Malaria
Malaria - Summary
Malaria is a tropical disease caused by infection of red blood cells by a protozoan parasite from the Plasmodium species, which is transmitted to humans following a bite from its vector, various species of the Anopheles mosquito.
Four species of malarial parasite cause almost all malarial infections in humans:
Plasmodium falciparum causes most cases of malaria and is the most likely to result in severe illness or death.
Plasmodium vivax and Plasmodium ovale may cause relapsing malaria.
Plasmodium malariae is less commonly seen in the UK and may present with late recrudescences many years after the person has left an endemic area.
Malaria due to Plasmodium falciparum may cause:
Cerebral malaria (nearly always fatal without treatment).
Severe anaemia.
Renal failure.
Pulmonary oedema.
Hypoglycaemia.
Hypovolaemia.
Disseminated intravascular coagulation.
Metabolic acidosis.
Complications during pregnancy.
Malaria should be considered if an adult or child has travelled to an area where malaria is endemic (especially within the last 6 months), regardless of whether they have taken prophylaxis, and they have any of the following non-specific symptoms:
A fever or history of fever (although absence of fever does not exclude a diagnosis of malaria).
General malaise.
Headache.
Myalgia.
Diarrhoea (may mimic gastroenteritis).
Cough.
Jaundice.
In children, also lethargy, drowsiness, nausea, vomiting, abdominal pain, sore throat, hepatomegaly, and splenomegaly.
If malaria is severe, there may be:
Depressed consciousness or coma.
Seizures.
Shock.
Severe pallor.
Respiratory distress, deep sighing, or laboured breathing.
Prostration.
In a child, posturing (decorticate or decerebrate).
People with suspected malaria who are very ill, pregnant, or at risk of malaria due to Plasmodium falciparum require immediate referral or admission.
If the person is drowsy or comatose Dextrogel®, Glucogel®, or intravenous dextrose should be given unless blood glucose is confirmed to be normal.
If the person is shocked: cefotaxime should be given intravenously (or intramuscularly if intravenous access is not possible) as these people may have a secondary bacterial infection.
For people not requiring immediate referral or admission, diagnosis should be confirmed by a blood sample to test for malaria.
A diagnosis of malaria cannot be excluded until an experienced haematologist or parasitologist has examined at least three films from specimens taken 12–24 hours apart and found them to be negative.
Treatment for confirmed non-falciparum malaria will usually be advised by a specialist and includes:
Chloroquine.
Primaquine for people with malaria due to Plasmodium vivax or Plasmodium ovale.
Paracetamol or ibuprofen for fever.
All cases of malaria should be notified to the public health authorities.
Have I got the right topic?
This CKS topic is based on the UK malaria treatment guidelines from the British Infection Society [Lalloo et al, 2007].
This CKS topic covers the primary care management of suspected imported malaria in the UK.
This CKS topic does not cover the management of malaria in secondary care or the prevention of malaria in people travelling abroad.
There is a separate CKS topic on Malaria prophylaxis.
The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.
How up-to-date is this topic?
How up-to-date is this topic?
Changes
July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the Medicines and Healthcare products Regulatory Agency [MHRA, 2011]. Prescriptions have been updated to reflect the revised dosing. Issued in July 2011.
November 2009 to March 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.
Update
New evidence
Evidence-based guidelines
Guidelines published since the last revision of this topic:
RCOG (2010) The diagnosis and treatment of malaria in pregnancy. Royal College of Obstetricians and Gynaecologists www.rcog.org.uk [Free Full-text (pdf)] **The recommendations in this CKS topic are in line with those recommendations relevant to primary care from this RCOG guideline**
WHO (2010) Guidelines for the treatment of malaria. Second edition. World Health Organization www.who.int [Free Full-text]
HTAs (Health Technology Assessments)
No new HTAs since 1 October 2009.
Economic appraisals
No new economic appraisals relevant to England since 1 October 2009.
Systematic reviews and meta-analyses
Systematic reviews published since the last revision of this topic:
Sinclair, D., Donegan, S., and Lalloo, D.G. (2011) Artesunate versus quinine for treating severe malaria (Cochrane Review). The Cochrane Library. Issue 3. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]
Sinclair, D., Gogtay, N., Brand, F., and Olliaro, P. (2011) Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria (Cochrane Review). The Cochrane Library. Issue 7. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]
van Eijk, A.M. and Terlouw, D.J. (2011) Azithromycin for treating uncomplicated malaria (Cochrane Review). The Cochrane Library. Issue 2. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]
Primary evidence
Randomized controlled trials published since the last revision of this topic:
Smithuis, F., Kyaw Kyaw, M., Phe, O., et al. (2010) Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infectious Diseases 10(10), 673-681. [Abstract] [Free Full-text]
Tshefu, A.K., Gaye, O., Kayentao, K., et al. (2010) Efficacy and saftey of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferioity trial. Lancet 375(9724), 1457-1467. [Abstract]
New policies
No new national policies or guidelines since 1 October 2009.
New safety alerts
No new safety alerts since 1 October 2009.
Changes in product availability
No changes in product availability since 1 October 2009.
Goals and outcome measures
Goals
To identify people who may have malaria
To immediately refer those who are at risk of falciparum malaria
To treat benign malaria appropriately
Background information
Definition
What is it?
Malaria is a tropical disease caused by infection of red blood cells by a protozoan parasite from the Plasmodium species, which is transmitted to humans following a bite from its vector, various species of the anopheles mosquito.
Cerebral malaria
This is defined as [WHO, 2006]:
Malaria due to Plasmodium falciparum with coma that is not attributable to any other cause (Glasgow coma score less than 11, Blantyre coma score less than 3), OR
Malaria with coma persisting for more than 30 minutes after a seizure.
However, in clinical practice malaria with any impairment of consciousness is considered to be cerebral malaria.
Cryptic malaria is a term used when malaria is diagnosed, but there is no travel history to identify a possible exposure. This is very rare and is thought to be related to an inadequate travel history, late detection, importation of the mosquito to the UK, or transmission via infected blood or an unknown mechanism [HPA, 2006a].
Airport malaria occurs when a person who has not recently travelled to an endemic area is infected with malaria from the bite of an infected mosquito which has been imported in an aircraft. The person is bitten in or around the vicinity of an international airport [Gratz et al, 2000; HPA, 2006a].
Glasgow and Blantyre coma scales
Glasgow and Blantyre coma scales
The Glasgow Coma Scale
Using the Glasgow Coma Scale (GCS)
The GCS is used to assess level of consciousness. People are scored according to their best eye, verbal, and motor responses, with the lowest possible score being 3/15 (deep coma or death), and the highest being 15/15 (fully awake).
The person's GCS score should be fully documented, with the individual scores for best eye, verbal, and motor responses stated; for example, a best score of 4 for eye response, 5 for verbal response, and 5 for motor response should be recorded as E4, V5, M5 and the total cumulative GCS score given with the denominator (15) always included (for example a score of 14/15).
GCS for adults and children who are able to talk (usually 5 years of age and older)
Best eye response — does not open eyes, score 1; opens eyes in response to painful stimuli, score 2; opens eyes in response to voice, score 3; opens eyes spontaneously, score 4.
Best verbal response — makes no sounds, score 1; incomprehensible sounds, score 2; inappropriate words, score 3; confused and disorientated, score 4; orientated and converses normally, score 5.
Best motor response — makes no movement in response to pain, score 1; extension in response to painful stimuli, score 2; abnormal flexion in response to painful stimuli, score 3; flexion or withdrawal in response to painful stimuli, score 4; localizes painful stimuli, score 5; obeys simple commands, score 6.
The Blantyre Coma Scale
Using the Blantyre Coma Scale (BCS)
The BCS is a modification of the GCS for use with children who are too young to talk.
A score of 2 or less indicates 'unrousable coma'. The maximum score is 5.
The BCS for preverbal children
Best eye movement — fails to watch or follow, score 0; watches or follows, score 1.
Best verbal response — no vocal response to painful stimulus, score 0; moans or abnormal cry with painful stimulus, score 1; cries appropriately with painful stimulus, score 2.
Best motor response — no response or inappropriate response, score 0; withdraws limb from painful stimulus, score 1; localizes painful stimulus, score 2.
Causes
What causes it?
Four species of malarial parasite cause almost all malarial infections in humans [White, 2009].
Plasmodium falciparum causes most cases of malaria imported into the UK — this type of malaria has no dormant stage and is the most likely to result in severe illness or death.
Plasmodium vivax and Plasmodium ovale may cause relapsing malaria.
Plasmodium malariae is less commonly seen in the UK and may present with late recrudescences many years after the person has left an endemic area [Chiodini et al, 2007; Fairhurst and Wellems, 2009].
In Malaysia, the macaque monkey malarial parasite Plasmodium knowlesi causes significant morbidity and mortality in humans [Fairhurst and Wellems, 2009].
Mixed infections with more than one species are common worldwide but are relatively rare in people with malaria in the UK. A mixed infection usually involves Plasmodium falciparum [Chiodini et al, 2007; Lalloo et al, 2007; White, 2009].
Malaria parasite life cycle
What is the life cycle of the malaria parasite?
An infected female mosquito releases 8–100 sporozoites (the infecting agent) into the person's bloodstream in one bite [White, 2009].
The sporozoites are transported in the bloodstream and enter the person's liver cells, where they multiply (asexually) to form a hepatic schizont which contains tens of thousands of merozoites [White, 2009].
This stage lasts 5.5 days in Plasmodium falciparum infection and 15 days in Plasmodium malariae infection. The incubation period for malaria is therefore at least 6 days [Lalloo et al, 2007].
In Plasmodium vivax and Plasmodium ovale infection only, some sporozoites develop into hypnozoites, which are a dormant stage and may start multiplying months or even years after the initial infection.
The hepatic schizonts rupture, and each one releases thousands of merozoites into the bloodstream.
Each merozoite has the potential to penetrate a red blood cell, where it develops into a schizont over a period of 48 hours (P. falciparum, P. vivax, or P. ovale), 72 hours (P. malariae), and 24 hours (P. knowlesi) [Fairhurst and Wellems, 2009]. The red blood cell schizonts rupture synchronously (coinciding with the classical malarial paroxysm of chills, rigors, fever, and drenching sweats) each releasing a further 24–32 merozoites which are each capable of infecting a new red blood cell [Fairhurst and Wellems, 2009].
In P. falciparum infection, infected red blood cells attach to vascular endothelium in vital organs, a process known as sequestration. The parasites therefore disappear from the circulation. The brain is affected the most, but the kidneys and other organs are also affected [White, 2009].
After several cycles, some of the merozoites do not divide, but develop into male and female gametocytes instead — these may persist in the circulation for several weeks and can mate (reproduce sexually) when taken up by the biting mosquito to form sporozoites, thus completing the cycle [White, 2009].
For a diagram of the life cycle of the malaria parasite, see http://commons.wikimedia.org.
Prevalence
How common is malaria in the UK?
In 2008, 1370 people with malaria in the UK were reported to the Malaria Reference Laboratory, and there were six deaths [HPA, 2009].
Over 70% (1087) of these cases were due to infection with Plasmodium falciparum.
Most P. falciparum infections were acquired in west Africa.
The most likely group of people to be affected were those visiting friends and family abroad, particularly in Nigeria and Ghana.
Where ethnicity had been recorded, 924 people with imported malaria were African or of African descent, 129 people were reported as white British, and 131 people were reported as south Asian or of south Asian descent.
Most of those from whom a history of prophylaxis use was obtained had either taken no prophylaxis (83% [668/809]) or had taken a drug for prophylaxis not recommended for their area of travel.
Statistics from the years 2003 and 2004 show that about two-thirds of people in England and Wales who have malaria live in London [HPA, 2006b]. Therefore general practitioners (GPs) who work outside London will only rarely see imported malaria.
Immunity
Is it possible to acquire immunity to malaria?
Disease-controlling immunity to malaria can develop with continual exposure to infection. This immunity prevents the development of symptomatic and severe disease, despite the presence of malarial parasites in the bloodstream. However, it does not clear all of the parasites from the bloodstream [Fairhurst and Wellems, 2009].
Immunity develops slowly during natural untreated infections [White, 2009].
Cross-strain protection is weak or negligible [White, 2009].
Disease-controlling immunity is believed to be short lived without continual exposure to infection [Fairhurst and Wellems, 2009].
People from endemic countries who have lived in the UK for a while are at a high risk of severe malaria if they return home.
This group of people are often unaware of the importance of antimalarial prophylaxis for themselves and their children [HPA, 2009].
Prognosis
What is the prognosis?
Plasmodium falciparum
Untreated, the prognosis of infection with P. falciparum is poor, with rapid progression to severe disease and death.
The parasites of P. falciparum sequestrate and this leads to extensive microvascular obstruction, and regional and systemic inflammatory effects such as cerebral malaria and renal failure [Fairhurst and Wellems, 2009].
With prompt treatment, the death rate in the UK is less than 1% [Lalloo et al, 2007].
Symptoms can recur after treatment due to incomplete clearance of the parasite (recrudescence) [WHO, 2006]. Recrudescence means that the parasites disappear from the blood initially, but then come back, and suggests a failure of drug treatment. Recrudescence usually occurs 2–4 weeks after the initial treatment, but may occur 10 weeks after treatment with mefloquine [White, 2009].
Residual neurological deficit can occur following cerebral malaria. Non-UK based studies have shown that, following cerebral malaria [White, 2009]:
About 60% of children with severe neurological deficit had hemiparesis, hemisensory deficits, hemianopia, cortical blindness, and cranial nerve palsies which resolved rapidly, and by 6 months only 4% had a persistent neurological deficit.
Between 10% and 23% of children had a residual neurological deficit — 10% had a language defect and there was an increased risk of epilepsy. The long term prognosis is not known.
Post-malarial neurological syndromes, including psychosis, Parkinsonian rigidity, and cerebellar dysfunction, may rarely develop after cerebral malaria, particularly if mefloquine has been given [White, 2009].
These syndromes are usually self-limiting and resolve within 2 weeks [White, 2009].
Plasmodium vivax
Malaria due to P. vivax can be very debilitating but is rarely life threatening unless the person has serious comorbidities [Lalloo et al, 2007].
Occasionally, serious complications, such as acute lung injury or splenic rupture, occur.
Relapse can occur after a variable interval of weeks (tropical strains) or months (temperate strains) when dormant liver forms (hypnozoites) release merozoites into the bloodstream [WHO, 2006].
Plasmodium ovale
Malaria due to P. ovale is rarely life threatening unless the person has serious comorbidities [Lalloo et al, 2007].
Relapse can occur after a variable interval of weeks (tropical strains) or months (temperate strains) when dormant liver forms (hypnozoites) release merozoites into the bloodstream [WHO, 2006].
Plasmodium malariae
Malaria due to P. malariae is rarely life threatening unless the person has serious comorbidities [Lalloo et al, 2007].
Plasmodium knowlesi
Malaria due to P. knowlesi can result in serious illness and death [Fairhurst and Wellems, 2009].
Complications
What are the complications?
Anaemia. Anaemia is caused by erythrocyte destruction in the spleen and circulation, and defective red cell formation in the bone marrow [White, 2009].
Malaria due to Plasmodium falciparum may cause [White, 2009]:
Cerebral malaria due to sequestration of red blood cells containing the parasite in the brain.
Without treatment it is nearly always fatal.
With treatment it has a mortality rate of 15% in adults, 20% in children, and 50% in pregnant women.
Severe anaemia.
Renal failure.
Pulmonary oedema.
Hypoglycaemia.
Hypovolaemia.
Disseminated intravascular coagulation.
Metabolic acidosis.
Malaria due to Plasmodium vivax:
Can cause acute lung injury (by being sequestered there; rare).
Acquired in Papua New Guinea and Papua Indonesia has recently been associated with cerebral malaria and severe anaemia [Fairhurst and Wellems, 2009].
Rupture of the spleen may occur in all types of malaria but is commonly associated with P. vivax. Splenic rupture may occur with acute or chronic infections and may be spontaneous or follow minor trauma including, rarely, palpation of the spleen [Fairhurst and Wellems, 2009].
Nephrotic syndrome. Chronic Plasmodium malariae infection may lead to nephrotic syndrome in young children living in endemic areas [Fairhurst and Wellems, 2009].
In pregnancy [Lalloo et al, 2007; Poespoprodjo et al, 2008; Fairhurst and Wellems, 2009; White, 2009]:
Malaria due to P. falciparum may cause:
Maternal death. (Cerebral malaria has a mortality rate of 50% in pregnancy. Acute pulmonary oedema and hypoglycaemia are common in pregnancy.)
Miscarriage.
Stillbirth.
Premature delivery.
Intrauterine growth retardation.
Neonatal mortality.
Non-falciparum malaria may:
Increase anaemia.
Reduce birth weight.
Cause premature labour.
Cause stillbirth.
When to suspect
When to suspect malaria
When to suspect - adult
When should I suspect malaria in an adult?
Suspect malaria if the adult has travelled to an area where malaria is endemic (especially within the last 6 months), regardless of whether they have taken prophylaxis, and if they also have any of the following non-specific symptoms:
A fever or history of fever; however absence of fever does not exclude a diagnosis of malaria.
A malarial paroxysm may last several hours; chills and rigors, followed by a spike of fever up to 40°C and then profuse sweating.
In most people, there is no pattern to the fever.
General malaise.
Headache.
Myalgia (muscle pain and tenderness).
Diarrhoea (may mimic gastroenteritis, with diarrhoea predominating over febrile symptoms).
Cough.
Jaundice.
Symptoms of malaria take at least 6 days to develop after infection.
Examination may be normal.
Suspect severe malaria if the person has any of the following:
Impaired consciousness or unrousable coma (which may be due to cerebral malaria or hypoglycaemia).
Seizures.
Pallor (due to anaemia).
Breathlessness, deep sighing respiration, or laboured breathing.
Spontaneous bruising or bleeding.
Shock.
Haemoglobinuria (Coca-Cola® coloured urine).
Basis for recommendation
Basis for recommendation
Suspicion of malaria
Expert opinion in the UK malaria treatment guidelines recommends that the possibility of malaria should be considered in anyone with a fever or history of a fever, or who is unwell, who has previously visited a malaria-endemic area. Falciparum malaria may occur from 6 days to many months after exposure, although almost all people will present within 6 months of infection. Infections with Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae may present more than 6 months after exposure and may present many years later [Lalloo et al, 2007].
The non-specific symptoms of malaria are based on expert opinion in text books and national guidance [Lalloo et al, 2007; Fairhurst and Wellems, 2009; White, 2009].
Malarial paroxysms
In most people, fever does not occur regularly [Lalloo et al, 2007]. In others, fever occurs regularly in a tertian (48-hour) or quartan (72-hour) pattern coinciding with rupture of the schizonts [Fairhurst and Wellems, 2009].
Suspicion of severe malaria
Features of severe malaria usually take several days to develop in an adult. Some complications, such as acute renal failure and respiratory distress, often develop when the person is recovering in hospital.
Impaired consciousness, coma, and seizures are features of cerebral malaria caused by sequestration in the brain of red blood cells containing parasites [Lalloo et al, 2007]. Hypoglycaemia (thought to be due to hyperinsulinaemia as a result of stimulation of pancreatic islet cells by parasite-derived factor or by quinine) may contribute to impaired consciousness [Fairhurst and Wellems, 2009; White, 2009].
Anaemia is due to the accelerated destruction of, and decreased production of, red blood cells [White, 2009].
Dyspnoea/deep sighing (Kussmaul) respiration or laboured breathing may be due to:
Metabolic acidosis, caused by reduced delivery of oxygen to tissues secondary to anaemia (reduced oxygen carriage), sequestration (microvascular obstruction), and hypovolaemia (reduced perfusion) [Fairhurst and Wellems, 2009].
Renal impairment, caused by acute tubular necrosis probably secondary to microvascular obstruction caused by sequestration [White, 2009].
Respiratory distress may also be due to pulmonary oedema or acute respiratory distress syndrome caused by sequestration of parasites in the lungs. There may be respiratory failure [Fairhurst and Wellems, 2009].
Spontaneous bleeding or disseminated intravascular coagulation is due to activation of the coagulation cascade and thrombocytopenia (due to increased splenic clearance) [Chiodini et al, 2007; White, 2009].
Secondary bacteraemia or septicaemia may cause shock; however, secondary bacterial infection is rare in adults with malaria (probably occurring in less than 1% of people) [Lalloo et al, 2007; White, 2009].
Haemoglobinuria is due to massive haemolysis (Blackwater fever) [White, 2009].
When to suspect - child
When should I suspect malaria in a child
Suspect malaria if the child has travelled to an area where malaria is endemic (especially within the last 6 months), regardless of whether they have taken prophylaxis, and if they also have any of the following non-specific symptoms:
Fever or history of fever.
Lethargy.
General malaise.
Drowsiness.
Nausea, vomiting, abdominal pain, or diarrhoea.
Sore throat.
Jaundice.
Other clinical features that support the diagnosis in children but which are often absent in the early stages of the disease include:
Hepatomegaly.
Splenomegaly.
Symptoms of malaria take at least 6 days to develop after infection.
Severe malaria may develop 6–12 hours after a child first develops symptoms. Suspect this if the child presents with:
Depressed consciousness or coma.
Seizures.
Severe pallor (due to anaemia).
Respiratory distress, deep sighing, or laboured breathing.
Prostration (inability to stand or sit).
Circulatory shock, which may be due to concurrent secondary bacterial infection (septicaemia or meningitis).
Posturing (decorticate or decerebrate).
Basis for recommendation
Basis for recommendation
Suspicion of malaria
The recommendation that the possibility of malaria should be considered in anyone with a fever or history of a fever, or who is unwell, who has previously visited a malaria-endemic area is based on expert opinion in the UK malaria treatment guidelines [Lalloo et al, 2007].
The non-specific symptoms of malaria are based on expert opinion in text books and national guidance [Lalloo et al, 2007; Fairhurst and Wellems, 2009; White, 2009].
Falciparum malaria may occur from 6 days to many months after exposure, although almost all people will present within 6 months of infection. Infections with Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae may present more than 6 months after exposure and may present many years later [Fairhurst and Wellems, 2009].
Suspicion of severe malaria
Children with malaria due to P. falciparum may deteriorate rapidly — within 6 hours of developing symptoms [White, 2009].
Impaired consciousness, coma, seizures, and decorticate or decerebrate posturing are features of cerebral malaria caused by sequestration in the brain of red blood cells containing parasites [Lalloo et al, 2007]. Respiratory depression may occur due to increased intracranial pressure [Maitland et al, 2005]. Hypoglycaemia (thought to be due to increased uptake of glucose by hyper-metabolic peripheral tissues, or by impaired hepatic gluconeogenesis) may contribute to the impaired consciousness [Fairhurst and Wellems, 2009; White, 2009].
Anaemia is due to haemolysis and reduced production of red blood cells [Lalloo et al, 2007].
Respiratory distress is often due to metabolic acidosis [Maitland et al, 2005].
Prostration is a feature of severe malaria in children [Lalloo et al, 2007].
Shock may be secondary to complicating bacteraemia, septicaemia, or meningitis. The symptoms of bacteraemia, septicaemia, or meningitis may be impossible to differentiate from those of severe malaria; and the two may also occur concurrently [Pasvol, 2005; Lalloo et al, 2007].
Jaundice, pulmonary oedema, and renal failure are uncommon in young children [White, 2009].
Differential diagnosis
What else might it be?
Malaria is difficult to diagnose as it may mimic other illnesses common in the UK, including:
Influenza or another viral illness.
Gastroenteritis (if there is diarrhoea).
A lower respiratory tract infection (if there is a cough).
Meningitis and encephalitis (may also coexist with malaria).
Septicaemia (may also coexist with malaria).
Viral hepatitis (if jaundiced).
Malaria may present with similar symptoms to other travel-related infections, including:
African tick fever — is usually acquired in rural areas of southern Africa between April and November. It commonly presents with fever, headache, and muscle pain. The diagnosis is supported by lymphadenitis and multiple inoculation eschars. An inoculation eschar is a black crust surrounded by a red halo at the site of the tick bite which represents an area of epidermal and dermal necrosis.
Brucellosis — has a worldwide distribution and presentation can vary from an acute febrile illness with rigors to a chronic low-grade relapsing fever. The diagnosis is supported by lymphadenopathy, hepatomegaly, splenomegaly, and septic arthritis.
Chikungunya fever — is present in Africa, Saudi Arabia, India, and south east Asia. It commonly presents with severe arthralgia, muscle pain, and high fever. The diagnosis is supported by prominent backache, generalized lymphadenopathy, and conjunctivitis.
East African trypanosomiasis (sleeping sickness) — follows a bite from a tsetse fly in east or southern Africa. It commonly presents with fever, headache, muscle pain, poor appetite, and malaise. The diagnosis is supported by a red chancre at the site of the bite, a rash, and posterior cervical lymphadenopathy.
Enteric fever (typhoid and paratyphoid fever) — is present in developing countries worldwide. It commonly presents with fever, headache, malaise, muscle pain, and loss of appetite. The diagnosis is supported by marked gastrointestinal symptoms (such as abdominal pain, constipation, and diarrhoea), rose spots, and a relative bradycardia (that is a slower pulse rate than would have been expected with a high fever).
Hepatitis — may present as an acute febrile illness. The diagnosis is supported by abdominal pain, jaundice, and tender hepatomegaly.
HIV seroconversion — may present as an acute febrile illness and should be considered in all men and women who report sexual contact with people from countries with a high prevalence of HIV.
Leptospirosis — can be acquired from fresh water or soil exposure in temperate and tropical regions worldwide. It commonly presents with fever, headache, nausea, and muscle pain. The diagnosis is supported by red conjunctiva and a rash. Weils disease may develop and may mimic severe malaria (hepatic and renal insufficiency, with jaundice and spontaneous bruising and bleeding).
Acute schistosomiasis (katayama fever) — is caused by parasitic blood flukes present in fresh water in tropical regions worldwide. It presents with fever, headache, muscle pain, malaise, and poor appetite 4–8 weeks after exposure (paddling, swimming in fresh water). The diagnosis is supported by generalized urticaria and an itchy rash at the site of penetration, lymphadenopathy, and a blood eosinophilia.
Viral haemorrhagic fevers:
Dengue — is present during the rainy season in tropical countries worldwide. It commonly presents with fever, headache, nausea, malaise, and anorexia. The diagnosis is supported by severe myalgia (break-bone fever), centrifugal rash, petechiae, lymphadenopathy, and a relative bradycardia. The haemorrhagic form is rare in travellers.
Other viral haemorrhagic fevers, such as yellow fever (Africa, South America), Lassa fever (western Africa), and Crimean-Congo haemorrhagic fever (Eastern Europe, Asia, Africa). The diagnosis is supported by early 'alarm' symptoms such as pharyngeal ulcers, retrosternal chest pain, conjunctival injection, and prostration.
Basis for recommendation
Basis for recommendation
Diseases common in the UK
This information is based on expert advice in the UK malaria treatment guidelines [Lalloo et al, 2007], a textbook [Fairhurst and Wellems, 2009], and an expert review [Pasvol, 2005].
Tropical diseases
This information is based on information in Manson's Tropical Diseases [Fairhurst and Wellems, 2009; Smith et al, 2009; Solomon and Thomson, 2009], the British Infection Society guidelines [Johnston et al, 2009], and a descriptive report [Lepidi et al, 2006].
Information resources
Where can I find more advice about when to suspect malaria?
Advice may be available from the local infectious disease unit.
Useful websites with information about malaria-endemic areas include:
Centers for Disease Control and Prevention (CDC)
National Travel Health Network and Centre (NaTHNaC)
Travax (only accessible to registered users).
Expert advice is available from the UK specialist tropical disease units (24-hour specialist telephone advice):
The Hospital for Tropical Diseases (HTD) London: telephone 0845 1555 000, and ask for the tropical infectious diseases physician on call.
The Liverpool School of Tropical Medicine (LSTM): telephone 0151 7053100 (Monday to Friday) or 0151 7062000 (out of hours), and ask for the tropical infectious diseases physician on call.
The Oxford Centre for Clinical Vaccinology and Tropical Medicine: telephone 01865 741841, and ask for the infectious diseases consultant on call.
Basis for recommendation
Basis for recommendation
Expert information sources are recommended by the Advisory Committee on Malaria Prevention in Travellers from the UK [Chiodini et al, 2007], the British Infection Society [Johnston et al, 2009], and by CKS expert reviewers.
Management
Management
Scenario: Management: covers how to decide who needs urgent admission, and the investigation and management of adults and children who can be managed in primary care.
Scenario: Management
Scenario: Management of malaria
Determining risk of falciparum malaria
How do I determine if the person is at risk of falciparum malaria?
Take a full travel history to determine if the person is at risk of falciparum malaria.
Ask about:
Countries visited, areas of travel within those countries, stopovers, and dates of entering and leaving malaria-endemic areas.
Purpose of visit, such as holiday, business, visiting family.
Areas visited, whether they were rural or urban, type of accommodation, and activities undertaken.
Seek up-to-date information about malaria-endemic areas (see Information resources).
Assume the person is at risk of falciparum malaria if they have visited a country where Plasmodium falciparum is endemic.
There is currently no risk of falciparum malaria in Argentina, Armenia, Azerbaijan, Georgia, Iraq, South Korea, Russia (near the Azerbaijan border), Turkmenistan, and Uzbekistan.
Seek immediate specialist advice if there is uncertainty as to whether the person is at risk of malaria due to P. falciparum.
Basis for recommendation
Basis for recommendation
Determining the risk of falciparum malaria by taking a full travel history
These recommendation are based on the UK malaria treatment guidelines [Lalloo et al, 2007], the Fever in returned travellers presenting in the United Kingdom: recommendations for investigation and initial management guidelines [Johnston et al, 2009], and the Guidelines for malaria prevention in travellers from the United Kingdom from the Health Protection Agency [Chiodini et al, 2007].
People with malaria who have visited Africa are at high risk for severe malaria as over 90% of infections will be caused by Plasmodium falciparum [Whitty et al, 2006].
Countries where there is a risk of benign malaria but not of falciparum malaria
This list was obtained from the Centers for Disease Control and Prevention (CDC) website.
Whether to refer immediately
Who should I refer immediately (without investigating)?
Refer immediately without undertaking investigations in primary care:
All those people who are very ill.
All pregnant women.
All people at risk of having malaria due to Plasmodium falciparum: this can be determined from the travel history.
Refer immediately, even if they are not very ill, since they are at risk of deteriorating rapidly especially at the beginning of treatment.
This includes people previously resident in, or born in, countries which have endemic falciparum malaria as they may have lost their disease-controlling immunity.
Compliance with malaria prophylaxis does not change the decision to refer the person, but it is important to document when prophylaxis was started, whether it was appropriate for the areas visited, missed doses (forgotten or vomited), or premature cessation.
If the person is drowsy or comatose:
Give Dextrogel®, Glucogel®, or intravenous dextrose, unless blood glucose is confirmed to be normal.
Arrange immediate admission to hospital.
If the person is shocked:
Give cefotaxime (or benzylpenicillin if cefotaxime is not available) intravenously (or intramuscularly if intravenous access is not possible) as these people may have a secondary bacterial infection.
Transfer immediately to hospital.
If the person is immunosuppressed (including people taking disease-modifying anti-rheumatic drugs, people taking post-transplant drugs or corticosteroids, those who are HIV positive, and people who have had a splenectomy):
Seek immediate advice from a specialist as these people need careful assessment.
For people who do not require immediate referral or admission, investigate, seeking specialist advice when appropriate.
Basis for recommendation
Basis for recommendation
These recommendations are mainly based on expert opinion.
All pregnant women with malaria should be referred to hospital immediately.
Falciparum malaria is severe in pregnancy, and is often complicated by recurrent hypoglycaemia, pulmonary oedema, premature delivery, and stillbirth [White, 2009].
Non-falciparum malaria may also cause premature labour. Pregnant women who take quinine are liable to develop hypoglycaemia [White, 2009].
CKS expert reviewers agreed that all pregnant women should be admitted for investigations, assessment of severity, and treatment.
All people with suspected falciparum malaria should be referred to hospital immediately.
This recommendation is based on expert opinion in the UK malaria treatment guidelines [Lalloo et al, 2007] and two narrative reviews [Moore et al, 2003; Whitty et al, 2006].
Falciparum malaria may progress rapidly, despite treatment, especially in infants, pregnant women, and elderly people.
Complications of malaria — especially in adults (such as acute lung injury and renal failure) — can occur after several days, even when the person is improving clinically in other ways.
Oral treatment may be poorly tolerated, especially if there is nausea and vomiting.
Immunity to malaria wanes if people are not re-exposed constantly. It is therefore not possible to judge the level of immunity from where the person used to live or based on their ethnicity.
Malarial prophylaxis
People are at risk of malaria even if they have taken the prophylaxis recommended for their area of travel properly, and are even more at risk if they have not.
CKS recommends taking an accurate history of the malarial prophylaxis taken and any reasons for discontinuation, because this information is necessary for determining appropriate management.
Treatment of hypoglycaemia
Hypoglycaemia is an important manifestation of severe malaria. Hepatic glycogen stores are exhausted rapidly, particularly in children [White, 2009].
Several CKS expert reviewers advised that healthcare professionals should attempt to correct blood glucose levels if this if suspected or confirmed; but this should not delay transfer to hospital.
Suspected secondary infection
The recommendation to give a broad spectrum antibiotic immediately to people who are shocked is based on expert opinion [Pasvol, 2005; Lalloo et al, 2007]. This is because immunosuppression may accompany severe malaria and cause bacterial septicaemia or meningitis. Severe malaria can also mimic bacterial septicaemia or meningitis.
Several CKS expert reviewers advised that immediate intravenous (or intramuscular if intravenous access is not possible) administration of cefotaxime is preferable to benzylpenicillin. This is because cefotaxime has a broader spectrum of activity.
People who are immunosuppressed
CKS expert reviewers were divided over whether people who are immunosuppressed should be admitted for investigations. CKS therefore recommends that healthcare professionals discuss each person immediately with a specialist.
Investigations
What investigations should I do on someone who does not require immediate referral?
Only investigate people who are relatively well, who are not pregnant, and who are not at risk of falciparum malaria.
In practice, most people will require immediate referral.
There is currently no risk of falciparum malaria in Argentina, Armenia, Azerbaijan, Georgia, Iraq, South Korea, Russia (near the Azerbaijan border), Turkmenistan, and Uzbekistan.
Urgently refer all people who are unwell, pregnant, or at risk of falciparum malaria for investigation and management.
Send a blood sample to test for malaria, urgently.
Ensure all blood test results can be reported within 4 hours. If there is a possibility of delay then refer the person to hospital for immediate testing.
Send 3.5 mL of venous blood in an EDTA (ethylenediaminetetraacetic acid) tube for:
Expert microscopy of thick and thin blood films.
Rapid diagnostic testing. This test can be used in addition to, but not instead of, microscopy.
Also request a full blood count as anaemia and thrombocytopenia are common in all forms of malaria.
Check urea and electrolytes or liver function tests if there is pre-existing renal or hepatic disease.
Discuss the results and further management at each stage with a specialist.
A diagnosis of malaria cannot be excluded until an experienced haematologist or parasitologist has examined at least three films from specimens taken 12–24 hours apart and found them to be negative.
A single negative blood film or antigen test does not exclude malaria.
If the first test is negative, repeat the blood film after 12–24 hours.
If the second test is negative, repeat the blood film again after a further 24 hours.
Basis for recommendation
Basis for recommendation
Countries where there is a risk of benign malaria but not of falciparum malaria
This list was obtained from the Centers for Disease Control and Prevention (CDC) website.
Need for immediate assessment
Malaria is a medical emergency. If malaria is suspected, the person must be evaluated immediately [Lalloo et al, 2007].
Blood should be sent to the laboratory without delay. With storage, EDTA-anticoagulated blood alters the morphology of parasites [BCSH, 2005].
Thick and thin smears
The gold-standard diagnostic procedure is examination of thick and thin blood smears by an expert microscopist; this is highly sensitive and specific [Lalloo et al, 2007].
A thick smear is used for the detection of malarial parasites.
A thick smear is very sensitive at detecting low numbers of parasites [Pasvol, 2005].
In pregnancy, a thick blood film may be negative despite a large number of parasites in the placenta [Lalloo et al, 2007].
A thin smear is mainly used for:
The identification of species.
Measuring the intensity of infection or parasitaemia. The count is usually expressed as the percentage of red blood cells infected [Pasvol, 2005]. However, in malaria due to Plasmodium falciparum, many late stage parasites are sequestered in the brain, kidneys, and other organs, and the parasite count may not reflect the parasite load [Moore et al, 2003].
Prognostic information.
Rapid diagnostic tests (RDTs) as an adjunct to thick and thin blood films
Expert opinion in current guidelines from the British Infection Society states 'the best RDTs are almost as sensitive as expert malaria microscopy for falciparum malaria, but less sensitive for non-falciparum malaria' [Johnston et al, 2009]. They are an adjunct to, but not a replacement for, the microscopic examination of blood films. Their disadvantages are that [Gatti et al, 2002; BCSH, 2005; Johnston et al, 2009]:
Occasionally, false-positive results occur. In addition, persistent antigens from a previous infection may give a false-positive test result.
They are less sensitive than microscopy.
It is not possible to determine the extent of the parasitaemia.
They cannot discriminate between mixed infections and those of P. falciparum alone.
Recently, a specific test for P. vivax has been developed. Many tests also include pan-malarial antibody which detects all species of malaria [White, 2009].
Send blood for a full blood count
This recommendation is based on an algorithm for the initial assessment and management of malaria in adults from the Health Protection Agency [British Infection Society and HPA, 2007] and a textbook [White, 2009]. In acute malaria [White, 2009]:
There is a progressive normochromic, normocytic anaemia.
The platelet count is reduced in all types of malaria, but is sometimes profoundly low.
CKS expert reviewers agreed that other blood tests were not routinely necessary unless there was pre-existing renal or hepatic disease.
Malaria cannot be excluded until three blood films are negative
These recommendations are based on expert opinion in a the UK malaria treatment guidelines [Lalloo et al, 2007] and an algorithm from the Health Protection Agency [British Infection Society and HPA, 2007].
Treatment in primary care
How should I treat someone not at risk of falciparum malaria who does not need immediate referral?
Treatment for confirmed non-falciparum malaria will usually be advised by a specialist.
Treat fever with paracetamol or ibuprofen.
Prescribe a 3-day course of chloroquine. For more information, see Prescriptions.
People with malaria due to Plasmodium vivax or Plasmodium ovale will need a course of primaquine after their chloroquine course to clear the hypnozoites from the liver.
Before prescribing primaquine:
Test the person for glucose-6-phosphate dehydrogenase deficiency (G6PD). Send 3.5 mL of venous blood in a tube containing EDTA (ethylenediaminetetraacetic acid).
If G6PD is confirmed, primaquine should either be avoided or given under expert supervision.
Seek specialist advice regarding the dosage and timing of treatment. The dose may differ depending on the type of malaria. Primaquine is only available on a named-patient basis from specialist importing companies or specialist manufacturers.
Pregnant women should not receive primaquine; they should take weekly chloroquine until delivery of the baby.
Notify all cases of malaria to the public health authorities. Blood films should be sent by the local laboratory to the Malaria Reference Laboratory for confirmation.
Ask the person to warn anybody that travelled with them that they are at risk of developing malaria, and that if they develop any symptoms they should seek immediate medical advice.
Basis for recommendation
Basis for recommendation
Treatment of fever
This recommendation is based on expert opinion from the World Health Organization treatment guideline [WHO, 2006].
Use of chloroquine
The recommendation for the use of chloroquine is based on expert opinion in the UK malarial treatment guidelines [Lalloo et al, 2007]. Chloroquine is accepted as the first choice treatment for malaria due to Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. The author of a narrative review [Whitty et al, 2006] commented that it became established as standard treatment before the development of modern trial methods. Case series suggest it remains effective in 98% of people with benign malaria; although it occasionally fails to treat P. vivax malaria, especially if acquired in eastern Asia where true resistance has been reported [Whitty et al, 2006].
Use of primaquine
It is important to test for glucose-6-phosphate dehydrogenase deficiency as primaquine may cause acute haemolysis in these people [Lalloo et al, 2007]. The details of the blood test are based on expert advice in a textbook [Pagana and Pagana, 2002].
The recommendation for the use of primaquine is based on expert opinion. CKS found no systematic reviews on the use of primaquine. Most case series were carried out before 1977 [Whitty et al, 2006]. Despite this lack of evidence, primaquine is recommended as the only available, effective treatment licensed in the UK for the radical cure of the hypnozoite stage of malaria due to P. vivax or P. ovale.
CKS recommends that specialist advice should be sought regarding the dosage and length of the course of treatment as the expert advice in a textbook [White, 2009] and a narrative review [Baird and Hoffman, 2004] is that previous commonly-used regimens have not provided an adequate dose.
Management of pregnant women with malaria due to P. ovale or P. vivax
Primaquine should not be used in pregnancy because there are no safety data. Expert consensus is that chloroquine is a better option [Lalloo et al, 2007; Micromedex, 2009].
In the third trimester there is a risk of neonatal haemolysis and methemoglobinemia with primaquine [BNF 58, 2009].
The recommendation to continue chloroquine until delivery is based on expert opinion in the UK malaria treatment guidelines [Lalloo et al, 2007].
Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).
Chloroquine
Chloroquine
Chloroquine is generally well tolerated, with gastrointestinal adverse effects and headache being most commonly reported. People of African ethnicity may experience a sensation of itching; the origin of this is unknown.
The benefits of chloroquine for the treatment of malaria outweigh the risks for people with epilepsy, psoriasis, or retinopathy, and for pregnant or breastfeeding women.
Seizures are uncommon except in people with pre-existing epilepsy.
Although retinopathy has been reported to be an adverse effect of long-term chloroquine treatment, it is not usually associated with short courses (for the treatment or prophylaxis of malaria).
Seek specialist advice on monitoring and/or dose adjustment if the person has severe kidney or liver disease (especially cirrhosis), or myasthenia gravis.
Consider drug interactions before prescribing chloroquine:
Do not use chloroquine with amiodarone (risk of arrhythmias), leflunomide or penicillamine (risk of hepatotoxicity), or mefloquine (risk of seizures).
Chloroquine may increase plasma levels of ciclosporin and digoxin. Monitor for ciclosporin or digoxin toxicity.
Cimetidine may increase plasma levels of chloroquine. Monitor for chloroquine toxicity.
Advise the person that antacids may also reduce the absorption of chloroquine. They should be taken at least 4 hours apart.
Evidence
Evidence
Supporting evidence
CKS found no studies on the diagnosis of malaria. Therefore, recommendations about diagnosis (including investigations) are based on expert opinion found in textbooks and narrative reviews.
Evidence on drugs to treat malaria has not been summarized. The available evidence is not helpful for informing the choice of drug treatment for imported malaria in the UK [Whitty et al, 2006], because:
Meta-analyses and systematic reviews are of limited value. This is because resistance patterns are changing and also vary between geographical areas.
Most trials of antimalarial drugs have been conducted in endemic areas in semi-immune people and therefore may overestimate the efficacy of the drug tested. People with immunity will clear parasites more quickly.
Many drugs tested in trials are not appropriate for use in non-immune people.
Chloroquine and primaquine are accepted treatments, but most of the trials on these drugs are old and were not conducted to modern standards.
Search strategy
Scope of search
A literature search was conducted for guidelines and systematic reviews on primary care management of Malaria.
Search dates
Dates not restricted to October 2009
Key search terms
Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.
exp malaria/, malaria.tw.
Table 1. Key to search terms.| Search commands | Explanation |
|---|---|
| / | indicates a MeSh subject heading with all subheadings selected |
| .tw | indicates a search for a term in the title or abstract |
| exp | indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree |
| $ | indicates that the search term was truncated (e.g. wart$ searches for wart and warts) |
Sources of guidelines
National Institute for Health and Clinical Excellence (NICE)
Scottish Intercollegiate Guidelines Network (SIGN)
National Guidelines Clearinghouse
British Columbia Medical Association
Institute for Clinical Systems Improvement
Guidelines International Network
National Library of Guidelines
National Health and Medical Research Council (Australia)
University of Michigan Medical School
Michigan Quality Improvement Consortium
National Resource for Infection Control
NHS Scotland National Patient Pathways
Agency for Healthcare Research and Quality
UK Ambulance Service Clinical Practice Guidelines
RefHELP NHS Lothian Referral Guidelines
Medline (with guideline filter)
Sources of systematic reviews and meta-analyses
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
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
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
DynaMed
Central Services Agency COMPASS Therapeutic Notes
Sources of national policy
Health Management Information Consortium (HMIC)
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