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      Malaria

      Latest update: - Authors: Nele Alders, Ula Maniewski-Kelner

      Malaria is a life- threatening disease caused by Plasmodium parasites transmitted by mosquitoes. There are five parasite species that can infect humans: 

      • Plasmodium falciparum
      • Plasmodium vivax
      • Plasmodium ovale
      • Plasmodium malariae
      • Plasmodium knowlesi

      Plasmodium falciparum is the deadliest amongst the species and the most prevalent on the African continent. Plasmodium vivax is the dominant malaria parasite in most countries outside of sub-Saharan Africa. Plasmodium malariae is uncommon but is found in most malaria endemic areas. Plasmodium ovale is relatively unusual outside of sub-Saharan Africa and comprises less than one percent of isolates. Plasmodium knowlesi is very rare and has been identified in southeast Asia. It's natural reservoir are macaques. It was initially discovered in Malaysia, but human cases have been reported from several neighbouring countries.

      Transmission

      Vector

      Infectious female Anopheles mosquitoes who only bite in the evening and night. They often go unnoticed because they are small and almost make no sound.

      Life cycle

      After a bite by an infectious mosquito, people are inoculated with sporozoites. These will enter the hepatocytes within minutes where they start to multiply quickly. After an incubation period of minimally one week, the malaria parasites will appear in the blood, where they will infect the red blood cells and start to multiply (trophozoites). After one (P. knowlesi), two (P. falciparum, P. vivax, P. ovale) or three (P. malariae) days, the reds blood cells start to burst. The released parasites will infect other red blood cells. This cycle will be repeated multiple times. Blood stage parasites are responsible for the clinical manifestations of the disease. After a few cycles, gametocytes (male microgametocytes and female macrogametocytes) will appear. If ingested by an Anopheles mosquito during a blood meal, the parasites can continue its lifecycle in the Anopheles mosquito.

      Incubation period

      Seven days to months and sometimes more than a year.

      Symptoms

      Travellers should be aware that malaria is a life-threatening disease that can be fatal within days of onset. They must be informed that medical advice must be sought immediately in the event of fever or other flulike symptoms, until at least 3 months after their return. Malaria can be treated effectively, but without treatment this disease can quickly cause complications and become fatal. The disease appears very similar to influenza - particularly during the first few days - with fever, headache, muscle pain and sometimes diarrhea or a cough.
      Plasmodium falciparum is the most common species and results in the most severe symptoms. Plasmodium falciparum-infected erythrocytes adhere to the vascular endothelium of blood vessel walls and do not freely circulate in the blood. When this sequestration of infected erythrocytes occurs in the vessels of the brain, it is believed to be a factor in causing the severe disease syndrome known as cerebral malaria, which is associated with high mortality. 
      The other three species (P. vivax, P. ovale, P. malariae) can give significant symptoms but are normally not deadly. If mortality occurs, it is usually due to the rupture of the spleen but in rare cases severe malaria with organ failure can develop. Late-onset P. vivax and P. ovale malaria may occur despite effective prophylaxis because these parasites cause relapses that cannot be prevented with medicines that are currently recommended for chemoprophylaxis.
      Plasmodium knowlesi is primarily seen by macaques in forested areas of South East Asia, but can cause severe malaria (similar to P. Falciparum) in humans too.
      Still every year a few people die in Belgium due to malaria. These are mainly people who didn’t adhere to preventive malaria medication or where there was a delay in seeking medical attention, establishing a diagnoses or involving expert care. 
      The diagnosis of malaria can be established with a simple blood analysis (EDTA- tube) by a reliable laboratory within a few hours.

      Risk areas

      Malaria occurs only in certain tropical and subtropical areas in South America, Central America, Africa and Asia. From 1500 to 3000 m there are less or no Anopheles mosquitos. The risk of infection may also vary according to the season, being highest at the end (or soon after) the rainy season.

      The malaria world map shows malaria risk areas of all the countries of the world. More information on the creation of the malaria maps can be found on Malaria maps- background. 

      View the map

      Prevention

      Malaria prevention is always a combination of several measures, abbreviated by the World Health Organization (WHO) as ABCDE:

      • Awareness: Be aware of the risk according to the area, the incubation period, the possibility of delayed onset and the main symptoms.
      • Bite prevention: Protect yourself from dusk till dawn.
      • Chemoprophylaxis: Use preventive medication if indicated.
      • Diagnosis: Immediately seek diagnosis and treatment if a fever develops one week or more after entering an area where there is a malaria risk and up to three months after return.
      • Environment: Avoid outdoor activities in environments that are mosquito breeding places.

      Travellers at higher risk

      Travellers with a higher risk of contracting malaria are those who spend a lot of time outdoors in the evening and at night, for example during a hike, or travellers who stay in rural non-touristic regions.

      People with a higher risk for developing severe malaria complications are:

      • children younger than 12 years
      • people older than 70 years
      • pregnant women
      • people with an immune disorder, such as a condition affecting the spleen
      • people in poor general health

      Travelers visiting friend and family (VFR) often underestimate the malaria risk. Previously built up immunity weans six months to several years after leaving the endemic area. Improving awareness in this specific population regarding this risk is important. 

      Preventive measures

      Travellers at risk for malaria should be advised on:

      • Mosquito bite prevention: which consists of a combination of mosquito-repellent measures especially from dusk through to sunrise. These measures are also necessary when taking chemoprophylaxis, as the tablets never guarantee 100% protection.
      • Chemoprophylaxis: whether this should be added to the other preventive measures depends on how high the risk is:
        • Low risk area (pink areas): Chemoprophylaxis is not needed.
        • Moderate risk area (orange areas): Usually mosquito bite prevention and awareness are recommended. In case of higher risk of contracting malaria or severe complications, or when mosquito bite prevention is not possible, chemoprophylaxis is recommended.
        • Seasonal risk (purple areas): Chemoprophylaxis is indicated during the rainy season, but not during dry season.
        • High risk (red areas): Chemoprophylaxis is recommended for all.

      Chemoprophylaxis

      The three most commonly prescribed medications for chemoprophylaxis are atovaquone-proguanil, doxycycline and mefloquine. Chloroquine could be prescribed in areas with P. vivax only or fully chloroquine sensitive P. falciparum, but since this is only the case in a few places in the world, the use is limited.

      Atovaquone-proguanil is directed at the liver phase of the malaria parasite life cycle (causal prophylactic effect). Other chemoprophylactic agents are only directed at the erythrocytic phase (suppressive prophylactic effect). They don’t prevent infection as such, but they have a suppressive prophylactic effect by eradicating the malaria parasites when they infect the red blood cells. This is the reason why medication needs to be taken 28 days after leaving a malaria risk area. Atovaquone-proguanil has a causal prophylactic effect if started at least 24 hours before entering a malaria endemic area and therefore only needs to be taken until 7 days after leaving a risk area in case of good adherence. However, in case it was not started 24 hours prior to entering an endemic area or daily doses have been skipped while the traveller is potentially exposed to malaria, atovaquone–proguanil prophylaxis should also be taken for 28 days after return.

      Doses
      		 Start from … before entering risk area   Until … after leaving risk  Pregnancy Breastfeeding Children
      Atovaquone-proguanil: 250mg/100mg  Adults: 1 tablet a day
      Children >5kg      		 1 day 7 days  If no alternative available 

      If child >5kg

      		 >5kg
      Doxycycline: 100mg Adults: 1 tablet a day
      Children >8y      		 1 day 28 days 1e trim. If no alternative available >8y
      Mefloquine: 250mg Adults: 1 tablet a week
      Children >5kg      		 2-3 weeks 28 days Yes Yes >5kg
      Chloroquine
      (Only in areas of little resistance)      		 Adults: 300mg base once a week Children: see below 1 week  28 days Yes Yes Yes

      Atovaquone-proguanil (Malarone®)

      Formulation: One adult tablet contains 250mg atovaquone and 100mg proguanil.
      Half- Life: Atovaquone 2-3 days, proguanil 12-25 hours
      Duration: Start 1-2 days before entering risk zone and take until 7 days after leaving.
      Dose:
      - Adults and children >40kg: 1 adult tablet per day
      - Children >5kg: Can be used in adjusted dose based on the weight. Adult tablets can be cut into quarters using a tablet cutter or the pharmacist can prepare a special formulation. 
      Administration: Take tablets with a fatty meal or with water containing milk to enhance absorption. In case of vomiting within the hour of administration, a repeat dose is advised.
      Protection: Offers more than 95% protection against P. falciparum. Available data indicate protection against primary attacks of P. vivax, however it will not protect against hypnozoite-induced episodes of P. vivax or P. ovale.
      Contra- indications:
      - Do not administer in case of severe kidney insufficiency (creatinine clearance <30ml/min).
      - Depression and epilepsy are not contra-indications.
      - It can be used in those known to be G6PD-deficient.
      Precautions:
      - It may enhance the anticoagulant effect of warfarin or other coumarin- anticoagulation (increased risk of bleeding risk). Monitoring the anticoagulant response (INR and signs of bleeding), closely following the addition or cessation of atovaquone-proguanil, is advised.
      - It should not be taken together with Vivotif (oral live attenuated typhoid fever vaccine) since it can diminish the efficacy of the vaccine. Preferably, an interval of 7 days with a minimum of 3 days is respected.
      Pregnancy and breastfeeding: Malaria infection poses a significant risk in pregnancy, yet data on safety of prophylaxis in pregnancy are sparse. The current advise is that atovaquone- proguanil should only be used if there is no suitable alternative available.
      According to the medication leaflet it can be used during pregnancy if there is a clear risk-benefit, but it mentions that it is contra-indicated in case of breastfeeding a child below 5kg. This is in line with the advice of the CDC. The WHO claims that there are insufficient data, and therefore it is not recommended.
      The guidelines in the United Kingdom and France recommend that it can only be used during pregnancy and breastfeeding if there is no suitable alternative available.   
      The studies performed during pregnancy are limited and retrospective. Animal studies showed no evidence for teratogenicity. A retrospective analyses looked at pregnancies and live births among active duty military woman in the United states. Among 198 164 pregnancies 50 were exposed to atovaquone-proguanil. They found a non-statistically significant increase in the risk of fetal loss. Overall 28% of exposed pregnancies ended in fetal loss, compared to 17.6% in unexposed pregnancies. However this is a small number of exposed pregnancies, the mothers in the exposed group were older and more of them (94%) were in the first trimester compared to the control groups ( 85% and 74%).
      A systemic review of the safety of atovaquone-proguanil for malaria prevention and treatment in pregnancy suggested that, although only limited data available, outcomes following exposure during pregnancy are similar to expected rates in similar populations. A registry-based cohort study of the inadvertent use of atovaquone-proguanil in weeks 3 to 8 after conception identified 149 pregnancies and found no significant association between exposure to atovaquone-proguanil in early pregnancy and the risk of a major birth defect.
      Side effects: Headaches and gastro-intestinal upsets may occur. 
      Advantages/disadvantages: Very well tolerated. Tends to be more expensive, especially for trips of long duration. Good for last- minute travellers because the drug is started 1-2 days before entering an endemic area. Paediatric tablets are available. 

      Doxycycline

      Formulation: 100mg or 200mg tablets are available.
      Half- Life: 15-24 hours
      Duration: Start 1-2 days before entering risk zone and take until 28 days after leaving.
      Dose:
      - Adults and children >50kg: 100 mg per day
      - Children from 8 years: 2mg/kg/day to a maximum of 100 mg/day.
      Administration: Take with enough liquid or during a meal to reduce the risk of oesophageal ulcers. Avoid administration with antacids (containing aluminium, calcium, magnesium, zinc, iron salts or bismuth) as much as possible since it can impair the absorption of doxycycline. 
      Protection: Between 92% and 96% for P. falciparum and 98% for primary P. vivax infection.
      Contra- indications:
      - Hypersensitivity to tetracyclines
      - Depression and epilepsy are not contra-indications.
      - It can be used in those known to be G6PD-deficient.
      Precautions: The metabolism of doxycycline is accelerated by carbamazepine and phenytoin. Tetracyclines possibly enhance the anticoagulant effect of coumarins (e.g., warfarin).
      Pregnancy and breastfeeding: It can be used in the first trimester of pregnancy but the full course (including 28 days after travel) must be completed before 15 weeks’ gestation. It can cross the placenta and can cause discoloration of teeth when given during the second or third trimester of pregnancy. 
      According to the medication leaflet it is contraindicated during breastfeeding. However the American Academy of paediatrics and the CDC say it is compatible with breastfeeding since it is excreted at a low concentration of 30-40% of that found in maternal blood and it is thought that the drug absorption by infants is inhibited by the calcium in breast milk. Furthermore, tetracycline was undetectable in breastfed infants whose mothers were taking tetracycline.
      Children: Prolonged use of doxycycline in children below the age of 8 year is contra-indicated due to the risk of yellow tooth discolouration and dental enamel hypoplasia with tetracyclines. In the early 1960s, dental side-effects were associated with the use of tetracycline, the incidence was greater with high doses of tetracycline and long term use. Doxycycline was developed later and is a newer medication in the tetracycline class but was labelled with the same side-effects as the earlier tetracyclines. However, recent studies report little or no effects of doxycycline on tooth staining or dental enamel hypoplasia in short term (3-10 days) use of doxycycline in children <8 years. Since currently no data on long term use is available the recommendations to avoid  doxycycline as malaria chemoprophylaxis for young children travellers below the age of 8 year remains unchanged.
      Side effects: Vulvovaginitis (candida). Photosensitivity, so avoidance of excessive sun exposure and the correct use of high SPF sunscreen is advised. Gastric and intestinal discomfort.
      Advantages/disadvantages: Tends to be less expensive than some of the other options, so good for long term travellers or a limited budget. Daily use and needs to be taken until 28 days after return which can influence adherence. 

      Mefloquine (Lariam®)

      Formulation: one adult tablet contains 250mg mefloquine
      Half- Life: 2–4 weeks
      Duration: Start 2-3 weeks before entering risk zone and take until 28 days after leaving. In case of previous proven tolerability and a lack of time, it could be started shorter before entering a risk zone, but at least 3 tablets should have been taken before entering an endemic area, e.g., a schedule with a loading dose of 250mg on day 1, 2 and 3 (or spread over the remaining days) with a fourth dose on day 10 and thereafter weekly, until 28 days after return.
      Dose:
      - Adults: 250mg once a week on the same day 
      - Children >5kg: Can be used in adjusted dose based on the weight. 4-5 mg/kg/week to a maximum of 250 mg. Adult tablets can be cut into quarters using a tablet cutter or the pharmacist can prepare a special formulation.
      Administration: If mefloquine has never been taken, it’s advised to start at least 2-3 weeks before travel to monitor side-effects. Since 2014, it’s mandatory to inform patients for potential side effects and a patient warning leaflet warning leaflet Nederlands/ Français needs to be signed and kept by the traveller during use. Taking mefloquine in the evening can sometimes reduce some of the side-effects. 
      Protection: 90% or more. Significant resistance of P. falciparum to mefloquine is a problem only in some areas of South East Asia but is reported sporadically from the Amazon basin.
      Contra-indications:
      - Convulsions/ epilepsy
      - Psychoneurological: depression, generalised anxiety disorders, psychosis, suicide risk
      - Vestibular disorders 
      - Cardiac conduction abnormalities
      - History of blackwater fever
      - Severe impairment of liver function
      - It can be used in those known to be G6PD-deficient.
      Precautions: Tiredness, stress, exhaustion, and excessive alcohol use can increase the potential psychoneurological side-effects.
      Pregnancy and breastfeeding: Can be used in pregnancy and breastfeeding (even if the infant is <5kg).
      Side effects:
      - In case of side effects, the use needs to be discontinued immediately.  
      - Insomnia, abnormal dreams, anxiety, depressed and suicidal mood, psychosis.
      Advantages/disadvantages: Not a good choice for last-minute travellers. Not always well tolerated, so the use is often limited to people with previous exposure. To be taken only once a week and can be taken during pregnancy. 

      Chloroquine or hydroxychloroquine sulfate (Plaquenil®)

      Chloroquine phosphate or hydroxychloroquine sulphate (Plaquenil) can be used in the prevention of malaria only in destinations where chloroquine resistance is not present.  Widespread resistance in most malaria-endemic countries has led to a decline in its use.

      Formulation: One adult tablet contains 200mg hydroxychloroquine sulphate (=155 mg base).
      Half- Life: 1–2 months
      Duration: Start 1-2 weeks before entering risk zone and take until 28 days after leaving.
      Dose:
      - Adults: 300 mg base (500 mg salt) once a week
      - Children >5kg: 5 mg/kg base (8.3mg/kg salt) orally once a week, up to maximum 300 mg base.
      Protection: Chloroquine-resistant falciparum malaria is widespread (effectively universal), but it remains effective against most P. vivax, all P. ovale, P. knowlesi and virtually all P. malariae. Chloroquine-resistant P. vivax is found in the Indonesian archipelago, the Malay Peninsula, including Myanmar, and eastward to Southern Vietnam, and may have spread further.
      Contra- indications:
      - Convulsions/ epilepsy
      - Concomitant use with amiodarone (ventricular arrhythmias), ciclosporin (ciclosporin toxicity), digoxin (increases plasmaconcentration), mefloquine (convulsions), moxifloxacin (ventricular arrhythmias).
      Precautions: It is highly toxic in overdose and children are particularly susceptible. Antacids can reduce the absorption of chloroquine so it should be taken with an interval of at least four hours.
      Pregnancy and breastfeeding: Can be used in pregnancy and breastfeeding.
      Side effects:  
      - Potential exacerbation of psoriasis and myasthenia gravis
      - Severe hypoglycaemia in diabetics and non-diabetics
      - Gastrointestinal disturbances
      - Headaches
      - Itching (especially in African descents)
      Advantages/disadvantages: Limited use due to increasing resistance.

      Tafenoquine (ArakodaTM®)

      Tafenoquine is not licensed in the European Union and therefor is not available in Belgium. It has been approved by the United States Food and Drug administration (FDA) since 2018 for the use of chemoprophylaxis for all malaria species in adults (>18 years) and the treatment of the dormant P. vivax and P. ovale liver-stage parasites (hypnozoites) from 16 years onwards.

      Formulation: Not licensed in the European Union.
      Half- Life: 14-28 days
      Duration: Start 3 days before entering risk zone and take until 1 week after leaving.
      Dose:
      -Adults (18y): 200mg daily for the 3 days preceding the trip, 200mg weekly during the trip and a single 200mg dose during the week after returning. 
      - Children: not licensed.
      Contra- indications:
      - G6PD deficiency or unknown G6PD status
      - History of psychotic disorder or current psychotic symptoms
      Pregnancy and breastfeeding: Not advised during pregnancy. Not advised in case of breastfeeding an infant with G6PD deficiency or unknown G6PD status.
      Side effects:  
      - Most common: headache, back pain, dizziness, nausea, diarrhoea
      - Elevated liver enzyme levels, insomnia, depression, abnormal dreams, and anxiety
      Advantages/disadvantages: Not available in European Union.

      Non-pharmaceutical forms of Artemisia 

      Artemisinin in any form does not work well as prevention against malaria. It has a short elimination half- life, meaning that it only remains in the blood at therapeutic levels for a short time.
      The non-pharmaceutical forms of Artemisia, for example in juice extractions, teas, infusion preparations or other herbal remedies for the prevention or treatment of malaria, is not supported by the WHO. The content varies substantially and there is a high risk of delivering subtherapeutic doses, which are insufficient to kill all the parasites and to prevent recrudescence. Medication derived from artemisinin used for malaria treatment is always given in combination with another antimalarial drug to avoid the occurrence of resistance and to prevent recrudescence. 

      The long- term traveller

      The long-term traveller is defined as those travelling through or visiting malaria-endemic countries for over 6 months, for example expatriates or backpackers.
      Since the risk of contracting malaria increases roughly linearly over time as exposure to malaria continues long-term travellers are at high risk from malaria. Even when urged to adhere to personal protective measures and reassured that long-term prophylaxis is safe and effective, traveller adherence likely will decline over time.

      The decision on whether prophylaxis is continued on a long-term basis might be influenced by the overall length of stay, the seasonal risk in the area, and access to medical facilities.  
      Backpackers have less control over their environment as they are constantly moving hence they are advised to continue chemoprophylaxis and anti-mosquito measures when travelling in malaria endemic areas.
      Expatriates are usually based at a single location where the risk of malaria is known and often lower because of better sanitation, they generally have access to medical care, a good standard of accommodation and are usually more aware of the malaria risks. Continuing chemoprophylaxis at least three to six months while settling into a new area is advised. During this period they can install mosquito preventive measures and get to know the local medical facilities. Once settled they could discuss stopping chemoprophylaxis with their medical doctor. It’s important not to stop chemoprophylaxis if there is an increased risk for malaria, for example pregnancy. 
      Before stopping chemoprophylaxis the following conditions should be met:

      • the residency and in particular the bedrooms are mosquito- free
      • outside, especially from dusk to dawn, anti-mosquito measures are used
      • in case of being unwell, certainly when febrile, medical help is sought immediately
      • access in less than 24 hours to a reliable medical centre for diagnosis and treatment is present
      • malaria treatment is available
      • malaria chemoprophylaxis is taken during holidays, short- or weekend trips to other malaria endemic areas

      Emergency treatment

      Emergency standby treatment can be recommended for certain travellers visiting remote areas with moderate malaria risk, or for expats. It is not a replacement for chemoprophylaxis and certainly not a good option for travellers visiting high malaria risk regions. It should be used when symptoms of possible malaria occur (fever) when the patient is unlikely to be within 24 hours of medical attention. It is meant to “buy time” and does not replace a proper consultation. 

      Standby emergency treatment should be started if it is impossible to consult a doctor and/or reach a diagnosis within 24 hours of the onset of fever. Medical attention should be sought as soon as possible for full assessment and to exclude other serious causes of fever. The agent used for emergency standby treatment should be different from the drugs used for chemoprophylaxis, to minimise drug toxicity and due to concerns over drug resistance.

      Atovaquone/proguanil is the first choice of emergency treatment for people travelling to moderate risk areas or travelling through regions with different malaria risks, as it can also be used in a different dosage as malaria prevention when the traveller enters a region with higher malaria risk. When atovaquone/proguanil has been used as chemoprophylaxis, it cannot be used as a treatment. 
      Combination preparations containing artemisinin derivatives are the first choice for expats residing in high malaria risk regions. 

      It is particularly important that the individual traveller is sufficiently well briefed to be able to use standby emergency treatment appropriately.
      For more information, see Emergency treatment for malaria.

      Malaria vaccine (RTS,S/AS01; Mosquirix®)  

      There is no effective malaria vaccine for travellers yet. 
      RTS,S/AS01 (Mosquirix ®) is an adjuvanted recombinant vaccine that  has been licensed by the European Medicines Agency for the use outside of the European Union in children aged 6 weeks to 17 months. Three doses should be given at monthly intervals with a fourth dose recommended 18 months after the third dose. The vaccine has been shown to significantly reduce malaria and deadly severe malaria among young children in low-resource settings. In children aged 5-17 months, the vaccine efficacy against the first or only episode of clinical malaria over 12 months of follow-up was 56%. Protection against P. falciparum malaria wanes over time and vaccination may delay the acquisition of natural immunity.

      Since October 2021 WHO recommends the broad use of the malaria vaccines among children living in regions with moderate to high P. falciparum malaria transmission. Mosquirix® also helps protection against infection of the liver with the hepatitis B virus but should not be used only for this purpose. 
      Due to its limited efficacy and rapidly weaning immunity, it is currently not advised for the use in travellers in the prevention of malaria. It can be exceptionally considered in expat children living in remote areas with a high malaria risk in combination with other malaria prevention strategies, in countries where vaccination against malaria is implemented.

      Malaria rapid diagnostic test

      A rapid antigen test for malaria is used in conjunction with a thick and thin smear in established laboratories. Theoretically this could be an interesting tool, but the use has not been validated in travellers and therefore can’t be sold as a diagnostic test for personal use. 

      It is available for purchase on the internet, but the use is discouraged because of the variable quality of the test, the frequent issues with the diluent and the lack of ability to perform and interpret the test correctly as a non-trained person. Due the limitations it’s not advised for use in travellers and unreliable to diagnose malaria and decide on the need of treatment. 

      Additional information

      References