Malaria


Malaria is a parasitic infection due to protozoa of the genus Plasmodium, transmitted to humans by the bite of Anopheles mosquitoes. Transmission by transfusion of parasite infected blood and transplacental transmission are also possible.
Most infections are due to 5 species: P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. All species may cause uncomplicated malaria; severe malaria (defined by the presence of complications) is almost always due to P. falciparum.
Clinical suspicion of malaria should be confirmed whenever possible by a parasitologicaldiagnosis. However, treatment of suspected malaria should not be delayed when confirmatory testing is not available: uncomplicated malaria can progress rapidly to severe malaria, and severe malaria may cause death within a few hours if left untreated.

Clinical features

Malaria should always be considered in a patient living in or coming from an endemic area, who presents with fever (or history of fever in the previous 48 hours).

Uncomplicated malaria

Fever is frequently associated with chills, sweating, headache, muscular ache, malaise, anorexia or nausea. In children, fever may be associated with abdominal pain, diarrhoea and vomiting. Anaemia is frequent in children and pregnant women.

Severe malaria

In addition to the above, the patient presents with one or more of the following complications:
– Impaired consciousness, delirium or coma.
– Seizures, generalised or focal (e.g. abnormal eye movements).
– Prostration (extreme weakness; in children: inability to sit or drink/suck).
– Respiratory distress: rapid and laboured breathing or slow, deep breathing.
– Circulatory collapse (shock): cold extremities, weak or absent pulse, slow capillary refill time (> 3 seconds), cyanosis.
– Jaundice (check mucosal surfaces of the mouth, conjunctivae and palms).
– Haemoglobinuria: dark red urine.
– Abnormal bleeding: skin (petechiae), conjunctivae, nose, gums; blood in stools.
– Acute renal failure: urine output < 12 ml/kg/day in children and < 400 ml/day in adults, despite adequate hydration.

Patients presenting with any of the above features or with severe anaemia (Anaemia, Chapter 1) must be hospitalised immediately.

Laboratory

Parasitological diagnosis

Microscopiy
Thin and thick blood films enable parasite detection, species identification, quantification and monitoring of parasitaemia.
Note: blood films may be negative due to sequestration of the parasitized erythrocytes in peripheral capillaries in severe malaria, as well as in placental vessels in pregnant women.

Rapid diagnostic tests (RDTs)1
Rapid tests detect parasite antigens. They give only a qualitative result (positive or negative) and may remain positive several days or weeks following effective treatment.
Note: even with positive diagnostic results, rule out other causes of fever.

Additional examinations

Haemoglobin (Hb) level
To be measured routinely in all patients with clinical anaemia, and in all patients with severe malaria.

Blood glucose level
To be measured routinely to detect hypoglycaemia (< 3.3 mmol/litre or < 60 mg/dl) in patients with severe malaria and those with malnutrition.

Treatment of malaria due to P. vivax, P. ovale, P. malariae, P. knowlesi

2

chloroquine (CQ) PO
Children and adults:
Day 1: 10 mg base/kg
Day 2: 10 mg base/kg 
Day 3: 5 mg base/kg

P. vivax and P. ovale can cause relapses due to activation of dormant parasites in the liver. A treatment with primaquine3 can be given to eliminate these parasites, after the initial treatment with CQ. However, this treatment is reserved for patients living in areas where reinfection is unlikely, i.e. non-endemic or low transmission areas.

Treatment of uncomplicated falciparum malaria

Antimalarial treatment

During pregnancy, see Antimalarial treatment in pregnant women.

The treatment is an artemisinin-based combination therapy (ACT)4 given by the oral route for 3 days. The first-line ACT is chosen according to therapeutic efficacy in the area under consideration. Coformulations (2 antimalarials combined in the same tablet) are preferred over coblisters (2 distinct antimalarials presented in the same blister). For dosing information, see table below.

If vomiting precludes oral therapy, treatment is started using IV or IM artesunate or IM artemether or rectal artesunate, depending on availability, until the patient can tolerate a complete 3-day oral treatment with an ACT.

Treatment of uncomplicated falciparum malaria

Notes:
In infants below the age/weight mentioned in the table above, there is little data on efficacy and safety of ACTs.
The combinations AL, AS/AQ and DHA/PPQ can be used. The dose should be calculated so as to correspond to 10-16 mg/kg/dose of lumefantrine; 10 mg/kg daily of amodiaquine; 20 mg/kg daily of piperaquine).
The combination AS-SP should not be used during the first weeks of life.
Clinical condition of young children can deteriorate rapidly; it may be preferable to start parenteral treatment straight away (see below).

In the event of failure of correctly administered treatment with a first line ACT, use another ACT.
Quinine PO is still recommended in some national protocols:
quinine PO D1 to D7
Children and adults < 50 kg: 10 mg/kg 3 times daily
Adults ≥ 50 kg: 600 mg 3 times daily

Reduced susceptibility to quinine has been observed in South-East Asia and Amazon region.

NoteP. falciparum is resistant to chloroquine (CQ) in Africa, South America, South-East Asia and Oceania but appears to remain sensitive to CQ in Haiti and the Dominican Republic. In these regions, CQ remains the first line treatment (see non-falciparum malaria).

Symptomatic treatment

Paracetamol PO in the event of high fever only (Fever, Chapter 1).

Treatment of severe malaria

The patient must be hospitalised.

Antimalarial treatment

During pregnancy, see Antimalarial treatment in pregnant women.

At dispensary level

Before transfer, administer the first dose of artesunate or artemether IM (loading dose, see below) or one dose of rectal artesunate in children less than 6 years:
10 mg/kg as a single dose i.e.:
Children 3 to < 6 kg: 1 suppository 50 mg
Children 6 to < 11 kg: 2 suppositories 50 mg
Children 11 to 20 kg: 1 suppository 200 mg

At hospital level

The drugs of choice is artesunate IV or IM; if artesunate is not available, use artemether IM.

For patients in shock: use artesunate IV or, if not available, quinine IV. The IM route is not appropriate.

artesunate slow IV injection (3 to 5 minutes) or, if not possible, slow IM injection, into the anterior thigh
Children less than 20 kg: 3 mg/kg/dose
Children 20 kg and over and adults: 2.4 mg/kg/dose
– One dose on admission (H0)
– One dose 12 hours after admission (H12)
– One dose 24 hours after admission (H24)
– Then one dose once daily
Administer at least 3 doses, then, if the patient can tolerate oral route, change to an ACT.

or artemether IM (anterior thigh)
Children and adults: 3.2 mg/kg on admission (D1) then 1.6 mg/kg once daily
As soon as the patient can tolerate oral route, change to an ACT.

For completion of therapy by oral route:
– If the duration of parenteral treatment was less than 7 days: treat 3 days with an ACT5 (see Treatment of uncomplicated falciparum malaria).
– If the duration of parenteral treatment was 7 days: to not give additional oral treatment.

Quinine IV is still recommended in some national protocols. The dose is expressed in quinine salt:
– Loading dose: 20 mg/kg to be 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).
For adults, administer each dose of quinine in 250 ml of glucose. For children under 20 kg, administer each dose of quinine in a volume of 10 ml/kg of glucose.
Do not administer a loading dose to patients who have received oral quinine, mefloquine within the previous 24 hours: start with maintenance dose.

As soon as the patient can tolerate oral treatment, administer either a 3-day course of ACT5 or oral quinine to complete 7 days of treatment.
If the combination AS-MQ is used as oral completion treatment following IV quinine, an interval of 12 hours should elapse between the last dose of quinine and the administration of MQ.

Symptomatic treatment and management of complications

Hydration

Maintain adequate hydration. As a guide, volume to be administered per 24 hours by oral or IV route, see Appendix 1a.
Adjust the volume according to clinical condition in order to avoid dehydration or fluid overload (risk of pulmonary oedema).

Fever

Paracetamol in the event of high fever only (Fever, Chapter 1).

Severe anaemia

– Blood transfusion is indicated:
• In children with Hb < 6 g/dl.
• In pregnant women with Hb < 7 g/dl (before 36 weeks) or Hb < 8 g/dl (at 36 weeks or later).

– In other patients with Hb < 7 g/dl, monitor clinical status and Hb level and consider transfusion on a case-by-case basis.

Hypoglycaemia

– If the patient is able to swallow:
50 ml of 10% glucose
or 40 ml of water + 10 ml of 50% glucose
or 50 ml of water + 5 g (1 teaspoon) of granulated sugar
or 50 ml of milk

– In an unconscious patient:
Children: 5 ml/kg of 10% glucose6  by IV injection (2 to 3 minutes) or infusion
Adults: 1 ml/kg of 50% glucose by slow IV injection (3 to 5 minutes)

– Check blood glucose level after 15 minutes. If blood glucose level remains < 3.3 mmol/litre or < 60 mg/dl, administer another dose or give glucose by oral route, according to the patient’s clinical condition. Hypoglycaemia may recur: maintain regular sugar intake (5% glucose, milk, according to circumstances) and continue to monitor for several hours.

Notes:
– In an unconscious or prostrated patient, in case of emergency or when venous access is unavailable or awaited, use granulated sugar by the sublingual route to correct hypoglycaemia.7
– The risk of hypoglycaemia is higher in patients receiving IV quinine.

Coma

Check/ensure the airway is clear, measure blood glucose level and assess level of consciousness (Blantyre or Glasgow coma scale).

In the event of hypoglycaemia or if blood glucose level cannot be measured, administer glucose.

If the patient does not respond to administration of glucose, or if hypoglycaemia is not detected:
– Exclude meningitis (lumbar puncture) or proceed directly to administration of an antibiotic (see Meningitis, Chapter 7).
– Insert a urinary catheter; place the patient in the recovery position.
– Reposition the patient every 2 hours; ensure eyes and mouth are kept clean and moist, etc.
– Monitor vital signs, blood glucose level, level of consciousness, urine output, hourly until stable, then every 4 hours.
– Monitor fluid balance.

Seizures

See Chapter 1. Address possible causes (e.g. hypoglycaemia; fever in children).

Respiratory distress

– Rapid laboured breathing:
Check for pulmonary oedema, which may occur with or without fluid overload: reduce IV infusion rate if the patient is receiving IV therapy, nurse semi-sitting, oxygen, furosemide IV: 1 mg/kg in children, 40 mg in adults. Repeat after 1 to 2 hours if necessary.
Associated pneumonia should also be considered (see Acute pneumonia, Chapter 2).

– Slow, deep breathing (acidosis):
Look for dehydration (and correct if present), decompensated anaemia (and transfuse if present).

Oliguria and acute renal failure

Look first for dehydration (Appendix 2), especially due to inadequate fluid intake or excessive fluid losses (high fever, vomiting, diarrhoea). Treat dehydration if present. Be aware of the risk of fluid overload and acute pulmonary oedema. Monitor for the return of urine output.

Acute renal failure (ARF) is found almost exclusively in adults and is more common in Asia than Africa. ARF should be suspected if urine output remains < 400 ml/day or < 20 ml/hour (< 12 ml/kg/day in children) despite adequate rehydration. Insert a urinary catheter, measure output. Restrict fluids to 1 litre/day (30 ml/kg/day in children), plus additional volume equal to urine output. Renal dialysis is often necessary.

Antimalarial treatment in pregnant women

Uncomplicated falciparum malaria

ACT are recommended in all trimesters. However, the combination AS/SP is contra-indicated in HIV-infected pregnant women taking co-trimoxazole preventive therapy.
Quinine PO (± clindamycin) may be an alternative to ACT.

Severe malaria

Artesunate IV or IM or artemether IM are recommended in all trimesters. Quinine IV is still recommended in some national protocols.

Prevention

8

– For pregnant women in areas with high risk of infection with P. falciparum, refer to the guide Essential obstetric and newborn care, MSF.

– In areas with seasonal malaria transmission, seasonal malaria chemoprevention in children < 5 years reduces mortality: administration once monthly of a combination such as amodiaquine + SP.

– In malaria endemic zones and in epidemic-prone contexts, all in-patient facilities (including HIV treatment centres and feeding centres), should be furnished with long-lasting insecticidal nets (LLINs).



Footnotes
Ref Notes
1

Most rapid tests detect the following antigens alone or in combination: HRP2 protein specific to P. falciparum ; an enzyme (Pf pLDH) specific to P. falciparum ; an enzyme (pan pLDH) common to all 4 plasmodium species. HRP2 may continue to be detectable for 2 to 3 weeks or more after parasite clearance; pLDH remains detectable for several days (up to 2 weeks) after parasite clearance.
Use pan pLDH tests as first choice in hyper and holo-endemic areas, as well as in areas of intense seasonal transmission and during outbreaks or complex emergencies. In other contexts, HRP2 tests (P. falciparum > 95%) or HRP2 + pLDH combination tests (P. falciparum < 95%) are preferred.

2 In general, P. vivax remains sensitive to CQ but resistance is found in Papua New Guinea, the Solomon Islands, Burma, India, Indonesia and East Timor. In these regions, follow national recommendations.
3 Primaquine PO for 14 days: 0.25 to 0.5 mg/kg once daily in children > 4 years; 15 mg once daily in adults.
Primaquine is contra-indicated in individuals with G6PD deficiency. If G6PD deficiency cannot be tested individually, the decision to prescribe primaquine must take into account the prevalence of deficiency in the population.
4 ACT: a combination of artemisinin or one of its derivatives (e.g. artesunate, artemether) with another antimalarial of a different class.
5 Do not use AS-MQ if the patient developed neurological signs during the acute phase. [ a b ]
6 In children, if ready-made G10% solution is not available: add 10 ml of G50% solution per 100 ml of G5% solution to obtain a G10% solution.
7 Place a level teaspoon of sugar, moistened with a few drops of water, under the tongue, then place the patient in the recovery position. Repeat after 15 minutes if the patient has not regained consciousness. As with other methods for treating hypoglycaemia, maintain regular sugar intake, and monitor.
8 See specialised literature for information regarding anti-vector measures and prevention in travellers.