Malaria

Defined as one or more of the following, occurring in the absence of an identified alternative cause and in the presence of P. falciparum asexual parasitaemia.

• Impaired consciousness: A Glasgow coma score < 11 in adults or a Blantyre coma score < 3 in children
• Prostration: Generalized weakness so that the person is unable to sit, stand or walk without assistance
• Multiple convulsions: More than two episodes within 24 h
• Acidosis: A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as respiratory distress (rapid, deep, laboured breathing).
• Hypoglycaemia: Blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL)
• Severe malarial anaemia: Haemoglobin concentration ≤ 5 g/dL or a haematocrit of ≤ 15% in children < 12 years of age (< 7 g/dL and < 20%, respectively, in adults) with a parasite count > 10 000/µL
• Renal impairment: Plasma or serum creatinine > 265 µmol/L (3 mg/dL) or blood urea > 20 mmol/L
• Jaundice: Plasma or serum bilirubin > 50 µmol/L (3 mg/dL) with a parasite count > 100 000/ µL
• Pulmonary oedema: Radiologically confirmed or oxygen saturation < 92% on room air with a respiratory rate > 30/min, often with chest indrawing and crepitations on auscultation
• Significant bleeding: Including recurrent or prolonged bleeding from the nose, gums or venepuncture sites, haematemesis or melaena
• Shock: Compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure < 70 mm Hg in children or < 80 mmHg in adults, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill).
• Hyperparasitaemia: P. falciparum parasitaemia > 10%

Defined as for falciparum malaria but with no parasite density thresholds.

A patient who presents with symptoms of malaria and a positive parasitological test (microscopy or RDT) but with no features of severe malaria is defined as having uncomplicated malaria. An electrocardiogram (ECG) should be performed before implementing treatment to rule out conduction disorders.

Available treatments

First-line treatment with artemisinin-based combination therapy

Other available treatments

ACT regimens must ensure optimal dosing to prolong their useful therapeutic life, i.e. to maximize the likelihood of rapid clinical and parasitological cure, minimize transmission and retard drug resistance.

ACTs containing piperaquine, mefloquine or lumefantrine are the recommended treatment, although artesunate + amodiaquine may also be effective in some areas.

Resistance of P. ovale and P. malariae to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. The blood stages of P. ovale and P. malariae should therefore be treated with the standard regimen of ACT, as for vivax malaria.

ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.

• The G6PD status of patients should be used to guide administration of either primaquine or tafenoquine for preventing relapse.
• To prevent relapse, children and adult (except pregnant women, infants aged < 1 months and women breastfeeding infants aged < 1 months, and people with G6PD deficiency), primaquine should be given at a high total dose (7 mg/kg) at 0.5 mg/kg/day for 14 days or 1 mg/kg/day for 7 days for prevention of relapses in patients with uncomplicated P. vivax or P. ovale malaria.
• In people with G6PD deficiency, primaquine base at 0.75 mg/kg once a week for 8 weeks can be given to prevent relapse, with close medical supervision for potential primaquine-induced haemolysis.
• When G6PD status is unknown and G6PD testing is not available, a decision to prescribe primaquine should be based on an assessment of the risks and benefits of adding primaquine.

It is essential that full doses of effective parenteral (or rectal) antimalarial treatment be given promptly in the initial treatment of severe malaria. This should be followed by a full dose of effective ACT orally. Two classes of medicine are available for parenteral treatment of severe malaria: artemisinin derivatives (artesunate or artemether) and the cinchona alkaloids (quinine and quinidine). Parenteral artesunate is the treatment of choice for all severe malaria.

Artesunate

• The recommended dose is 2.4 mg/kg at H0, H12, H24, and then every 24 hours for 7 days (maximum of 9 doses). 
• IV infusion should be continued for at least 24 hours (3 doses), and after 24h, maintain Artesunate until criteria of severe malaria are no longer observed. 
• When oral treatment becomes possible, the patient should be switched from Artesunate to a full course of oral firstline treatment for uncomplicated malaria: dihydroartemisinin-piperaquine (DHAP) or artemether/lumefantrine (AL). 
• The WHO recommends waiting for 8–12 hours after the end of the IV infusion before beginning the oral treatment. However, focus should be given to choosing an interval that takes into account the patient’s comfort.

Follow-on Artesunate treatment:

Following IV artesunate treatment, 15% of patients experience post-artesunate delayed hemolysis (PADH) two to three weeks after the initiation of treatment. Fifty per cent of patients require transfusion. No means of preventing or predicting PADH are currently available. In addition to monitoring parasitemia on Day 3, Day 7, and Day 28, clinical and laboratory monitoring is therefore also recommended on day 7, day 14, day 21 and day 28.

Quinine

Quinine is still relevant in certain circumstances: treatment with artesunate cannot be initiated immediately (artesunate not available), known allergy to artemisinin, patient returning from an area with known artesunate resistance (South-East Asia, see Question 1). If the patient is first treated with intravenous quinine, it is advisable to switch to artesunate within 24 hours if possible. There is probably no advantage in switching at a later time.

Loading dose: 20 mg/kg administered over 4 hours, then keep the vein open with an infusion of 5% glucose over 4 hours, then maintenance dose: 8 hours after the start of the loading dose, 10 mg/kg every 8 hours (alternate quinine over 4 hours and 5% glucose over 4 hours)

Treat parenterally for at least 24 hours, then, if the patient can tolerate the oral route, change to a complete 3-day course of an artemisinin-based combination (or if not available oral quinine to complete 7 days of quinine treatment). If not, continue parenteral treatment until the patient can change to oral route (without exceeding 7 days of parenteral treatment).

Adjustment of parenteral dosing in renal failure or hepatic dysfunction 

The dosage of artemisinin derivatives does not have to be adjusted for patients with vital organ dysfunction. However quinine accumulates in severe vital organ dysfunction. If a patient with severe malaria has persisting acute kidney injury or there is no clinical improvement by 48 hours, the dose of quinine should be reduced by one third, to 10 mg/kg bw every 12 hours. Dosage adjustments are not necessary if patients are receiving either haemodialysis or haemofiltration.

Although P. vivax malaria is considered to be benign, with a low case-fatality rate, it may cause a debilitating febrile illness with progressive anaemia and  can also occasionally cause severe disease, as in P. falciparum malaria. Reported manifestations of severe P. vivax malaria include severe anaemia, thrombocytopenia, acute pulmonary oedema and, less commonly, cerebral malaria, pancytopenia, jaundice, splenic rupture, haemoglobinuria, acute renal failure and shock.

Prompt effective treatment and case management should be the same as for severe P. falciparum malaria. Following parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine in countries where chloroquine is the treatment of choice. A full course of radical treatment with primaquine should be given after recovery.

Follow-on treatment 

Parasitemia must be controlled at D3, D7 and D28, to ensure that it has become negative, and that there has been no treatment failure or relapse.

The current recommendation is to give parenteral antimalarial drugs for the treatment of severe malaria for a minimum of 24h once started (irrespective of the patient’s ability to tolerate oral medication earlier) before giving the oral follow-up treatment, if patient can tolerate oral medication.

After initial parenteral treatment, once the patient can tolerate oral therapy, it is essential to continue and complete treatment with an effective oral antimalarial drug by giving a full course of effective ACT (artesunate + amodiaquine, artemether + lumefantrine or dihydroartemisinin + piperaquine).

If the patient presented initially with impaired consciousness, ACTs containing mefloquine should be avoided because of an increased incidence of neuropsychiatric complications. 

When an ACT is not available, artesunate + clindamycin, artesunate + doxycycline, quinine + clindamycin or quinine + doxycycline can be used for follow-on treatment. Doxycycline is preferred to other tetracyclines because it can be given once daily and does not accumulate in cases of renal failure, but it should not be given to children < 8 years or pregnant women. As treatment with doxycycline is begun only when the patient has recovered sufficiently, the 7-day doxycycline course finishes after the artesunate, artemether or quinine course. When available, clindamycin may be substituted in children and pregnant women.

Treatment of severe malaria during pregnancy

Women in the second and third trimesters of pregnancy are more likely to have severe malaria than other adults, and, in low-transmission settings, this is often complicated by pulmonary oedema and hypoglycaemia. Maternal mortality is approximately 50%, which is higher than in non-pregnant adults. Fetal death and premature labour are common.

Parenteral antimalarial drugs should be given to pregnant women with severe malaria in full doses without delay. Parenteral artesunate is the treatment of choice in all trimesters.Treatment must not be delayed. If artesunate is unavailable, intramuscular artemether should be given, and if this is unavailable then parenteral quinine should be started immediately until artesunate is obtained.

Obstetric advice should be sought at an early stage, a paediatrician alerted and blood glucose checked frequently. Hypoglycemia should be expected, and it is often recurrent if the patient is receiving quinine. Severe malaria may also present immediately after delivery. Postpartum bacterial infection is a common complication and should be managed appropriately.