Changes

January 2024 — minor update. Prognosis section updated in line with the UKHSA, 2024 publication Guidelines for malaria prevention in travellers from the UK. 

Update

Goals

To support primary healthcare professionals to:

• Promptly identify people who may have malaria.
• Arrange immediate admission for people who are at risk of severe or complicated malaria.
• Refer all others suspected of having non-severe non-falciparum malaria for prompt diagnosis and appropriate treatment.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

What is it?

• Malaria is a life-threatening illness caused by infection of red blood cells by Plasmodium parasites.
• Several species of Plasmodium (P. vivax, P. falciparum, P. ovale, and P. malariae) cause malaria in humans. Human infection with P. knowlesi, a malaria parasite of monkeys in South-East-Asia, can also occur.
• Transmission of malaria to humans occurs through the bite of infected female Anopheles mosquitoes.
• The infecting agent (sporozoite) is inoculated into humans in the saliva of infected mosquitoes during a blood meal.
• The sporozoites travel in the bloodstream to the liver where they enter liver cells and mature into schizonts which eventually rupture and release tens of thousands of merozoites.
• Each merozoite can infect a red blood cell where they mature and divide to form more parasites. These are released into the bloodstream when the red blood cell ruptures and go on to infect other red blood cells. The number of parasites in the blood increases rapidly and produces clinical illness.
• Some parasites in the red blood cells form male and female gametocytes. These mate if taken up by a mosquito and mature to release sporozoites ready to be inoculated into a new human host.
• Malaria is not an infection which is acquired in the UK, as Anopheles mosquitoes are usually found in tropical and subtropical areas of the world:
  • Malaria can be imported to the UK by people who have become infected in areas where malaria is endemic.
  • Travellers (in particular children) visiting friends and relatives are more likely than tourists to become infected with malaria as they tend to visit remote places, stay longer, and are less likely to take malaria chemoprophylaxis. 
  • UK surveillance data from 2016 showed that where a history of chemoprophylaxis was known 60% (n = 225) of those who acquired malaria while travelling abroad had not taken antimalarial medication. Those who had taken medication had not completed the course [Moyo, 2019]. 2019 Public Health England data suggest 87% (n = 775) of people infected had not taken prophylaxis.
• Malaria can also occur (rarely) in the UK as a result of:
  • "Airport malaria" or "baggage malaria" — malaria imported to non-endemic areas by infected Anopheles mosquitoes hiding in planes or in baggage.
  • Person-to-person transmission during:
    • Blood transfusion or implantation of infected tissues.
    • Pregnancy.
    • Injecting drug use.

[Public Health England, 2019; Behrens, 2021; WHO, 2021]

What causes malaria?

• Malaria is caused by infection with the protozoan parasite Plasmodium. Species of Plasmodium that are known to cause malaria in humans include:
  • P. falciparum — found worldwide in tropical and subtropical areas. It is the most prevalent malaria parasite on the African continent and is responsible for the majority of malaria deaths.
  • P. vivax — found in Asia, Latin America, and some parts of Africa. It is the most common malaria parasite outside sub-Saharan Africa. P. vivax has dormant liver stages which can cause ‘relapses’ of malaria months or years after the initial infection.
  • P. ovale — found mostly in Africa (especially West Africa) and the islands of the western Pacific. P. ovale has dormant liver stages which can cause ‘relapses’ of malaria months or years after the initial infection.
  • P. malariae — found in South America, Asia, and Africa. If untreated, P. malariae can cause lifelong chronic infection.
  • P. knowlesi — a malaria parasite of monkeys in South-East Asia which can cause severe and sometimes fatal illness in humans.
  • Mixed infections with more than one species of Plasmodium (usually including P. falciparum) can occur.

[Groger, 2017; Public Health England, 2019; CDC, 2020; WHO, 2021] 

How common is malaria in the UK?

• Malaria is the commonest imported tropical disease in the UK and is a notifiable disease.
• In 2019 1719 cases of malaria were reported in the UK (1626 in England, 58 in Scotland, 25 in Wales, and 10 in Northern Ireland).
  • Cases are largely due to P. falciparum and infections are mostly acquired in West Africa (Sierra Leone and Nigeria). There was only one P. vivax infection which was acquired in South Asia.
• In the UK in 2019:
  • There were 15 deaths, 14 due to P. falciparum. Median age at death was 58 years.
  • Sixty-five percent of cases were in males with a median age of 42 years. The median age in females was 40 years.
  • Twelve percent of cases were in children aged under 18 years.
  • London has the majority of cases (54%) and the largest increase in cases was seen in the North-west region.
  • The causative Plasmodium species involved were identified as:
    • P. falciparum in 1475 people (85.8%) — all deaths from malaria were due to P. falciparum.
    • P. vivax in 72 people (4.2%).
    • P. ovale in 114 people (6.6%).
    • P. malariae in 43 people (2.5%).
    • 14 people (0.8%) had mixed infections.
  • The reason for travel (known in 1627 cases) was:
    • Visiting friends and relatives in their country of origin, 84%.
    • Holiday, 7%.
    • Business (including armed forces and civilian aircrew), 9%.
• Globally infections with non-falciparum species are increasing.

[Public Health England, 2019; Hawadak, 2021]

What is the prognosis?

• If malaria is identified promptly, appropriate treatment is given, and no organ dysfunction has occurred, most people make a rapid and complete recovery. If malaria treatment is delayed or inappropriate, severe or fatal malaria can develop.
• Severe malaria
  • Untreated severe malaria is fatal in the majority of cases.
  • Progression to severe malaria may take days or occur within a few hours. 
  • Poor prognostic factors include high levels of parasitaemia, peripheral P. falciparum blood schizonts, pigment deposits in leucocytes, metabolic acidosis, older age, coma, and renal impairment.
  • Most cases of severe malaria are due to P. falciparum infection but other species can also cause serious illness. Infections with P. vivax can be associated with severe anaemia, splenic rupture, acute respiratory distress syndrome, acute renal failure, and death. P. ovale can cause jaundice, severe anaemia, and respiratory distress syndrome.
    • Infants, young children, pregnant women, and older people are at particular risk of severe disease.
  • Human infections with P. knowlesi (a malaria parasite of monkeys) occur in many countries in South-East Asia (including Brunei, Myanmar, Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam) and can cause severe and fatal illness.
    • The first case of imported P. knowlesi infection was identified in the UK in 2006. P. knowlesi is very difficult to distinguish morphologically from P. malariae, which usually causes a milder illness.
• Malaria mortality
  • Deaths related to imported malaria infection are more likely to occur in older people (over 65 years of age). This is in contrast to endemic areas of Africa where mortality is highest in pregnant women and young children [Behrens, 2021]. Globally, malaria cases and  deaths increased in 2020, with the most serious situation observed in Africa, especially West Africa. Contributory factors include reduced or delayed diagnosis and clinical care, shortage of  medical resources, disruption to control measures, and disruption to the availability of malaria medication [UKHSA, 2024].
  • Mortality from severe malaria in pregnancy is estimated to be between 2 and 10 times higher than in non-pregnant women in endemic areas [RCOG, 2010].
  • A retrospective cohort study (n = 25,054) of people with P. falciparum malaria diagnosed in the UK between 1987 and 2006 [Checkley, 2012] found that an increased risk of mortality was associated with:
    • Older age (greater than 65 years) compared to age 18–35 years (adjusted OR 10.68, 95% CI 6.4–17.8).
    • Travel as a tourist compared to visits to friends and relatives (adjusted OR 8.2, 95% CI 5.1–13.3).
    • Birth in a non-endemic country compared to birth in African countries where malaria is endemic (adjusted OR 4.6, 95% CI 3.1–9.9).
  • Risk factors for severe malaria include:
    • Non-use or inappropriate use of chemoprophylaxis.
    • Older age, childhood, or pregnancy.
    • Male sex.
    • Delay in seeking care.
    • Delay in diagnosis.
    • Incorrect treatment.
    • Infection with P. falciparum.
    • Non-immunity — people born in countries where malaria is endemic may have some immunity to malaria infection from continual exposure to the parasite. Immunity rapidly declines when exposure to Plasmodium stops, for example when a person moves from an endemic to non-endemic country.
    • Immunocompromise.
    • Travel for tourism.
  • Prognostic indicators of poor outcome include neurological dysfunction (coma or seizures), acidosis, hypoglycaemia, and respiratory distress.

[RCOG, 2010; Lalloo, 2016; Njim, 2019; Kotepui, 2020]

What are the complications?

• Complications of malaria include:
  • Acute kidney injury — a common complication in the short-term due to hypovolaemia and dehydration. Renal tubular necrosis can also occur in severe disease.
  • Cerebral malaria — severe malaria due to P. falciparum with coma, or malaria with coma persisting for more than 30 minutes after a seizure.
  • Acute respiratory distress syndrome.
  • Spontaneous bleeding and coagulopathy.
  • Sepsis.
  • Severe anaemia — more likely in young children due to direct red cell lysis, autoimmune haemolysis, and disturbed bone marrow function.
  • Hypoglycaemia — more likely in pregnant women and may be worsened by quinine.
  • Metabolic acidosis — secondary to tissue hypoxia from hypovolaemia, hypotension, and anaemia.
  • Nephrotic syndrome.
  • Jaundice.
  • Splenic rupture — seen in P. vivax infection.

• In pregnancy:
  • Severe malaria is more likely, particularly in the second and third trimesters, and is often associated with pulmonary oedema and hypoglycaemia.
  • Cerebral malaria has a mortality rate of 50% (higher than non-pregnant adults).
  • Intrauterine growth retardation, premature delivery, and fetal death (stillbirth) are possible complications in pregnant women infected with malaria. 

[Moore, 2017; CDC, 2020; Park, 2020; Behrens, 2021]

When should I suspect malaria?

• Suspect malaria in anyone who has returned from or previously visited an area endemic for malaria, who is unwell, or has a fever or history of fever, regardless of malaria chemoprophylaxis — specific country information can be found on the UK Health Security Agency website.
  • Almost all cases of P. falciparum malaria present within 6 months of exposure and most within 2–3 months.
  • Infection with other malaria species, such as P. ovale and P. vivax may present months or years after exposure due to reactivation of hypnozoites (a dormant liver stage).
  • Presentation may be delayed in people who have taken chemoprophylaxis.
  • Most missed cases of malaria are wrongly diagnosed as non-specific viral infections, influenza, gastroenteritis, and hepatitis.
• Clinical features of malaria include:
  • Fever (often 39°C or higher), sweats, and/or chills — absence of fever should not remove the suspicion of malaria.
  • Headache.
  • General malaise, lethargy, and fatigue — somnolence is more common in children than in adults.
  • Anorexia, gastrointestinal disturbance (such as nausea, abdominal pain, vomiting, diarrhoea), and jaundice.
  • Poor feeding in children.
  • Myalgia and arthralgia.
  • Sore throat, cough, lower respiratory tract symptoms, and respiratory distress.
  • Confusion.
  • Hepatomegaly, splenomegaly, and somnolence are more common on examination in children.
• Features of severe or complicated malaria in adults include:
  • Cerebral malaria — impaired conscious level (Glasgow coma score less than 11) or seizures.
  • Renal impairment (may present with oliguria).
  • Acidosis (may present with acidotic breathing).
  • Hypoglycaemia (< 2.2 mmol/L) — common in pregnant women.
  • Respiratory distress which may be due to pulmonary oedema or acute respiratory distress syndrome (ARDS) — common in pregnant women.
  • Severe anaemia (may present with pallor).
  • Spontaneous bleeding/disseminated intravascular coagulation.
  • Shock (BP < 90/60 mmHg).
  • Sepsis — more common in pregnant women.
  • Haemoglobinuria — P. falciparum can cause severe haemolysis with dark red urine (‘blackwater fever’).
  • Parasitaemia > 10%.
• Features of severe or complicated malaria in children include:
  • Cerebral malaria — impaired conscious level (Glasgow coma score less than 11 or Blantyre coma score less than 3), seizures, altered respiration, and posturing (decorticate or decerebrate).
  • Severe anaemia (may present with pallor).
  • Respiratory distress or acidosis (may present with acidotic breathing).
  • Hypoglycaemia (< 2.2 mmol/L).
  • Prostration (inability to stand or sit).
  • Parasitaemia > 2% red blood cells parasitized.

[Lalloo, 2016; CDC, 2020; Behrens, 2021]

How should I assess a person with suspected malaria?

• Take a history asking about:
  • Symptoms of malaria (such as fever, sweats, chills, malaise, myalgia, headache, vomiting, diarrhoea, and cough) and timing of onset.
  • Travel history including:
    • Country and area of travel.
    • Stopovers and other countries transited through.
    • Date of return.
    • Type of travel and activities while abroad — people returning from visiting friends and family in endemic areas are more at risk of malaria than tourists.
  • Possible differential diagnoses:
    • Immediately isolate anyone suspected of having a viral haemorrhagic fever (VHF) such as Ebola, Lassa fever, or Marburg in a side room — further assessment must be in line with Public Health England guidelines on Management of Hazard Group 4 viral haemorrhagic fevers and similar human infectious diseases of high consequence.
  • Preventative measures such as:
    • Malaria chemoprophylaxis (drug, dose, adherence, and cessation) — full adherence to appropriate prophylaxis does not guarantee protection against malaria.
    • Precautions taken against biting insects for example insecticide-impregnated bednets and repellent.
    • Travel immunizations against other travel related infections such as yellow fever.
  • Risk of severe malaria:
    • Severe malaria is more likely in children, pregnant women, older people, and immunocompromised people (for example those with splenectomy or HIV/AIDS).
• Examine the person, looking for:
  • Signs of severe malaria such as impaired consciousness, confusion, hypotension, respiratory distress, or jaundice.
    • Check vital signs such as blood pressure, pulse, temperature (fever may not be present), respiration rate, and oxygen saturation.
    • The Glasgow and Blantyre coma scales can be used to assess level of consciousness.
  • Pallor — suggestive of anaemia.
  • Hepatomegaly or splenomegaly (more common in children).
• Arrange appropriate investigations:
  • Malaria is a medical emergency and if suspected, a blood test to confirm the diagnosis must be carried out without delay.
  • Diagnosis of malaria is only possible with microscopy of thick and thin blood films (the gold standard) or an antigen detection test.
    • Most people will need immediate referral to secondary care (an Infectious Disease or appropriate Medical Assessment Unit) to allow testing with a same-day result.
    • If the person is well and local facilities can ensure return of a result to the requesting doctor within 2 hours, testing may be carried out from primary care after discussion with an Infectious Disease specialist.
    • EDTA should be used for blood samples.
    • If the first blood films are negative, further blood testing must be arranged 12–24 hours later and again after a further 24 hours to rule out infection.
    • In pregnancy, thick films can be negative, despite the presence of parasites in the placenta. Expert advice should always be sought if malaria is suspected.

Differential diagnosis

• Malaria is difficult to diagnose as it may mimic other illnesses encountered in the UK, including:
  • Meningitis or encephalitis.
  • Lower respiratory tract infection.
  • COVID-19.
  • Influenza and other viral infections such as Epstein-Barr virus or cytomegalovirus.
  • Gastroenteritis.
  • Urinary tract infection.
  • Lymphoma.
  • Sepsis.
  • Viral hepatitis.
  • HIV seroconversion.
  • Legionella.
  • Leptospirosis.
• Malaria may present with similar symptoms to other travel-related infections, including:
  • Viral haemorrhagic fevers such as Lassa fever, Crimean-Congo haemorrhagic fever, Marburg, and Ebola — patients suspected of having a viral haemorrhagic fever require strict isolation.
  • Enteric fevers such as typhoid or paratyphoid.
  • Arboviruses such as Dengue, West Nile virus, and Japanese encephalitis.
  • Rickettsial infection such as scrub typhus and relapsing fever.
  • Trypanosomiasis.
  • Rabies.

Scenario: Management

From birth onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of malaria.

Search dates

October 2016 - September 2021

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• Malaria, Vivax/ or Malaria/ or Malaria, Falciparum/
• ((cryptic or falciparum) adj malaria).ti,ab.
• Plasmodium.kw.
• Malaria.kw.
• Antimalarial$.kw.

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.