Malaria

Context

Why is it important?

• Despite the success of various malaria eradication programs, malaria remains a tropical disease with a significant global burden In 2024, there were an estimated 282 million malaria cases globally, with the African subcontinent carrying the majority of the global disease burden.1 In 2024, the WHO African Region was home to 95% of malaria cases (265 million) and 95% (579 000) of malaria deaths.
• This challenge is set to be compounded by climate change as the increase in global temperatures and changing rainfall patterns lead to change in mosquitoes’ behaviour, with a possible extension of geographical areas suitable for habituation.2
• Malaria is the most common, imported tropical disease in the UK with an average of 1,425 cases per annum.3
• Malarial infection is a cause of preventable death in the UK – early diagnosis and treatment is therefore critical.
• Malaria is associated with significant morbidity rate of 7 to 25% in those requiring ITU admission, but this is thought to be due to the complications of intensive care rather than malaria itself.4

Definition

Malaria is a tropical disease which is caused by the protozoa parasite – plasmodia. There are over 200 species of plasmodium. However, only five (5) infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. The first four (4) exclusively infect humans.  All plasmodium species are transmitted by the female, anopheles mosquito.5

Learning Bite

P. Falciparum is responsible for the majority of cases of imported malaria in the UK. It is also responsible for the most severe form of malaria.

Geographic Distribution

Malaria occurs in tropical and subtropical where the anopheles habituate, and also where the plasmodium parasite can complete its sexual reproductive life cycle in the vector. 

Malaria occurs in Central and South America, Africa, Asia, Eastern Europe, and the South Pacific. However, the highest rate of transmission occurs in Africa (South of Sahara) and Oceania such as Papua New Guinea.

Fig.1 – The average annual malarial cases (all species) reported by non-endemic countries between 2005 and 2015 exported from endemic (red) to non-endemic (blue). (Image retrieved from Tatem, et al.6. No changes were made to the source material.)

Fig.2 – The average annual import of malaria between 2005 and 2015 from endemic to non-endemic depicted as flow lines. Only average flow rates > 50 cases were mapped. (Image retrieved from Tatem. et al.6. No changes were made to the source material.)

Red line > 200 cases, Pink line 100 – 200 cases, and yellow line 50 – 100 cases.

PfPR = prevalence of falciparum malaria.

Learning Bite: The majority of imported malaria to the UK occurred from sub-Sahran Africa, particularly Western Africa: Nigeria, Ghana, Sierra Leone, Côte D’Ivoire, and Cameroon.3

Learning Bite

Travelers presenting with fever should be screened for imported, tropical diseases. Specific country information on tropical diseases can be found here.

Patient Demographic of Imported Malaria

Those of Black African ethnicity and/or African descent represents the largest demographic of patients presenting with imported malaria.3

Interestingly, Marks et al.4 examined 124 patients admitted to the ITU with severe malaria in a centre in London. The majority of patients were young, Caucasian travellers (49%) followed by Africans visiting friends/family (33%).

While Africans were less likely to require ITU admission, those who did require ITU were equally unwell as other ethnicities. Thus, ethnicity on its own confers no advantage against imported malaria.4

Learning bite

Young Caucasian travellers represent a significant demographic affected by severe malaria.4

Pathophysiology

The pathophysiology of malaria is linked to the life cycle of the plasmodium parasite which occurs in two stages.5

Stage One: The Vector

1. Following a blood meal of an infected human host, an anopheles mosquito ingests gametocytes.
2. While in the mosquito’s stomach, the male gametocyte (microgametocyte) penetrates the female gametocyte (macrogametocytes) to produce zygotes.
3. The zygotes undergo development from ookinetes to oocysts in the midgut of the mosquito.
4. The oocysts grow and rupture to release sporozoites which travel to the mosquito’s salivary glands, from which they can be injected into a new human host.

Learning Bite

Malaria may also be transmitted by blood transfusion, contaminated needle, organ transplantation, or via maternal transmission.

Stage Two: The Host

1. During a blood meal, the Anopheles mosquito inoculates the human host with sporozoites.
2. The sporozoites infect liver cells where they mature into schizonts which rupture and release merozoites.
3. The sporozoites of some species (P. vivax and P. Ovale*) differentiate into hypnozoites (dormant, cryptic cells) which lay dormant in the liver and may lead to delayed presentation/ recurrence. These hypnozoites may result in a latency period ranging from < 2 weeks to > 1 year.
4. These merozoites infect erythrocytes where they multiply via asexual reproduction. Some of these merozoites commit to produce male or female gametocytes. 
5. In the erythrocyte, the merozoites undergo development from the ringed stage to trophozoites to schizonts.
6. These mature schizonts burst to release merozoites which initiate another replication phase.
7. This replication cycle occurs every 24 (P. Knowlesi), 48 (P. falciparum, P. Ovale, and P. vivax) and 72 (P. malariae) hours leading to the cyclical fever typical of malaria.
8. It is this rupture of erythrocytes which is believed to lead to the clinical manifestation of malaria.

Fig.3 – Life cycle of the plasmodium parasite causing malaria. Image retrieved from Greenwood, et al.7. No changes were made to the source material.

*P. ovale hypnozoite phase has only been documented in clinical case reports and remains a point of contention.5

Learning bite

The typical incubation period ranges from 7 to 30 days which varies based on the species of plasmodium. P. falciparum has the shortest incubation period. On the other hand, P. vivax and P. ovale may have long latency periods due to the formation of hypnozoites. The latency period in P. vivax and P. ovale* has been shown to vary from < 2 weeks > 1 year.

Learning bite

Hypnozoites are more difficult to eradicate and may lead to disease recurrence if appropriate treatment is not given. P. falciparum and P. malariae have shown a phenomenon of recrudescence (parasites exist in the blood asymptomatically which reactivates) with a recurrence period ranging from < 2 months to > 2 years (P. falciparum) or > 40 years (P. malariae).

Immuno-pathophysiology

Vitamin A Toxication Hypothesis

Current hypothesis regarding malarial symptomatology is linked to endogenous vitamin A intoxication of the host induced by the parasite.8

1. The parasite selectively absorbs Vitamin A from the host’s liver. Upon emerging, the retinoic acid (9RA) form is used to destabilize the cell membrane of red blood cells causing haemolysis and anaemia.
2. Rupture of erythrocytes by mature schizonts lead to the release of malarial pigment (haemozoin) and malarial toxin (glycophosphatidylinositol).
3. The release of parasites into the bloodstream leads to the symptoms of malaria including fever, headache, muscle aches, gastrointestinal symptoms, seizures, coma, respiratory distress, and retinopathy. These are all hypothesised to be linked to Vitamin A toxicity.
4. Malaria is linked with preterm birth, intrauterine growth restriction and low birth weight which is also attributed to the membrane destabilising and growth inhibitory effects of retinoids.

Summary: It is hypothesised that the malaria parasite induces an elevated levels of unbound vitamin A which produces mass membrane destabilisation, pro-oxidation, cytotoxic and teratogenic consequences.

 Immune Dysregulation Hypothesis

The release of the malarial pigment and toxin activates the mononuclear cells and stimulate cytokines. One of the hypotheses is that this immune activation leads to an imbalance between pro-inflammatory and anti-inflammatory pathways. The pro-inflammatory state leads to systemic inflammation and cellular dysfunction which in turn is responsible for organ dysfunctions and the symptoms/clinical manifestations of malaria.

The two theories may not be mutually exclusive as retinoid-treated malignant cells have been shown to release inflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha, interleukin (IL)-1b, IL-6 and IL-8. Thus, excess retinoic acid itself may lead to a proinflammatory state.

Malaria has a variable presentation. The most common presentation is fever, which often presents in a cyclical pattern based on the parasite’s life cycle. It tends to present with non-specific symptoms such as myalgia, malaise, headache, fever and gastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhoea.

Given these vague symptoms, it is important to enquire about travel history, as travel to any endemic area should immediately prompt malaria as a differential which in turn should prompt appropriate testing. It is important to note that malaria is not a clinical diagnosis.

Learning bite

Malaria presents with vague symptoms and is, therefore, not a clinical diagnosis. Travel history and a high degree of suspicion is key!

More severe disease may manifest as disturbance of the:

• Central nervous system: reduced GCS, prostration, seizures;
• Cardiovascular system: circulatory collapse; splenic rupture
• Gastrointestinal system: jaundice, hypoglycaemia, splenomegaly;
• Renal system: kidney injury;
• Respiratory system: pulmonary oedema;
• Metabolic system: metabolic acoidosis, hyperparasitaemia, hyperlactataemia;
• Haematological system: severe anaemia, thrombocytopaenia, coagulopathy, disseminated intravascular coagulation (DIC).

Currently there are three scoring systems to assess severity:

1. WHO Criteria for Severe Malaria
2. Coma Acidosis Malaria (CAM)
3. Malaria Score in Adults (MSA)

WHO Criteria for Severe Malaria

The WHO criteria for Severe Malaria is a 10-component scale which examines for end- organ dysfunction, laboratory findings and metabolic status.

The presence of one of these parameters results in a diagnosis of severe malaria:

• Cerebral Malaria (GCS < 11)
• Shock
• Acidosis (Bicarbonate level < 15 mmol)
• Severe anaemia (haematocrit < 20%)
• P. falciparum level > 2% or 100,000 parasites/ uL
• Visible jaundice
• Renal failure (Urea > 17mmol)
• Asexual P. falciparum parasitemia (parasite percentage > 10%)
• Plasma glucose level < 2.2 mmol/ L
• Respiratory distress

The WHO scoring system is considered too broad to be utilised as a triage tool.

Coma Acidosis Malaria (CAM)

• Base Deficit
• GCS
• Bicarbonate score
• Respiratory rate

Derivation of the Coma Acidosis Malaria – View the table here.

The main component of the CAM is GCS and base deficit. Serum bicarbonate levels and respiratory rate are markers of base deficit. A numeric value of 0-2 is given to each of the parameter based on their result.

The CAM score of >/= 2 has been shown to have a sensitivity of 100% with regards to ITU admission.8

The positive predictive values have shown to range from 68 to 80%, with a negative predictive value of 100%.9

Malaria Score in Adults

• Severe anaemia – 1 point
• Acute renal failure – 2 points
• Respiratory distress – 3 points
• Cerebral malaria – 4 points

The MSA ranges from 0-10.8

The sensitivity of MSA is 89.9%, specificity 70.6% with a positive predictive value of 94.1% when 5 is taken as the cut-off value.9

However, neither the CAM nor the MSA have been validated as a scoring system for patients with imported malaria.3

Learning Bite

In the non-endemic setting, GCS is used to identify patients at risk of poor outcome and cerebral malaria. Patients presenting with GCS < 11 is defined as cerebral malaria.4

• Full Blood Count (anaemia, thrombocytopaenia, low/normal/high white cell count)
• Urea and Electrolytes (AKI, hyponatramia)
• Liver function tests (high bilirubin, high AST/ALT, high LDH)
• Clotting (often normal. In severe disease, can have prolonged PT and APTT, low fibrinogen, high D-dimer)
• Venous blood gas (metabolic acidosis)
• Thick and thin blood films

The diagnosis of malaria is made with thick and thin blood films. Thick films are used to assess for the presence of the plasmodium parasite. It also measures the parasitaemia percentage by counting parasites per microscope field or by counting the parasites per hundred blood cells.

Thin films in turn are utilised to identify the species of plasmodium. (Images retrieved from CDC.10 No changes have been made to the source material.)

Fig.4 Rings of P. falciparum in a thick blood smear10

Fig.5 Rings of P. falciparum in a thick blood smear10

If the first blood films are negative, but the suspicion for malaria remains high, then further testing should be repeated 12-24 hours later and then a 3rd sample 24 hours later.

Learning Bites

• Blood films may be falsely negative for falciparum malaria in pregnant women as the parasite may concentrate in the placenta.
• All patients presenting with severe malarial infection should be tested for HIV co-infection if not previously known. Co-infection has been shown to result in a detrimental impact on HIV viral load.4

• Travellers going to malaria-endemic zones should be offered chemoprophylaxis with one of the following medications: Mefloquine, Doxycycline, Atovaquone plus proguanil.11
• Intravenous artemether-lumefantrine (artesunate) is currently the first-line treatment for severe malaria in adults and children4 (please consult your trust guidelines/ local infectious disease specialist before commencing treatment).
• If artesunate is unavailable, quinine may be used for severe or complicated malaria. However, patients treated with intravenous quinine should be monitored for hypoglycaemia. Moreover, quinine should be used in combination with doxycycline or clindamycin. Doxycycline is not recommended for children < 12 years due to risk of teeth discolouration and dental hypoplasia.
• Artemisinin combination therapy (ACT) may be used for uncomplicated malaria or for mixed infection in adults and children.
• If ACT is unavailable, then quinine or atovaquone-proguanil should be used.
• Chloroquinine either alone (for P. malariae or P. Knowlesi infection) or in combination with primaquine (for P. vivax or P. Ovale) are alternatives for uncomplicated malaria.
• Mefloquine is no longer used in the UK to treat malaria due to its complication profile.

Special Populations

Pregnant Patients

• Uncomplicated malaria in the first trimester should be treated with quinine and clindamycin.
• Uncomplicated malaria in the second and third trimesters should be treated with artemether-lumefantrine.
• Severe malaria in any trimester should be treated with artemether-lumefantrine.
• Exchange transfusion is no longer recommended as a treatment modality in the UK.3
• The need for organ support is made on an individual basis by the ITU team.
• Note, malaria is transmissible to the foetus via the placenta.

Paediatric Patients

• Admit all paediatric patients for a minimum of 24-hours.
• Monitor observations including glucose every 4-hours.
• If the patient deteriorates, repeat thick films should be sent.
• First line for the treatment of uncomplicated malaria is artemether-lumefantrine. If unavailable then atavoquone with proguanil should be used.
• Complicated or severe malaria should be managed with IV artesunate. If unavailable, then IV quinine should be used until artesunate is available.

Please consult the children’s BNF for weight-adjusted doses of the aforementioned medication.

Malaria is a notifiable disease, and all cases should be notified to Public Health England.

Learning Bites

• All patients diagnosed with falciparum malaria should be admitted to the hospital for 24-hours due to their risk of rapid deterioration, especially children.
• Cerebral malaria, ARDS, and AKI are the commonest complications requiring ITU admission.

Management of patients with severe malaria:

• These patients tend to deteriorate rapidly and as such should be managed in a resus-equivalent setting.
• Establish intravenous access with two large bore cannulae, minimum 18 or 16 gauge.
• Send appropriate laboratory testing including group & save. Don’t forget your thick and thin films.
• Early involvement of ITU is important depending on the organ support that is needed.

Pitfall

Artemisinin therapy can cause a delayed haemolysis; thus, follow-up blood test is required.

• Any traveller presenting with fever should be screened for imported tropical diseases.
• Malaria may also be transmitted through blood transfusions, contaminated needles, organ transplantation, or via maternal transmission.
• The incubation period typically ranges from 7–30 days, depending on the species of plasmodium. P. falciparum has the shortest incubation, whereas P. vivax and P. ovale may have long latency periods due to hypnozoite formation.
• Hypnozoites are harder to eliminate and may lead to disease recurrence if not adequately treated.
• In non-endemic settings, the Glasgow Coma Scale (GCS) helps identify patients at risk of poor outcomes. A GCS <11 indicates cerebral malaria.
• Blood films may be falsely negative for falciparum malaria in pregnant patients, as the parasite may concentrate in the placenta.
• Patients with severe malaria should be tested for HIV if not previously known, as co-infection can worsen HIV viral load.
• All cases of falciparum malaria require at least 24-hour hospital admission due to the risk of rapid deterioration, particularly in children.
• The most common complications requiring ITU admission are cerebral malaria, ARDS and AKI.

1. World Health Organization. Malaria. Geneva: WHO; 2025 Dec 4. [cited 10 Nov 2025].
2. Samarasekera U. Climate change and malaria: predictions becoming reality. The Lancet. 2023 Jul 29; 402 (10399).
3. UK Health Security Agency. Malaria imported into the UK: 2021 [internet]. 2023 [cited 19 Oct 2023].
4. Marks ME, Armstrong M, Suvari MM, Batson S, et al. Severe imported falciparum malaria among adults requiring intensive care: a retrospective study at the hospital for tropical diseases, London. BMC Infect Dis. 2013 Mar 03; 13(118).
5. Sato S. Plasmodium – a brief introduction to the parasites causing human malaria and their basic biology. J Physiol Anthropol. 2021 Jan 07; 40(1).
6. Tatem AJ, Jia P, Ordanovich D, Falkner M, Huang Z, Howes R. The geography of imported malaria to non-endemic countries: a meta-analysis of nationally reported statistics. The Lancet. 2016 Oct 21; 17(1): P98-107. [cited 23 Oct 2023].
7. Greenwood BM, Fidock DA, Kyle DE, Kappe SHI, et al. Malaria: progress, perils, and prospects for eradication. JCI 2008 Apr 1; 11(4): 1266-1276. Image C Life cycle of the plasmodium parasite causing malaria; [cited 24 Oct 2023].
8. Mawson AR. The pathogenesis of malaria: a new perspective. Pathog Glob Health. 2013 April; 107(3): 122-129.
9. Mishra SK, Panigrahi P, Mishra R, Mohanty S. Prediction of outcomes in adults with severe falciparum malaria: a new scoring system. Malar J. 2007 Feb 27; 6(24).
10. Centers for Disease Control and Prevention (CDC). Malaria: Image gallery. CDC, Last reviewed 2024 Sept.
11. UK Health Security Agency. Guiedelines for the malaria prevention in travellers from the UK 2024. UKHSA.
12. Bailey P, Behrens R, Brown M, Checkley A, Chiodini P, et al. Malaria diagnosis and treatment guideline. HTD. Last updated 2016 Nov 07.