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Malaria
  1. Tom E Fletcher and
  2. N J Beeching
  1. Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, UK
  1. Correspondence to Dr Nick J Beeching, Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK; tomfletcher{at}doctors.org.uk

Abstract

Malaria is a life-threatening disease, with its largest impact being due to Plasmodium falciparum infection in Africa. Military populations continue to be at a high risk of malaria and reported case series have frequently revealed poor compliance with preventative measures. The symptoms of malaria are non-specific and its management depends on awareness of the diagnosis and early recognition and treatment. This is aided by new and simple rapid diagnostic tests, but these should not replace the examination of blood films if these are available. Artemisinin combination therapy provides a more rapid and dependable cure of uncomplicated P falciparum infection, with artesunate now being the drug of choice in severe infection.

  • Malaria
  • Military
  • Clinical presentation
  • Plasmodium Falciparum
  • Rapid Diagnostic tests
  • Severe malaria

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Key messages

  • Malaria is a life-threatening disease with its largest impact occurring in children in Africa.

  • Military populations are a high risk group with poor compliance to preventative measures frequently reported.

  • An ‘ABCD’ approach for prevention of malaria should be used: Awareness of the risk, Bite avoidance, Compliance with chemoprophylaxis and prompt Diagnosis of malaria.

  • Artemisinin combination therapy is the treatment of choice for uncomplicated falciparum malaria with artesunate recommended in severe cases.

Introduction

Malaria is a common and life-threatening disease in many tropical and sub-tropical areas. Worldwide, more than two billion people are at a risk of malaria, and there are approximately 500 million clinical cases of malaria each year, with a million deaths.1 ,2 Endemic countries are visited by more than 125 million travellers each year3 and every year between 10 000 and 30 000 of these travellers fall ill with malaria after returning home.4

Malaria is caused by blood parasites of the genus Plasmodium, transmitted by the bite of infected female anopheline mosquitoes. Five species can infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi. P knowlesi commonly infects monkeys, but is now considered the fifth human malaria species having been found to cause illness in southeast Asia.5 In areas where malaria is highly endemic, groups at the highest risk include young children and pregnant women. In areas where there is year-round malaria transmission, older children and adults develop partial immunity due to repeated infection and are at a relatively low risk for severe disease.

Approximately three-quarters of reported infections in UK travellers are due to P falciparum and there are approximately 10 deaths annually. Two-thirds of cases occur in people of African or South Asian ethnic origin and over half of the cases occur in those who have been visiting friends and family in endemic areas. Most patients with P falciparum malaria acquire infection in Africa with West Africa being the commonest geographical source. Most P vivax infections are acquired in South Asia.6

In the past decade, in some Asian and African countries, the morbidity and mortality from malaria caused by P falciparum are starting to decline. This is associated with a surge in political commitment and international funding for malaria control, improved diagnostics and the increased use of artemisinin-based combination therapy (ACT). As a result, there has been renewed discussion about the possibility of malaria elimination. However, this progress must be balanced against increasing parasite resistance to artemisinins and insecticides. New drugs and insecticides are needed urgently, while use of an effective vaccine as part of national malaria control programmes remains an elusive goal.

This review aims to provide a general overview of malaria, including strategies for prevention and highlights recent advances in diagnosis and treatment. It has a military focus, but also recognises high risk civilian populations that may be encountered on humanitarian operations.

Military populations and outbreaks

Medical force protection is imperative for conservation of the fighting force, and military medical services have long worked hard to prevent their personnel from contracting or spreading diseases. In the process they have made seminal contributions in the prevention of infectious diseases, none more so than Sir Ronald Ross KCB FRS (Figure 1). He discovered the malarial parasite in the gastrointestinal tract of the Anopheles mosquito, which laid the foundation for combating the disease (Figure 2).

Figure 1

Sir Ronald Ross KCB FRS—courtesy and copyright Wellcome images.

Figure 2

Anopheles mosquito. This close-up photograph shows a female Anopheles albimanus, a malaria vector of central America, as she was feeding on a human host. Courtesy of James Gathany, CDC.

Military personnel continue to be deployed to malaria risk areas for prolonged periods of time.7–10 Historically, failure to appreciate the importance of malaria has led to disastrous results, and was well reported in fighting units in the South Pacific during World War II.8 Malaria also represented one of the most important medico-military problems for US forces stationed in Vietnam.11 Several factors contributed to the particular severity of malaria in the Vietnam War: the relative inexperience of line officers with regard to malaria and preventative measures in high-risk locations; P falciparum as the predominant circulating species; and the existence of chloroquine-resistant P falciparum species.11 During the course of the conflict, there were 65 000 admissions in US forces and the disease ranked second as a cause of man-days lost from duty in the US Army.11 A prominent feature during this period was the strong association of disease occurring in combat troops versus support troops and disease activity being related to the estimated size of local Viet Cong/North Vietnamese forces.12

More recently, failure to use personal protective measures (ie, topical insect repellent, bed netting and permethrin-treated clothing) and chemoprophylaxis contributed to outbreaks of malaria in US servicemen deployed to Afghanistan9 and UK soldiers in Kenya13 and Sierra Leone10 (Table 1). Military deployments can often occur at short notice. This limits pre-deployment preparation of troops and the required periods for chemoprophylaxis. Troops may be widely dispersed in jungle areas where environmental vector control is impossible, use of impregnated mosquito nets impractical and military activity highest during the hours when vectors themselves are most active.

Table 1

Outbreaks of malaria in deployed military populations

Another major factor is poor compliance with chemoprophylaxis among military personnel both during and after deployments,18 sometimes related to side-effects which are common.19 However, adherence to medical force protection measures can be improved through education and simplification of the chemoprophylaxis regimens.20 It has also been shown that chemoprophylaxis is frequently omitted in Role 4 hospitals in soldiers who are aeromedically evacuated.21

Military personnel returning from a malarious area to one that has no local malaria, but which has vectors with the potential to transmit the parasites, pose a special problem. In the past, malaria was endemic in coastal areas of southeast Britain, especially Essex, Kent and Sussex22 and several hundred cases of autochtonous (local) cases of malaria occurred in Kent after troops returned from Macedonia and other areas following the First World War.23 In endemic regions, transmission of malaria by blood transfusion remains a major problem for blood banks24 ,25 and occasional cases of transfusion-related malaria have been reported in non-endemic areas following blood donations by military personnel who have returned from overseas.26–28 Similarly, outbreaks of malaria have been reported in injecting drug users who have shared needles with veterans of overseas campaigns.29 ,30 Less common routes of infection that have affected military personnel include infection in a non-endemic area by mosquitoes that have recently arrived on a plane from elsewhere, termed ‘airport malaria’31 and being bitten while in transit, the so-called ‘runway malaria’.32

Prevention of malaria in travellers/military population

A useful strategy for the prevention of malaria is the ‘ABCD’ approach: Awareness of risk, Bite avoidance, Compliance with chemoprophylaxis and the prompt Diagnosis of malaria.

Assessment and awareness of risk

The two most common malarial species, P falciparum and P vivax, are endemic in distinct geographical regions with P falciparum predominating in sub-Saharan Africa, and P vivax in the Indian subcontinent, Mexico, Central America and China. Both species occur in Southeast Asia and South America.1 P ovale is primarily found in West Africa, P knowlesi in Asia and P malariae is more widespread. Malarial risk varies widely between regions within countries and from rural to urban environments. The key to a complete risk assessment is a detailed travel itinerary. This should include planned activities, excursions and accommodation, as well as the time spent in endemic areas and the time of year that travel is planned.33–35

Travellers to endemic areas often fail to appreciate the malaria risk and this is frequently cited as a reason for non-compliance with chemoprophylaxis. Less than half of travellers who acquire malaria have taken advice before travelling.33 In the UK, the majority of imported cases of malaria are travellers and UK residents visiting friends and relatives abroad. They are less likely to seek pre-travel advice and often fail to recognise malaria as a serious disease.36 ,37

Bite prevention

Anopheles mosquitoes bite mainly at night and during the early evening, and there are a number of bite prevention measures that reflect this. Covering up with permethrin impregnated clothing is effective and should be combined with repellent use. Several repellents have been shown to be effective but the chemical N,N-diethyl-M-toluamide or DEET (20%–50%) has been the most studied and gives 6–12 h of protection.38 It is safe for children over 2 months and pregnant women.39 Most ‘natural’ and other popular repellents have a limited duration of activity, and require too frequent re-application.

Sleeping under impregnated bed-nets has been shown to reduce the risk of malaria in endemic populations and this should be equally effective for travellers. When used consistently and in combination, these methods are highly effective at preventing malaria.40 These methods will also help to prevent other mosquito-borne infections such as dengue.

Chemoprophylaxis

In malaria-endemic areas, chemoprophylaxis remains an important strategy for preventing malaria. However, the drugs may induce recognised side-effects that limit adherence by travellers and military personnel. Due to these side-effects, certain anti-malarials are also contraindicated for specific military occupations, such as pilots. Another problem is that the drugs must be taken meticulously during travel and most regimens continue for a significant period after leaving an endemic area. This requires considerable personal discipline and malaria often develops after returning home as a result of early discontinuation of chemoprophylaxis.41

In many parts of the world, P falciparum has developed resistance to chloroquine, but in the 23 countries where there is no documented resistance, chloroquine may still be used. There are three main anti-malarials that are used in regions of P falciparum chloroquine resistance: atovaquone-proguanil (Malarone), doxycyline and mefloquine.

A recent Cochrane review42 showed that there was inconclusive evidence about which of these three drugs is either the most effective in preventing malaria or the safest in terms of serious adverse events. The review did provide some evidence that atovaquone-proguanil and doxycycline have better tolerability compared with mefloquine, and for all three drugs compared with choloroquine-proguanil. Compared with mefloquine, atovaquone-proguanil and doxycycline users had fewer neuropsychiatric adverse events. Atovaquone-proguanil users also had fewer adverse effects of any type and better total mood disturbance scores.

Another strategy used by some nations is terminal prophylaxis with primaquine, that is, taking a single dose of primaquine at the end of the travel period. It is generally indicated only in those who have prolonged exposure or who have visited areas of intense P vivax transmission.43 It eradicates residual gametocytes and hypnozoites in order to prevent relapses and potential onwards transmission to malaria receptive areas including parts of North America and Europe.

Atovaquone-proguanil (Malarone)

This is a relatively new once daily regimen that has the advantage of only needing to be taken for 1 week after leaving an endemic area due to its hepatic stage action. It is unlicensed in pregnancy due to insufficient data and can be given to children >11 kg weight. It is the most expensive licensed anti-malarial.

Doxycyline

This long acting antimicrobial of the tetracycline class is a once daily drug that is effective in suppressing the blood stages of malaria. Therefore, it needs to be taken before travel, during travel and for 1 month after leaving a malaria-endemic area. It can safely be used in pregnancy after the first trimester and in children >12 years. Doxycycline may also protect against other travel-related infections including rickettsial infections, Q fever, leptospirosis and traveller's diarrhoea.44 It can cause significant oesophageal irritation that limits adherence and personnel should mitigate this by taking the tablets with adequate fluids (at least 100 mL of water) in an upright sitting or standing position. Drug-induced photosensitivity is another relatively frequent side-effect, and its use can be complicated by vaginal candidiasis in women.45

Chloroquine and proguanil

This combination is generally well tolerated, cheap and suitable for pregnant or breastfeeding women. However, its use is limited by increasing P falciparum resistance to chloroquine and is a more complicated regimen than the alternatives.

Mefloquine

Mefloquine, taken once-weekly, suppresses the blood stages of malaria and needs to be taken before, during and for 1 month after travel to an endemic area. Mefloquine use in pregnancy is unlicensed but teratogenicity has not been proven. Its use is now supported by the Advisory Committee on Malaria Prevention for UK travellers in the second and third trimesters, and may be justified in the first trimester after taking expert advice. The main controversy about mefloquine is its neuropsychiatric side-effects46 and the US military has recently changed its policy. It now recommends that in areas where doxycycline and mefloquine are equally efficacious, doxycycline is the drug of choice.47

Diagnosis

When the diagnosis of malaria is considered, a blood test for malaria should be performed immediately. Traditionally this involved the examination of thick and thin blood films for malarial parasites, and this remains the gold standard routine diagnostic investigation in the UK. However, due to an increasing lack of expertise in blood film preparation and analysis, rapid diagnostic tests (RDTs) are now standard in most UK laboratories and on deployed operations, but their cost remains prohibitive in many countries (Figure 3).

Figure 3

A positive malaria rapid diagnostic test. Courtesy of Jayne Jones, Diagnostic Laboratory, Liverpool School of Tropical Medicine.

The currently available RDTs detect one or more of the parasite antigens, histidine-rich protein 2, lactate dehydrogenase or aldose and are usually specific for P falciparum infections, some non-P falciparum or mixed infections.48 RDTs are not as sensitive or specific as expert thick and thin film examination (Figures 4), but are used in parallel and in settings where microscopy is not available. The sensitivities of commercially available RDTs are reported as approaching 100% but they may remain falsely positive for several weeks after the infection has been treated owing to persistence in the blood of parasite antigens.49 ,50 Most RDTs perform well for the detection of P falciparum, but have reduced sensitivity for P vivax infection and low sensitivity for the three other species of Plasmodium. There is considerable variability in the efficacy of RDTs between manufacturers, but this can be mitigated through the use of quality controlled tests by well-trained personnel. RDTs are better for detection of P falciparum or P vivax infections, but may not detect other species of malaria. This was cited as one of the reasons for the late diagnosis of P ovale infections in French military personnel returning from West Africa.51

Figure 4

Giemsa-stained thin film revealing multiple ring-forms of Plasmodium falciparum. Courtesy of Steven Glenn, Laboratory and Consultation Division, CDC.

However, the interpretation of a positive RDT or blood film is, in some circumstances, very difficult. In countries where malaria is endemic, asymptomatic infection is common and the presence of parasites in the blood does not always equate with disease.50 A child with a fever and a cough with a positive blood film or RDT may in fact have pneumonia and not be ill due to the malaria infection. This leads to over-diagnosis and over-treatment of malaria, and often to failure to identify and treat the true cause of the illness.52

It is also well recognised that a single negative blood film/RDT does not rule out malaria; infected red blood cells sequester in the tissues in the later stages of the parasite life-cycle and may not be detectable in the blood at the time of the test.53 If the differential diagnosis includes malaria and initial tests are negative, repeat analysis should be undertaken at 12 h and again at a further 24 h.

Parasite nucleic acid detection by PCR is more sensitive and specific than microscopic examination for diagnosis54 and can rapidly identify antimalarial resistance,55 ,56 but is currently done in reference laboratories and reserved for retrospective diagnosis and epidemiological research. It is likely to become more common for routine diagnosis in the near future.

Box 1

Features of severe or complicated falciparum malaria in adults (adapted from Lalloo and Hill33)

Clinical

Impaired consciousness or seizures

Shock (BP <90/60)

Pulmonary oedema or acute respiratory distress syndrome (ARDS)

Haemoglobinuria

Spontaneous bleeding (DIC)

Laboratory

Parasite count >2% red blood cells

Hypoglycaemia (<2.2 mmol/l)

Acidosis (<7.3)

Aneamia – haemoglobin <80g/L

Renal impairment (Creatinine >265 µmol/L or oliguria <0.4 ml/kg hr)

(DIC – Disseminated Intravascular Coagulation)

Box 2

Questions for the clinician to consider when managing a possible case of malaria

  1. Have you adequately excluded the diagnosis of malaria?

  2. Have you taken into account factors that can give you false negative investigations (ie chemoprophylaxis)?

  3. If it is malaria, what species are you dealing with?

  4. What is the level of parasitaemia?

  5. Is antimalarial drug resistance likely to be an issue?

  6. Are there clinical or laboratory features of severe/complicated infection?

Clinical presentation

The minimum incubation period for malaria is 6 days. Most patients with P falciparum infection present in the first or second month after exposure, but P vivax or P ovale infections commonly present later than 6 months after exposure and presentation maybe delayed for years.57 The key to not missing the diagnosis is to consider it in any patient, with fever or history of fever, who has ever travelled to a malaria-endemic area (Box 1).

The symptoms of malaria are non-specific, but most patients complain of fever, headache and general malaise.58 Gastrointestinal disturbance, jaundice or respiratory symptoms occasionally occur and can lead to misdiagnosis with malaria erroneously diagnosed as non-specific viral infections, influenza, gastroenteritis or hepatitis.

Children are less likely than adults to complain of chills, arthralgia/myalgia or headaches and more likely to present with non-specific symptoms (fever, lethargy, malaise and somnolence). Gastrointestinal symptoms (nausea, abdominal pain, vomiting and diarrhoea) are particularly common.58

The physical examination of patients with uncomplicated malaria is often unremarkable apart from a fever which is almost always present, but the classic ‘textbook’ fever pattern is not seen in most patients. Physical findings may include mild anaemia and a palpable spleen. Children are more likely to have hepatomegaly, splenomegaly and somnolence than adults.59

If the diagnosis of falciparum malaria has been delayed, severely ill patients may present with jaundice, confusion or seizures. Delays in diagnosis are associated with an increased risk of developing severe malaria and requirement for intensive care. Box 1 summarises the features of severe falciparum malaria in adults that influence subsequent management.

Acute infections with P knowlesi can cause substantial morbidity and mortality.60 Vivax malaria is also increasingly recognised to be an important cause of chronic and acute illness in endemic settings, causing chronic anaemia, respiratory syndromes and coma.61 Similarly, life-threatening complications of vivax malaria are being reported more often in returned travellers, including military personnel.62 These include acute respiratory distress syndrome, renal failure, severe hepatitis, coma and splenic rupture.63 The pathogenesis is poorly understood but is not thought to relate to sequestration of parasites.

Recrudescence and relapse

Both recrudescent and relapsing infections manifest as a return of disease after its apparent cessation. Recrudescence usually occurs within days or weeks and P falciparum is the usual cause. It is due to parasites remaining in the bloodstream undetected due to ineffective treatment or host immunological response. In relapse, hypnozoites are released from liver cells causing a second wave of parasitaemia that may occur months after the primary infection and is associated with P ovale and P vivax.

Investigations

In all patients with malaria a full blood count, urea and electrolytes, liver function tests, clotting and blood glucose should be performed routinely.

Thrombocytopenia is a characteristic feature of malaria and is present in about 60%–70% of cases of imported malaria in both adults and children, but is rarely associated with bleeding, even at very low platelet counts.64 ,65 Anaemia is more common in children than in adults (78% occurrence in children vs 29% in adults).66

In patients who are ill, serum lactate, arterial blood gas, blood culture, urine culture and chest X-ray should also be performed. In febrile patients with impaired consciousness or seizures, meningitis should be considered and lumbar puncture performed. Concomitant infection is also well reported, with septicaemia complicating severe malaria, particularly in children.66 In endemic areas, Salmonella bacteraemia has been associated with P falciparum infections, particularly in children.67

Management

Supportive

In the UK, it is recommended that all patients with P falciparum malaria should be admitted to a hospital for a minimum of 24 h and that patients with severe or complicated malaria should be managed in a high dependency unit. Intensive care management is frequently required for those with complicated fluid balance, acute respiratory distress syndrome, severe acidosis and renal impairment. This is normally associated with higher parasite counts. There is a significant risk of hypoglycaemia both as a result of severe malaria and as a side-effect of quinine therapy, and blood glucose should be checked every 2 h initially. Cardiac monitoring is required during intravenous quinine administration due to the risk of arrhythmia, normally occurring in older patients with cardiac disease.

The parasite count (percentage of infected red blood cells) should be monitored daily in conjunction with other standard blood parameters. Too frequent parasite count monitoring may cause confusion, as the degree of parasitaemia may increase in the first 24 h of treatment, depending on the stage of the parasite development on admission.

Anti-malarials

The treatment of malaria depends on the species, severity and geographical origin of the disease. For current treatment specifics consult the latest edition of the British National Formulary and British National Formulary for children.

Non-falciparum malaria

The treatment of non-falciparum malaria involves treating the erythrocytic forms that cause symptoms, and in P vivax and P ovale infection, the eradication of liver forms (hypnozoites) to prevent relapse. Chloroquine is the drug of choice for blood forms of P ovale, P malariae and P knowlesi. It is effective in most cases of P vivax infection, but increasing resistance is well recognised in Papua New Guinea and Southeast Asia.61 ,68 Chloroquine should still be used as first-line therapy for P vivax infection, but in the event of failure, second-line therapy should be ACT.

Primaquine is the drug of choice for the elimination of hypnozoites of P vivax and P ovale infection. Patients must be screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to use due to the risk of haemolysis in those with G6PD deficiency. Primaquine should be started concurrently with chloroquine at a dose of 30 mg for 14 days for P vivax infections due to the increased risk of relapse at 15 mg/day dosing.69 US guidelines also recommend using this higher dose for P ovale infection70 but British guidelines suggest that 15 mg/day for 14 days is adequate for confirmed P ovale infection. British recommendations for treatment of patients with G6PD deficiency are close monitoring, or using an alternative regimen of 45–60 mg of primaquine weekly for 8 weeks. However, in some cases it may be appropriate to withhold primaquine treatment and to treat relapses promptly. Primaquine is contraindicated in pregnancy and in this situation suppressive chloroquine should be administered weekly until delivery.71

Falciparum malaria

Until recently, the standard therapy for uncomplicated falciparum infection has been quinine, in combination with doxycycline or clindamycin (in pregnancy), to achieve complete parasite clearance. Other drugs used in treatment include atovaquone-proguanil or, historically, mefloquine. However, WHO now recommends ACT for the treatment of uncomplicated P falciparum malaria, and this is being increasingly used in the UK.

Artemesinins are derived from a Chinese medicinal herb ‘qing hao’ and have been used to treat malaria since the 4th century AD. Their potency as anti-malarial drugs was re-discovered around 1971 by researchers in China. They are active against all stages of the parasite life cycle, including gametocytes. They are used worldwide in combination with other antimalarials in formulations such as artemether-lumefantrine (Riamet, Coartem) and artemether-amiodiaquine (ASAQ Winthrop). ACT is attractive as it has a shorter treatment duration (3 vs 7 days), more rapid action and better tolerability than quinine.72

Severe falciparum malaria

Intravenous quinine was previously the drug of choice for the treatment of severe P falciparum malaria, and is still regularly used when artesunate is not available and in non-severe cases who cannot tolerate oral medication. Intravenous quinine should be given as an infusion over 4 h with an initial loading dose of 20 mg/kg in 5% dextrose or dextrose–saline, unless the patient has been taking regular mefloquine prophylaxis, in which case 10 mg/kg should be given. It should then be followed by 10 mg/kg infused over 4 h every 8 h, until the patient improves and is able to take oral medication. It requires cardiac monitoring, particularly in older patients or those with pre-existing cardiac disease due to the risk of arrhythmia.

Artesunate is increasingly recommended for the treatment of severe malaria due to its survival advantage compared with intravenous quinine (relative risk reduction of 34.7%, number needed to treat one death was 13).73 ,74 There are also increasing concerns about the spread of quinine resistance from Southeast Asia.

In adults and children, the recommended treatment dose of artesunate is 2.4 mg/kg as an intravenous infusion at admission (time=0), then at 12 h and 24 h, then once a day. Intravenous dose adjustment is required after 48 h and in cases with severe hepatic or renal dysfunction. In situations where intravenous infusions are not possible it may be administered by the intra-muscular route or rectally. Unfortunately artemisinin-resistant malaria has already been demonstrated and is starting to emerge on the Thai-Cambodian border.75 There is no added benefit to be gained by giving quinine and artesunate together.

Intensive care management

Patients with severe malaria should be managed in a critical care environment to allow close monitoring and the early recognition of complications. Features of the pathophysiology of severe malaria are comparable with those seen in severe sepsis syndrome (Box 2). High levels of pro-inflammatory cytokines lead to increased vascular permeability, pathological vasodilatation and increased loss of intravascular fluids resulting in intravascular volume depletion.76 ,77

In patients with hypotension or signs of dehydration, volume expansion corrects the haemodynamic abnormalities and improves organ function. However, in severe malaria there is concern about over-aggressive fluid resuscitation precipitating pulmonary oedema and increasing intracranial pressure in cerebral malaria. This mandates careful volume supplementation, often combined with invasive monitoring volume status.78

Control of seizures should be achieved initially using intravenous benzodiazepines and, if recurrent, with phenytoin sodium or phenobarbital. Prophylactic anti-convulsants have no role. Metabolic abnormalities such as hypoglycaemia and acidosis are very common, and often multi-factorial in origin. Hypokalaemia is frequently seen in severe malaria, often becoming apparent on correction of acidosis.78

Early-positive pressure ventilation helps prevent the high mortality associated with acute respiratory distress syndrome in severe malaria79 and should be combined with utilisation of a lung-protective strategy. Additional care must be taken to control the partial pressure of carbon dioxide because a rise in PaCO2 may increase intracranial pressure and precipitate death.

A significant proportion of patients with malaria present with renal impairment. It is difficult at initial assessment, even in resource-rich settings, to differentiate between those patients with reversible pre-renal acute kidney injury to those with established acute tubular necrosis. The majority will respond to anti-malarial chemotherapy and fluid repletion alone, but patients with an elevated creatinine require close urine output monitoring. If urine output is poor and there is an associated deterioration in renal function, early initiation of dialysis improves mortality.80

Despite appropriate medical treatment and intensive care management, the mortality of severe malaria remains high. Although reported prior to artesunate use, Bruneel et al81 revealed a mortality of 11% for cases of severe malaria admitted to a French Intensive Therapy Unit. The main factors that were associated with death were shock, acidosis, coma, pulmonary oedema and coagulopathy.

In view of similarities between severe malaria and severe sepsis syndrome, administration of recombinant-activated protein C has been tried without success in severe malaria in isolated cases.82 ,83 Other adjuvant therapies such as mannitol, steroids, iron-chelating agents and N-acetyl cysteine have been tried but are also of unproven benefit.84

Exchange transfusion

There is a theoretical advantage in removing parasitised red blood cells in patients with extremely high parasite counts, but there is no evidence to support the use of an exchange transfusion.85 With the increasing utilisation of artesunate therapy in severe cases, and its rapid parasite clearance, any potential benefit is limited and it is therefore not recommended. If it is being considered, individual cases should be discussed with malaria experts at either the Liverpool or London School of Tropical Medicine.

Malaria in pregnancy

In endemic countries, an estimated 10 000 women and 75 000–200 000 of their infants die as a result of malaria infection during pregnancy.86 P falciparum malaria in pregnancy is more likely to be severe and complicated. Malaria in pregnancy increases the risk of maternal anaemia, stillbirth, spontaneous abortion, low birth weight and neonatal death.87

Current WHO guidelines88 recommend that in uncomplicated malaria, artemisinin-based combination treatment should be used in the second and third trimesters, but should be used in the first trimester only if it is the only effective treatment available. The treatment of choice for P falciparum malaria in the first trimester is quinine; doxycycline is contraindicated but clindamycin can be substituted for it, and is equally effective.

In severe malaria in pregnancy, artemisinins are preferred over quinine in the second and third trimesters because of the risk of hypoglycaemia associated with quinine. However, in the first trimester, until more evidence becomes available on the risk to benefit ratio of artemisinins, both artesunate and quinine may be considered as options.88

In non-falciparum malaria, primaquine (for eradication of P vivax or P ovale hypnozoites) is contraindicated. After treatment for these infections, a pregnant woman should take weekly chloroquine prophylaxis until after delivery, when hypnozoite eradication can be considered.71

Malaria in children

WHO has estimated that more than 80% of malarial deaths occur in children younger than 5 years of age in sub-Saharan Africa.89 In the UK, children account for around 15%–20% of all imported malaria cases. This group must be considered separately from adults because children have different risk factors for developing malaria and a higher risk of severe disease since they are more likely to be non-immune to malaria.

In developing countries, there has been little progress towards reducing current mortality rates (15%–30%) for children admitted to hospital with severe malaria and other life-threatening infections. The key to reducing mortality and morbidity from malaria is the prompt delivery of effective drug treatment, which increasingly is ACT and parenteral artesunate/quinine, depending on severity and drug availability. Most of the pharmacokinetic data and dosing schedules for artemisinin preparations have been developed from adult studies and paediatric dosing optimisation studies are required.90

More than 50% of deaths from severe childhood illnesses, including malaria, occur within 24 h of hospital admission,91 and respiratory distress and impaired consciousness (prostration or coma) are well-established recognisable clinical signs that suggest a poor prognosis, and should be used to rapidly identify those in need of immediate treatment.92

It is often difficult initially to distinguish between sepsis and severe malaria in children who sometimes have dual infections. Blood cultures should be taken at the time of admission and a lumbar puncture performed on all children with impaired consciousness. Empirical parenteral antibiotics should also be given to any seriously ill child with malaria using drugs such as third generation cephalosporins.

Rapid blood transfusion can be life-saving in severe malarial anaemia, but blood bank facilities in rural hospitals may be inadequate and blood donors used. Careful fluid management in children is important, especially following the results of a recent multi-centre study in Africa showing that fluid boluses significantly increased 48-h mortality in critically ill children with impaired perfusion.93 Nutritional requirements of children with severe malaria, who are frequently malnourished, also need to be considered.94

Conclusions

Malaria remains a major world health problem with its largest impact being due to P falciparum infection in African children who with pregnant women are the main at-risk groups. Military populations continue to be at a high risk of malaria and reported case series have frequently revealed poor compliance with preventative measures. Management of malaria depends on awareness of the diagnosis and early recognition and treatment of infection reduces progression to severe disease. This is aided by new and simple RDTs, but these should not replace the examination of blood films if available. Asymptomatic parasite carriage should be considered in endemic areas as should the possibility of dual bacterial infection in ill children. ACT provides a more rapid and dependable cure of uncomplicated P falciparum infection with artesunate now being the drug of choice in severe infection.

References

Footnotes

  • Contributors TF and NJB both planned and co-wrote the review article. NJB is overall guarantor.

  • Competing interests None.

  • Provenance and peer review Not commissioned; internally peer reviewed.