Malaria is an important cause of death and illness in children and adults, especially in tropical countries. Malaria is caused by infection of red blood cells with protozoan parasites of the genus Plasmodium. The parasites are inoculated into the human host by a feeding female anopheline mosquito. The four Plasmodium species that infect humans are P. falciparum, P. vivax, P. ovale and P. malariae. Increasingly, human infections with the monkey malaria parasite, P. knowlesi, have also been reported from the forested regions of South-East Asia.
LIFE CYCLE OF PLASMODIUM
The first symptoms of malaria are nonspecific and similar to the symptoms of a minor systemic viral illness. They comprise: headache, lassitude, fatigue, abdominal discomfort, and muscle and joint aches, usually followed by fever, chills, perspiration, anorexia, vomiting and worsening malaise. At this early stage, with no evidence of vital organ dysfunction, the patients can readily be treated with full rapid recovery provided prompt and effective treatment is given. If, however, ineffective medicines are given or if treatment is delayed, particularly in P. falciparum malaria, the parasite burden continues to increase and severe malaria may ensue.
Severe malaria usually manifests with one or more of the following: coma (cerebral malaria), metabolic acidosis, severe anaemia, hypoglycaemia, acute renal failure or acute pulmonary oedema. By this stage of the disease, the case fatality in people receiving treatment is typically 10–20%. However, if left untreated, severe malaria is fatal in the majority of cases.
DIAGNOSIS OF MALARIA
Prompt and accurate diagnosis of malaria is part of effective disease management. The diagnosis of malaria is based on clinical suspicion and on the detection of parasites in the blood (parasitological or confirmatory diagnosis).
Malaria is clinically suspected mostly on the basis of fever or a history of fever. The WHO recommendations for clinical diagnosis/suspicion of uncomplicated malaria in different epidemiological settings are as follows:
- in settings where the risk of malaria is low, clinical diagnosis of uncomplicated malaria should be based on the possibility of exposure to malaria and a history of fever in the previous three days with no features of other severe diseases.
- in settings where the risk of malaria is high, clinical diagnosis should be based on a history of fever in the previous 24 h and/or the presence of anaemia, for which pallor of the palms appears to be the most reliable sign in young children.
In all settings, clinical suspicion of malaria should be confirmed with a parasitological diagnosis. However, in settings where parasitological diagnosis is not possible, the decision to provide antimalarial treatment must be based on the prior probability of the illness being malaria. The two methods in routine use for parasitological diagnosis are light microscopy and rapid diagnostic tests (RDTs). The latter detect parasite-specific antigens or enzymes and some have a certain ability to differentiate species.
TREATMENT OF UNCOMPLICATED P. falciparum MALARIA
To counter the threat of resistance of P. falciparum to monotherapies, and to improve treatment outcome, WHO recommends that artemisinin-based combination therapies be used for the treatment of uncomplicated P. falciparum malaria. Uncomplicated malaria is defined as symptomatic malaria without signs of severity or evidence (clinical or laboratory) of vital organ dysfunction.
Artemisinin-based combination therapy (ACT)
These are combinations in which one of the components is artemisinin and its derivatives (artesunate, artemether, dihydroartemisinin). The artemisinins produce rapid clearance of parasitaemia and rapid resolution of symptoms, by reducing parasite numbers 100- to 1000-fold per asexual cycle of the parasite (a factor of approximately 10,000 in each 48-h asexual cycle), which is more than the other currently available antimalarials achieve. Because artemisinin and its derivatives are eliminated rapidly, when given alone or in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required.
This long duration of treatment with the artemisinins can be reduced to 3 days when given in combination with slowly eliminated antimalarials. With this shorter 3-day course, the complete clearance of all parasites is dependent on the partner medicine being effective and persisting at parasiticidal concentrations until all the infecting parasites have been killed.
The currently available options are:
- Artemether plus Lumefantrine (AL),
- Artesunate plus Amodiaquine (AS+AQ),
- Artesunate plus Mefloquine (AS+MQ),
- Artesunate plus Sulfadoxine-Pyrimethamine (AS+SP) and
- Dihydroartemsinin plus Piperaquine (DHA+PPQ)
Artemether plus Lumefantrine
The recommended treatment is a 6-dose regimen over a 3-day period. The dosing is based on the number of tablets per dose (of 20/120mg A/L) according to pre-defined weight bands
5–14 kg: 1 tablet;
15–24 kg: 2 tablets;
25–34 kg: 3 tablets; and
> 34 kg: 4 tablets, given twice a day for 3 days.
This extrapolates to 1.7/12 mg/kg body weight of Artemether and Lumefantrine, respectively, per dose, given twice a day for 3 days, with a therapeutic dose of 4 mg/kg of Artemether and 24mg/kg of Lumefantrine per day.
Artesunate plus Amodiaquine
This is currently available as a fixed-dose formulation with tablets containing 25/67.5 mg, 50/135 mg or 100/270 mg of Artesunate and Amodiaquine. A target dose of 4 mg/kg/day Artesunate and 10 mg/kg/day Amodiaquine once a day for 3 days,
Artesunate plus Mefloquine
A target dose of 4 mg/kg/day Artesunate given once a day for 3 days and 25 mg/kg of Mefloquine either split over 2 days as 15 mg/kg and 10 mg/kg or over 3 days as 8.3 mg/kg/day once a day for 3 days.
Artesunate plus Sulfadoxine-Pyrimethamine
A target dose of 4 mg/kg/day Artesunate given once a day for 3 days and a single administration of 25/1.25 mg/kg Sulfadoxine-Pyrimethamine on day 1.
Dihydroartemisinin plus Piperaquine
This is currently available as a fixed-dose combination with tablets containing 40 mg of Dihydroartemisinin and 320 mg of Piperaquine. A target dose of 4 mg/kg/day Dihydroartemisinin and 18 mg/kg/day Piperaquine once a day for 3 days,
Pregnant women with symptomatic acute malaria are a high-risk group, and they must promptly receive effective antimalarial treatment. Malaria in pregnancy is associated with low birth weight, increased anaemia and, in low-transmission areas, an increased risk of severe malaria and death. Pregnant women in the first trimester with uncomplicated falciparum malaria should be treated with quinine plus clindamycin for seven days (and quinine monotherapy if clindamycin is not available). Artesunate plus clindamycin for seven days is indicated if this treatment fails.
The amounts of antimalarials that enter breast milk and are consumed by the breast feeding infant are relatively small. Tetracycline is contraindicated in breast feeding mothers because of its potential effect on the infant’s bones and teeth. Primaquine should not be used in nursing women, unless the breastfed infant has been determined not to be G6PD-deficient.
Quinine treatment for severe malaria was established before modern clinical trial methods were developed. Several salts of quinine have been formulated for parenteral use, but the dihydrochloride is the most widely used. Peak concentrations following intramuscular quinine in severe malaria are similar to those following intravenous infusion. Pharmacokinetic modelling studies suggest that a loading dose of quinine (i.e. 20 mg salt/kg body weight – twice the maintenance dose) reduces the time needed to reach therapeutic plasma concentrations. The maintenance dose of quinine (10 mg salt/kg body weight) is administered at 8-h intervals, starting 8 h after the first dose. Rapid administration of quinine is unsafe. Each dose of parenteral quinine must be administered as a slow, rate-controlled infusion (usually diluted in 5% dextrose and infused over 4 h). The infusion rate should not exceed 5 mg salt/kg body weight per hour.
TREATMENT OF SEVERE P. falciparum MALARIA
In a patient with P. falciparum asexual parasitaemia and no other obvious cause of symptoms, the presence of one or more of the following clinical or laboratory features classifies the patient as suffering from severe malaria
- impaired consciousness or unrousable coma
- prostration, i.e. generalized weakness so that the patient is unable walk or sit up without assistance
- failure to feed
- multiple convulsions – more than two episodes in 24 h
- deep breathing, respiratory distress (acidotic breathing)
- circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults and < 50 mm Hg in children
- clinical jaundice plus evidence of other vital organ dysfunction
- abnormal spontaneous bleeding
- pulmonaryoedema (radiological)
- hypoglycaemia (blood glucose < 2.2 mmol/l or < 40 mg/dl)
- metabolic acidosis (plasma bicarbonate < 15 mmol/l)
- severe normocytic anaemia (Hb< 5 g/dl, packed cell volume < 15%)
- hyperparasitaemia (> 2%/100 000/μl in low intensity transmission areas or > 5% or 250 000/μl in areas of high stable malaria transmission intensity)
- hyperlactataemia (lactate > 5 mmol/l)
- renal impairment (serum creatinine> 265 μmol/l).
The main objective is to prevent the patient from dying. Secondary objectives are prevention of disabilities and prevention of recrudescence. The mortality of untreated severe malaria (particularly cerebral malaria) is thought to approach 100%. With prompt, effective antimalarial treatment and supportive care the mortality falls to 15–20% overall. Death from severe malaria often occurs within hours of admission to hospital or clinic, so it is essential that therapeutic concentrations of a highly effective antimalarial are achieved as soon as possible.
Artesunate 2.4 mg/kg body weight IV or IM given on admission (time = 0), then at 12 hand 24 h, then once a day is the recommended treatment.
Quinine is an acceptable alternative if parenteral artesunate is not available: quinine 20 mg salt/kg body weight on admission (IVinfusion or divided IM injection), then 10 mg/kg body weight every 8 h; infusion rate should notexceed 5 mg salt/kg body weight per hour.
Artesunate 2.4 mg/kg body weight IV or IM given on admission (time = 0), then at 12 h and 24 h, then once a day;
Quinine 20 mg salt/kg body weight on admission (IV infusion or divided IM injection), then 10 mg/kg body weight every 8 h; infusion rate should not exceed 5 mg salt/kg body weight per hour; Artemether 3.2 mg/kg body weight IM given on admission then 1.6 mg/kg body weight per day should only be used if none of the alternatives are available as its absorption may be erratic.
Following initial parenteral treatment, once the patient can tolerate oral therapy, it is essential to continue and complete treatment with a complete course of an effective oral antimalarial like
- Artemether plus Lumefantrine,
- Artesunate plus Amodiaquine,
- Dihydroartemisinin plus Piperaquine,
- Artesunate plus Sulfadoxine-Pyrimethamine,
- Artesunate plus Clindamycin or Doxycycline,
- Quinine plus Clindamycin or Doxycycline.
Treatments not recommended
Heparin, prostacyclin, desferoxamine, pentoxifylline, low molecular weight dextran, urea, high-dose corticosteroids, acetylsalicylic acid, deferoxamine, anti-tumour necrosis factor antibody, cyclosporin, dichloroacetate, adrenaline and hyperimmune serum are not recommended. In addition, the use of corticosteroids increases the risk of gastrointestinal bleeding and seizures, and has been associated with prolonged coma resolution times when compared with placebos.
Adapted from WHO Guidelines for the treatment of Malaria 2010