg/kg/day divided into 2 doses, either orally or intravenously. In children aged under 8 years and pregnant women quinine is combined with intravenous clindamycin at the dose of 5 mg/kg every 8 hours after a loading dose of 10 mg/kg.
Quinine may cause hypotension, hypoglycaemia, conduction disturbances and arrhythmias.
Oral dosing should start as soon as possible.
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:
Weight over 35 kg: 4 tablets (25-35 kg: 3 tablets; 15-24 kg: 2 tablets; 5-14 kg: 1 tablet); the same dose is repeated after 8 hours and after that at 12-hour intervals in altogether 6 doses (three 24-hour periods).
May also be used during the first trimester of pregnancy, if quinine is not available.
The first-line treatment during the first trimester of pregnancy is oral quinine 10 mg/kg three times daily for 7 days (250 mg tablets, available on a named patient basis only). A sufficient dose for adults is usually 500-750 mg three times daily. Quinine is combined with clindamycin 450 mg three times daily.
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: a single dose of four 250 mg tablets, followed by 2 tablets 6-8 hours later and then 2 tablets once daily for 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.
Artemisin derivatives have not been reported to cause adverse effects when used during pregnancy.
In severe or complicated malaria, artesunate is used intravenously during pregnancy. It is safe for children.
During the first trimester of pregnancy, oral artemether-lumefantrine combination should still only be used, according to the WHO, when there are compelling reasons. It is safe for children.
Doxycycline should be used during pregnancy for compelling reasons only; it is contraindicated in children aged under 8 years.
Mefloquine can be used during pregnancy; it is contraindicated in children weighing less than 5 kg.
Primaquine is contraindicated during pregnancy and breastfeeding. 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
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Askling HH, Bruneel F, Burchard G et al. Management of imported malaria in Europe. Malar J 2012;11:328. [PubMed]
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Dondorp AM, Fanello CI, Hendriksen IC et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010;376(9753):1647-57. [PubMed]
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