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Malaria
SPECIAL SITUATIONS
Malaria
What’s new?
Naomi F Walker C
Behzad Nadjm Christopher J M Whitty
C C
Abstract
C
Malaria remains a leading cause of mortality worldwide and a cause of morbidity in returning travellers in the UK. The management of malaria, recent advances in diagnosis and current areas of controversy are summarized, primarily for clinicians in non-endemic countries who do not routinely encounter it. The most important message is that malaria is very common and presentation is non-specific, so a malaria test is essential. Early diagnosis and prompt effective treatment prevent unnecessary deaths. Health promotion for travellers to endemic areas is essential to reduce the burden of imported malaria.
travel to malaria-affected regions steadily increase. Malaria is the leading potentially fatal cause of febrile illness in returned travellers.3 Although uncomplicated malaria is rarely fatal, European case fatality rates for falciparum malaria are around 1%, and up to 25% in an intensive care setting.4,5 Factors associated with the development of severe malaria include older age, increased time to presentation and delayed diagnosis, pregnancy and HIV infection. Most patients returning to Europe with malaria do not report taking malaria prophylaxis.6 This article, aimed at clinicians in non-endemic countries, addresses clinical aspects of malaria pathophysiology, presentation, diagnosis and management, highlighting recent developments and areas of controversy. Every death from malaria should be preventable if the condition is diagnosed early and treated promptly with effective drugs. The most important messages from this article are that malaria is common and that imported malaria can be largely prevented by effective prophylaxis.4
Keywords Anopheles; antimalarials; falciparum; knowlesi; malaria; malariae; ovale; Plasmodium; vivax
Introduction and epidemiology In the last decade, investment in malaria control strategies has contributed to a significant reduction in malaria cases and deaths worldwide. Despite this, malaria remains a leading cause of morbidity and mortality, with an estimated 219 million cases and 660,000 deaths in 2010. The burden of disease lies in Africa and is associated with poverty. Of all malaria deaths, 86% occur in children under 5 years.1 In parts of Africa, the average person will catch malaria four or more times a year, so the disease is much more common than influenza in the UK. In addition, whereas global access to malaria diagnostics and effective treatments is improving, emerging anti-malarial drug resistance is a cause for concern.2 In Europe and the USA, malaria is an important imported infection and is likely to be increasingly so as tourism and other
Pathophysiology Malaria is caused by protozoal parasites of the genus Plasmodium. Five species of Plasmodium cause disease in humans (Table 1); falciparum malaria causes almost all the deaths. In humans, malaria is transmitted by female Anopheles mosquitoes that bite typically after dark. The pathophysiology of disease is incompletely understood. The virulence of Plasmodium falciparum is related to the blood stage of the parasite and is multifactorial including: sequestration (sticking down) of infected red blood cells within the microcirculation, probably causing hypoxia of tissues, especially the brain infection of erythrocytes of all ages, compared to other forms of malaria that are selective for younger cells, enabling higher levels of parasitaemia activation of various parts of the immune system, leading to cytokine-driven pathology.7,8 Plasmodium vivax and Plasmodium ovale malaria lay down hypnozoites in the liver. The parasite lies dormant in these cells for months or even years, emerging to cause clinically apparent malaria, often several times. Consequently, infection with these species requires separate treatment directed at eliminating the hypnozoite stage.
Naomi F Walker MA MRCP DTM&H is a Wellcome Trust Clinical Research Training Fellow in Tropical Medicine and Public Health at Imperial College London, UK and University of Cape Town, South Africa. Competing interests: none declared. Behzad Nadjm MRCP MD DTM&H is a Senior Clinical Researcher at the Oxford Clinical Research Unit, Hanoi, Vietnam, and Honorary Consultant Physician at University College London Hospitals NHS Trust, UK. Competing interests: none declared. Christopher J M Whitty FRCP is a Consultant Physician at the Hospital for Tropical Diseases and University College London Hospitals NHS Trust, and Professor of International Health at the London School of Hygiene & Tropical Medicine, UK. Competing interests: none declared.
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Rapid diagnostic tests are increasingly used in clinical practice as an adjunct to (not a replacement for) microscopy Elderly patients are at particular risk of mortality Clear evidence suggests intravenous artesunate is preferable to intravenous quinine for severe malaria and is increasingly used in clinical settings, despite supply difficulties Reports of artesunate-resistant falciparum malaria and chloroquine-resistant vivax malaria exist, although they do not affect first-line therapy in most settings
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Species of Plasmodium causing human disease Species
Distribution
Severe disease
Recurrent disease (relapses)
Features
P. falciparum
Widespread
þþþ
e
P. vivax P. ovale P. malariae
Widespread West Africa Africa
þ (þ) (þ)
þ þ e
P. knowlesi
Malaysia, Thailand, Myanmar
þ
e
Most fatalities Severe disease Hypnozoites present: long incubation and relapse possible Long incubation possible Cause of nephrotic syndrome Zoonosis Microscopically similar to P. malariae Severe disease/fatalities
(þ) Very rare. þ Rare. þþþ Common. See: Cox-Singh J, Davis TME, Lee K, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life-threatening. Clin Infect Dis 2008; 46: 165e71.
Table 1
Clinical manifestations of disease
appears well, they should return for a repeat test the next day; occasionally the first test can be negative. More than three tests are unnecessary to exclude malaria in a single febrile episode unless symptoms change. It is important to consider that travellers returning from malaria-endemic regions who test negative
Symptoms develop from around 6 days after an infected bite. Most falciparum infections present within 1 month, but can do so later, especially in those taking prophylaxis. Vivax, malariae and ovale infections commonly have a longer incubation period and vivax and ovale can relapse after an extended period because of activation of hepatic hypnozoites. This is different from recrudescence where parasites reappear in the blood following failed treatment that has not completely cleared parasites. P. vivax, P. ovale and Plasmodium malariae are much less likely to cause severe disease than P. falciparum but falciparum and malariae malaria do not relapse. A second episode of falciparum malaria suggests treatment failure or re-infection. A history of fever is usual, although not invariable; because the temperature fluctuates it may not be found at presentation.9 Other symptoms are non-specific and can be misleading, commonly resulting in misdiagnosis such as influenza, hepatitis, gastroenteritis or meningitis. If a patient is unwell and has recently returned from malarial areas the only way to exclude malaria is to do an urgent malaria test. If malaria is diagnosed (or suspected), assessing for features of severe malaria, which differ between children and adults10 (Table 2) is crucial. The presence of any of these features constitutes potentially severe malaria. In children with severe falciparum malaria, respiratory distress, anaemia, convulsions and hypoglycaemia are more common than in adults. Pulmonary oedema, acute respiratory distress syndrome (ARDS) and acute renal failure occur rarely in children, but occur in over half of all cases of life-threatening malaria in non-immune adults.
Features of severe or potentially complicated malaria
Clinical Confusion, drowsiness or coma Generalized convulsions Acute pulmonary oedema/ARDS/ALI Respiratory distress (acidosis) Jaundice (haemolytic) Shock e ‘algid malaria’ Abnormal bleeding (generally DIC) Very dark urine e ‘blackwater fever’ Prostration (extreme weakness without other signs) Laboratory findings Hyperparasitaemia (>5%)a Acute renal failure Severe anaemia (Hb <8.0 g/dl) Hypoglycaemiab
Child
þþþ þþþ þþ þ þþ þþ þ (þ) þ
þþþ þþþþ þ þþþ þ þþ þ þ þþþ
þþþ þþþ þþ þþ
þþþ þ þþþ þþþ
þ Rare, þþ Uncommon, þþþ Common, þþþþVery common. ALI, acute lung injury; ARDS, adult respiratory distress syndrome; DIC, disseminated intravascular coagulation. Adapted from Guidelines for the treatment of malaria. World Health Organization; 2nd edn, 2010. a UK guidelines suggest >2% as an indication for parenteral therapy (UK Malaria Treatment Guidelines. Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA. J Infect 2007; 54(2): 111e121). b Common in pregnant women.
Diagnosis Diagnostic delay, either because the patient presents late, or because a doctor has not suspected the diagnosis, is a key factor in mortality from malaria in non-endemic countries.11 Suspecting the diagnosis is paramount and malaria can occur even with perfect prophylaxis. If malaria tests are negative and the patient
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Adult
Table 2
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To admit or not to admit? UK guidelines recommend that all patients with P. falciparum malaria should be admitted to hospital for at least the first 24 hours, including those who do not initially meet the criteria for severe disease.13 This is particularly important for children, pregnant women and the elderly, who are at increased risk of complications. Because of the lifecycle of malaria, patients can deteriorate rapidly despite adequate treatment, so apparently well patients can be much sicker the next day and parasite counts often rise between the first and second days even with effective treatment. A patient with non-falciparum malaria (vivax, ovale, malariae) can generally be managed as an outpatient, unless they are clinically unwell or unable to take oral drugs.
for malaria may have other potentially serious infections, including HIV-related ones (see Assessment of returning travellers with fever on pages 66e72 of this issue).
Diagnostic tests Recent decades have seen an expansion in malaria diagnostics, particularly the use of rapid diagnostic tests. Despite this, microscopy of thick and thin blood films remains the mainstay of diagnosis (Figure 1). All malaria diagnostic tests are intended to detect blood-stage disease; there are no reliable tests for dormant malaria in an asymptomatic patient. Rapid diagnostic tests: rapid diagnostic tests (RDTs) for malaria are now widely available.12 Table 3 summarizes the strengths and limitations of RDTs along with the alternative diagnostic methods. They are particularly useful as an additional test in laboratories with relatively few cases in a year, but do not give information on the parasite density (which has prognostic value). They are a useful adjunct to malaria films for diagnosis in a non-endemic setting, but should not be used as a substitute for blood films.
Management of patient with severe falciparum malaria The essential step in managing a patient with severe malaria is to give an appropriate parenteral antimalarial, at an effective dose, quickly. Two antimalarials e quinine and artesunate e are recommended for parenteral treatment and both are effective, but artesunate is associated with lower mortality. However, it is better to start quinine immediately than delay whilst waiting for artesunate if it is not available. All cases of severe malaria should be discussed with clinicians experienced in managing the disease (see Practice points). Evidence from two large randomized controlled trials demonstrates that intravenous artesunate is superior to quinine in terms of mortality in adults in Asia and children in Africa.14,15 The AQUAMAT trial, which enrolled over 5000 children in nine African countries, demonstrated a 22.5% (95% confidence interval 8.1e36.9) relative reduction in mortality from severe falciparum malaria.15 A recent Cochrane review reported a risk ratio in adults of 0.61 (95% confidence interval 0.5e0.75) for artesunate in comparison to quinine in severe malaria.16 The dose is 2.4 mg/kg at 0, 12 hours and 24 hours, then once daily. Patients with severe malaria should have a minimum of three doses. All patients should receive follow-on therapy to avoid recrudescence (see below). The benefits of artesunate include a rapid reduction in parasitaemia and a relatively favourable adverse effect profile, particularly in patients in whom the adverse effects of quinine (cardiac arrhythmias or hypoglycaemia) are likely to be problematic. Despite this, access to intravenous artesunate is limited in Europe and the USA due to a restricted supply of stock. With more widespread use, reports of previously unrecognized adverse effects of parenteral artesunate are emerging, including neutropenia and late unexplained haemolysis.17 Quinine remains an effective antimalarial and should be used for severe falciparum malaria when a supply of intravenous artesunate is not immediately available. Unless quinine or mefloquine has been taken in the preceding 12 hours, or there is a clear acute cardiac history, a loading dose of quinine is required for the first dose (Table 4).18 The dose of quinine is 10 mg/kg by slow infusion three times a day after an initial loading dose of 20 mg/kg. ECG monitoring is recommended in elderly patients or those with a cardiac history. All patients treated with intravenous therapy (artesunate or quinine) should be given a full course of treatment with oral antimalarials once they are able to tolerate oral medication. Any of the options given in Table 5 is appropriate.
Polymerase chain reaction (PCR): detection of Plasmodiumspecific nucleic acid sequences by PCR is highly sensitive. This method is however limited by speed, cost and availability of technology, and is currently not used routinely in clinical practice. Serology: serological (antibody) tests have no place in the clinical diagnosis of acute malaria.
Treatment General principles Once malaria has been identified the two key questions are: is this falciparum or non-falciparum? if falciparum, is it severe (sometimes called complicated) or non-severe (Table 2)?
Figure 1 Malaria blood slide (reproduced courtesy of the Hospital for Tropical Diseases).
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Diagnostic tests for malaria Test Blood films Thick
Thin Rapid diagnostic tests
PCR
Strengths
Limitations
Practical implications
Highly sensitive (up to 50 parasites per microlitre blood/0.001% parasitaemia) Specificity, speciation, quantification of degree of parasitaemia Sensitivity (reported 84e100% for falciparum malaria)9
Does not allow accurate quantification of degree of parasitaemia
Gold standard diagnostic test for clinical practice
High degree of sensitivity. Accurate speciation including knowlesi malaria
Less sensitive than thick film as smaller volume of blood examined. Less sensitive for diagnosis and speciation of non-falciparum forms. Remains positive for variable duration following treatment (<1 month for HRP-2), unsuitable for monitoring response to therapy.
High cost of equipment and maintenance
Potential role in developing world, where confidence in microscopy is variable, is currently being established. In UK, a useful adjunct to blood slide microscopy in hospitals where malaria is uncommonly seen and on-call staff have little experience in microscopy Not used routinely in clinical practice outside of specialist settings
PCR, polymerase chain reaction.
Table 3
that aggressive fluid management may be detrimental.19 The implications of this for the management of adult imported malaria are not clear. However, in adults with severe malaria pulmonary oedema may occur, and this may be precipitated by excessive intravenous hydration. Pre-renal failure may be assessed with small fluid boluses, and fluid replaced cautiously if required. Antibiotic therapy is indicated in patients presenting with shock or other evidence of bacterial co-infection. Shock is uncommon in adults with severe malaria, so its occurrence suggests a concurrent diagnosis of sepsis. Bacterial co-infection with malaria in children in malaria endemic settings is common, under-recognized and may complicate imported malaria in an intensive care setting.5,20 Thrombocytopenia is common and often severe, but is rarely associated with bleeding and needs treatment only when bleeding occurs. ARDS usually presents late, often after the parasitaemia has been cleared. Management of ARDS, disseminated intravascular coagulation (DIC) and acute renal failure in malaria are as for other causes. Renal failure almost invariably resolves, although this may take days or weeks on renal support. The use of exchange blood transfusion or haemophoresis (in which blood is drawn off whilst uninfected blood is transfused) is controversial. Theoretical benefits include reduction in parasite load. No large randomized controlled trial has been performed but a meta-analysis failed to show any overall impact on mortality.21 However, it is not recommended where artesunate is used as parasite clearance is much more rapid.
Adjunctive treatments in the early management of severe malaria: supportive treatment for severe malaria is similar to that for other diseases. Intravenous fluids and blood transfusion for severe anaemia may be indicated. Fluid resuscitation in severe malaria is controversial. A recent randomized controlled trial of fluid management in severe febrile illness in children in Kenya, 57% of whom had malaria parasitaemia, has suggested
Summary of treatment options for severe falciparum malaria Drug
Dose
Artesunate (IV) 2.4 mg/kg at 0, 12 hours, and 24 hours then 2.4 mg/kg once daily Quinine (IV) Slow infusion: loading dose 20 mg/kg then 10 mg/kg three times per day
Notes Minimum treatment course: three doses
Adverse effects include hypoglycaemia and cardiac arrhythmias. Electrocardiographic monitoring recommended if elderly or history of cardiac arrhythmias
Key points: 1) Start treatment as soon as possible. 2) Both treatment options are effective. 3) Artesunate is preferable when available. 4) Follow IV therapy with a full course of oral treatment for falciparum malaria (see Table 5, ‘Summary of pharmacotherapy for non-severe malaria’).
Management of patients with non-severe falciparum malaria Severe malaria should be excluded. If there is no indication for parenteral treatment, the patient should be admitted to hospital
Table 4
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Summary of pharmacotherapy for non-severe malaria in adults Drugs used in treatment of malaria (adult doses given except where specified) Indication
Drug
Side effects/contraindications
Non-severe falciparum (initial treatment): choice of three regimens
For adults: quinine sulphate 600 mg every 8 hours for 5e7 days For children: 10 mg/kg quinine salt every 8 hours for 7 days D second agent as follow-on (see below)
Mild adverse effects: tinnitus, hearing loss, dizziness, nausea, blurring vision Unpleasant taste Hypoglycaemia Can induce arrhythmias in context of preexisting cardiac disease Serious cardiovascular and neurological adverse effects occur rarely West Africans often report previous itching but this is usually associated with chloroquine Not in early pregnancy e insufficient data
Atovaquoneeproguanil (MalaroneÒ) 4 ‘standard’ tablets daily for 3 days Weight <40 kg requires reduced dose Artemetherelumefantrine (RiametÒ). Doses at 0, 8, 24, 36, 48 and 60 hours >35 kg: 4 tablets per dose 25e35 kg: 3 tablets per dose 14e24 kg: 2 tablets per dose 5e14 kg: 1 tablet per dose Second agent for follow-on treatment: choice of three agents
Non-falciparum
Eradicating hypnozoites (additional treatment for ovale, vivax and mixed infection)
Doxycycline 200 mg orally daily for 7 days
Clindamycin For adults: 450 mg every 8 hours for 7 days For children: 7e13 mg/kg/dose every 8 hours for 7 days Sulphadoxineepyrimethamine (FansidarÒ) In children only e single dose: Up to 4 years (>5 kg) ½ tablet 5e6 years 1 tablet 7e9 years 1 ½ tablets 10e14 years 2 tablets 15e18 years 3 tablets In adults: chloroquine 600 mg base orally followed by 300 mg at 6, 24 and 48 hours D treatment for hypnozoites to prevent relapse in vivax and ovale (see below) Primaquine 15 mg (ovale) or 30 mg (vivax) per day orally for 14 days Children require weight-related dosing. If G6PD deficient, seek expert advice.
Use worldwide as first-line treatment for nonsevere malaria in adults and children Not currently licensed in the UK for use in children <12 years Avoid in early pregnancy Relatively contraindicated in combination with rifampicin May cause gastritis, photosensitivity and complications of antibiotic use Contraindicated in pregnancy and children <12 years Choice in pregnancy and children <12 years, but liquid formulation difficult to obtain
May cause skin rashes and (rarely) Stevens eJohnson syndrome Can be taken safely whilst breastfeeding, in absence of other co-morbidities
Occasional treatment failures with vivax malaria, especially cases from East Asia, Papua New Guinea. Second-line agents e as for falciparum. Contraindicated in pregnancy Screening for G6PD deficiency required before use e primaquine causes haemolysis in patients with G6PD deficiency and is contraindicated
G6PD, glucose-6-phosphate dehydrogenase.
Table 5
Management of non-falciparum malaria Non-falciparum malaria is rarely severe but care should be taken to avoid missing a mixed infection, where P. falciparum is also present. Where there is any uncertainty, treat as falciparum
for at least 24 hours and given oral anti-malarial therapy as described in Table 5. No routine follow-up is required, but the opportunity should be taken to discuss improved preventative strategies.
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malaria can occur it is advisable to get the most up-to-date advice. For the UK this is available at the Public Health England Malaria Reference Laboratory (http://www.hpa. org.uk/Topics/InfectiousDiseases/InfectionsAZ/Malaria/ Guidelines/mala10guidelinesPrevention/) and the National Travel Health Network and Centre (NaTHNaC, http://www.nathnac.org/pro/index.htm); in the USA the CDC also publishes regularly updated advice. Chloroquinebased regimens are no longer effective. Seek early medical attention if you have fever or other symptoms in Africa or malaria-endemic Asia or South America, and for up to 12 months after return. No traveller is immune to malaria.
malaria. Chloroquine remains the mainstay of treatment for nonfalciparum malaria, followed by primaquine to eradicate hypnozoites of ovale and vivax (Table 5). Primaquine can cause severe haemolysis in some patients with glucose-6dehydrogenase (G6PD) deficiency e its use should be deferred until the results of screening for this enzyme are available. Where a diagnosis of G6PD deficiency has been established, advice should be sought (see Practice Points below). Management of mixed species infection In mixed infection patients should be treated for falciparum malaria; quinine and artesunate are effective in all species, whereas resistance to chloroquine in P. falciparum is widespread. Additional treatment is required to eradicate dormant hypnozoites if there is co-infection with vivax or ovale.
A
Malaria in pregnancy The management of malaria in pregnancy can be complicated and is beyond the scope of this article; specialist advice is recommended both for falciparum and non-falciparum malaria and for febrile pregnant women returning from endemic areas who have an initial negative test for malaria.22 In addition to increasing the likelihood of severe malaria and reducing the sensitivity of diagnostic tests, malaria presents a significant risk to the pregnancy. There is a very small theoretical risk of teratogenicity from some antimalarials but, as in all instances of malaria, rapid treatment with an effective antimalarial is the key to good management.
REFERENCES 1 World malaria report 2012. Geneva: World Health Organization, 2012. 2 Dondorp AM, Fairhurst RM, Slutsker L, et al. The threat of artemisininresistant malaria. N Engl J Med 2011; 365: 1073e5. 3 Gautret P, Schlagenhauf P, Gaudart J, et al. Multicenter EuroTravNet/GeoSentinel study of travel-related infectious diseases in Europe. Emerg Infect Dis 2009; 15: 1783e90. 4 Checkley AM, Smith A, Smith V, et al. Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study. Br Med J 2012; 344: e2116. 5 Marks ME, Armstrong M, Suvari MM, et al. Severe imported falciparum malaria among adults requiring intensive care: a retrospective study at the hospital for tropical diseases, London. BMC Infect Dis 2013; 13: 118. 6 Jelinek T. Imported falciparum malaria in Europe: 2007 data from TropNetEurop. Euro Surveill 2008; 13, pii; 18895. 7 Miller LH, Ackerman HC, Su XZ, Wellems TE. Malaria biology and disease pathogenesis: insights for new treatments. Nat Med 2013; 19: 156e67. 8 Riley EM, Stewart VA. Immune mechanisms in malaria: new insights in vaccine development. Nat Med 2013; 19: 168e78. 9 Nic Fhogartaigh C, Hughes H, Armstrong M, et al. Falciparum malaria as a cause of fever in adult travellers returning to the United Kingdom: observational study of risk by geographical area. QJM 2008; 101: 649e56. 10 WHO. Guidelines for the treatment of Malaria. 2nd edn. Geneva: World Health Organization, 2010. 11 Newman RD, Parise ME, Barber AM, Steketee RW. Malaria-related deaths among U.S. travelers, 1963-2001. Ann Intern Med 2004; 141: 547e55. 12 Murray CK, Gasser Jr RA, Magill AJ, Miller RS. Update on rapid diagnostic testing for malaria. Clin Microbiol Rev 2008; 21: 97e110. 13 Lalloo DG, Shingadia D, Pasvol G, et al. UK malaria treatment guidelines. J Infect 2007; 54: 111e21. 14 Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717e25. 15 Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376: 1647e57.
Drug-resistant malaria Falciparum malaria is now almost entirely resistant to chloroquine, and resistance to sulphadoxineepyrimethamine (FansidarÒ) is widespread. Although most non-falciparum malaria remains chloroquine sensitive, vivax malaria treatment failures with chloroquine are reported in parts of Asia.1 Resistance to artemisinins is emerging in South East Asia although fortunately this rarely results in clinical failure.
Prevention This is the area of imported malaria where the greatest impact could be made. A recent retrospective analysis of malaria deaths in returned travellers in the UK reported that appropriate malaria chemoprophylaxis had been taken by fewer than 40% of patients with malaria4 and similar results are found in the USA.11 Travellers visiting friends and relatives in endemic areas from which their families originally came constitute a large proportion of malaria cases overall and are the least likely to take chemoprophylaxis.23 Take every opportunity to give the following four key messages. Avoid mosquito bites by covering up with clothing and using insect repellent, and sleep under treated mosquito nets; most malaria transmission occurs after midnight, especially in Africa. Chemoprophylaxis is essential when travellers are going to high-transmission countries, especially in Africa. Since malaria drug resistance patterns change and outbreaks of
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16 Sinclair D, Donegan S, Isba R, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2012. Issue 6. Art. No.: CD005967. 17 Eder M, Farne H, Cargill T, Abbara A, Davidson RN. Intravenous artesunate versus intravenous quinine in the treatment of severe falciparum malaria: a retrospective evaluation from a UK centre. Pathogens Glob Health 2012; 106: 181e7. 18 British National Formulary 65. London: BMJ Publishing Group Ltd and Royal Pharmaceutical Society, 2013. 19 Maitland K, Babiker A, Kiguli S, Molyneux E. The FEAST trial of fluid bolus in African children with severe infection. Lancet 2012; 379: 613. author reply 13e14. 20 Nadjm B, Mtove G, Amos B, et al. Severe febrile illness in adult hospital admissions in Tanzania: a prospective study in an area of high malaria transmission. Trans R Soc Trop Med Hyg 2012; 106: 688e95. 21 Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 2002; 34: 1192e8. 22 Takem EN, D’Alessandro U. Malaria in pregnancy. Mediterr J Hematol Infect Dis 2013; 5: e2013010.
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23 Smith AD, Bradley DJ, Smith V, et al. Imported malaria and high risk groups: observational study using UK surveillance data 1987e2006. Br Med J 2008; 337: a120.
Practice points C
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Malaria is common, and up to one in five travellers from Africa, and a significant number from Asia and Latin America who present with fever, will have it. Always do a blood film For severe malaria, artesunate is the drug of choice but if this is not available locally use parenteral quinine For advice on difficult clinical cases contact the on-call registrar at The Hospital for Tropical Diseases (020 3456 7890) or Liverpool School of Tropical Medicine (0151 705 3100) Prophylaxis advice can be obtained from: http://www.hpa.org. uk/Topics/InfectiousDiseases/InfectionsAZ/Malaria/Guidelines/ mala10guidelinesPrevention/
Ó 2014 Published by Elsevier Ltd.
Malaria
What’s new?
Naomi F Walker C
Behzad Nadjm Christopher J M Whitty
C C
Abstract
C
Malaria remains a leading cause of mortality worldwide and a cause of morbidity in returning travellers in the UK. The management of malaria, recent advances in diagnosis and current areas of controversy are summarized, primarily for clinicians in non-endemic countries who do not routinely encounter it. The most important message is that malaria is very common and presentation is non-specific, so a malaria test is essential. Early diagnosis and prompt effective treatment prevent unnecessary deaths. Health promotion for travellers to endemic areas is essential to reduce the burden of imported malaria.
travel to malaria-affected regions steadily increase. Malaria is the leading potentially fatal cause of febrile illness in returned travellers.3 Although uncomplicated malaria is rarely fatal, European case fatality rates for falciparum malaria are around 1%, and up to 25% in an intensive care setting.4,5 Factors associated with the development of severe malaria include older age, increased time to presentation and delayed diagnosis, pregnancy and HIV infection. Most patients returning to Europe with malaria do not report taking malaria prophylaxis.6 This article, aimed at clinicians in non-endemic countries, addresses clinical aspects of malaria pathophysiology, presentation, diagnosis and management, highlighting recent developments and areas of controversy. Every death from malaria should be preventable if the condition is diagnosed early and treated promptly with effective drugs. The most important messages from this article are that malaria is common and that imported malaria can be largely prevented by effective prophylaxis.4
Keywords Anopheles; antimalarials; falciparum; knowlesi; malaria; malariae; ovale; Plasmodium; vivax
Introduction and epidemiology In the last decade, investment in malaria control strategies has contributed to a significant reduction in malaria cases and deaths worldwide. Despite this, malaria remains a leading cause of morbidity and mortality, with an estimated 219 million cases and 660,000 deaths in 2010. The burden of disease lies in Africa and is associated with poverty. Of all malaria deaths, 86% occur in children under 5 years.1 In parts of Africa, the average person will catch malaria four or more times a year, so the disease is much more common than influenza in the UK. In addition, whereas global access to malaria diagnostics and effective treatments is improving, emerging anti-malarial drug resistance is a cause for concern.2 In Europe and the USA, malaria is an important imported infection and is likely to be increasingly so as tourism and other
Pathophysiology Malaria is caused by protozoal parasites of the genus Plasmodium. Five species of Plasmodium cause disease in humans (Table 1); falciparum malaria causes almost all the deaths. In humans, malaria is transmitted by female Anopheles mosquitoes that bite typically after dark. The pathophysiology of disease is incompletely understood. The virulence of Plasmodium falciparum is related to the blood stage of the parasite and is multifactorial including: sequestration (sticking down) of infected red blood cells within the microcirculation, probably causing hypoxia of tissues, especially the brain infection of erythrocytes of all ages, compared to other forms of malaria that are selective for younger cells, enabling higher levels of parasitaemia activation of various parts of the immune system, leading to cytokine-driven pathology.7,8 Plasmodium vivax and Plasmodium ovale malaria lay down hypnozoites in the liver. The parasite lies dormant in these cells for months or even years, emerging to cause clinically apparent malaria, often several times. Consequently, infection with these species requires separate treatment directed at eliminating the hypnozoite stage.
Naomi F Walker MA MRCP DTM&H is a Wellcome Trust Clinical Research Training Fellow in Tropical Medicine and Public Health at Imperial College London, UK and University of Cape Town, South Africa. Competing interests: none declared. Behzad Nadjm MRCP MD DTM&H is a Senior Clinical Researcher at the Oxford Clinical Research Unit, Hanoi, Vietnam, and Honorary Consultant Physician at University College London Hospitals NHS Trust, UK. Competing interests: none declared. Christopher J M Whitty FRCP is a Consultant Physician at the Hospital for Tropical Diseases and University College London Hospitals NHS Trust, and Professor of International Health at the London School of Hygiene & Tropical Medicine, UK. Competing interests: none declared.
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Rapid diagnostic tests are increasingly used in clinical practice as an adjunct to (not a replacement for) microscopy Elderly patients are at particular risk of mortality Clear evidence suggests intravenous artesunate is preferable to intravenous quinine for severe malaria and is increasingly used in clinical settings, despite supply difficulties Reports of artesunate-resistant falciparum malaria and chloroquine-resistant vivax malaria exist, although they do not affect first-line therapy in most settings
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Species of Plasmodium causing human disease Species
Distribution
Severe disease
Recurrent disease (relapses)
Features
P. falciparum
Widespread
þþþ
e
P. vivax P. ovale P. malariae
Widespread West Africa Africa
þ (þ) (þ)
þ þ e
P. knowlesi
Malaysia, Thailand, Myanmar
þ
e
Most fatalities Severe disease Hypnozoites present: long incubation and relapse possible Long incubation possible Cause of nephrotic syndrome Zoonosis Microscopically similar to P. malariae Severe disease/fatalities
(þ) Very rare. þ Rare. þþþ Common. See: Cox-Singh J, Davis TME, Lee K, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life-threatening. Clin Infect Dis 2008; 46: 165e71.
Table 1
Clinical manifestations of disease
appears well, they should return for a repeat test the next day; occasionally the first test can be negative. More than three tests are unnecessary to exclude malaria in a single febrile episode unless symptoms change. It is important to consider that travellers returning from malaria-endemic regions who test negative
Symptoms develop from around 6 days after an infected bite. Most falciparum infections present within 1 month, but can do so later, especially in those taking prophylaxis. Vivax, malariae and ovale infections commonly have a longer incubation period and vivax and ovale can relapse after an extended period because of activation of hepatic hypnozoites. This is different from recrudescence where parasites reappear in the blood following failed treatment that has not completely cleared parasites. P. vivax, P. ovale and Plasmodium malariae are much less likely to cause severe disease than P. falciparum but falciparum and malariae malaria do not relapse. A second episode of falciparum malaria suggests treatment failure or re-infection. A history of fever is usual, although not invariable; because the temperature fluctuates it may not be found at presentation.9 Other symptoms are non-specific and can be misleading, commonly resulting in misdiagnosis such as influenza, hepatitis, gastroenteritis or meningitis. If a patient is unwell and has recently returned from malarial areas the only way to exclude malaria is to do an urgent malaria test. If malaria is diagnosed (or suspected), assessing for features of severe malaria, which differ between children and adults10 (Table 2) is crucial. The presence of any of these features constitutes potentially severe malaria. In children with severe falciparum malaria, respiratory distress, anaemia, convulsions and hypoglycaemia are more common than in adults. Pulmonary oedema, acute respiratory distress syndrome (ARDS) and acute renal failure occur rarely in children, but occur in over half of all cases of life-threatening malaria in non-immune adults.
Features of severe or potentially complicated malaria
Clinical Confusion, drowsiness or coma Generalized convulsions Acute pulmonary oedema/ARDS/ALI Respiratory distress (acidosis) Jaundice (haemolytic) Shock e ‘algid malaria’ Abnormal bleeding (generally DIC) Very dark urine e ‘blackwater fever’ Prostration (extreme weakness without other signs) Laboratory findings Hyperparasitaemia (>5%)a Acute renal failure Severe anaemia (Hb <8.0 g/dl) Hypoglycaemiab
Child
þþþ þþþ þþ þ þþ þþ þ (þ) þ
þþþ þþþþ þ þþþ þ þþ þ þ þþþ
þþþ þþþ þþ þþ
þþþ þ þþþ þþþ
þ Rare, þþ Uncommon, þþþ Common, þþþþVery common. ALI, acute lung injury; ARDS, adult respiratory distress syndrome; DIC, disseminated intravascular coagulation. Adapted from Guidelines for the treatment of malaria. World Health Organization; 2nd edn, 2010. a UK guidelines suggest >2% as an indication for parenteral therapy (UK Malaria Treatment Guidelines. Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA. J Infect 2007; 54(2): 111e121). b Common in pregnant women.
Diagnosis Diagnostic delay, either because the patient presents late, or because a doctor has not suspected the diagnosis, is a key factor in mortality from malaria in non-endemic countries.11 Suspecting the diagnosis is paramount and malaria can occur even with perfect prophylaxis. If malaria tests are negative and the patient
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Table 2
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To admit or not to admit? UK guidelines recommend that all patients with P. falciparum malaria should be admitted to hospital for at least the first 24 hours, including those who do not initially meet the criteria for severe disease.13 This is particularly important for children, pregnant women and the elderly, who are at increased risk of complications. Because of the lifecycle of malaria, patients can deteriorate rapidly despite adequate treatment, so apparently well patients can be much sicker the next day and parasite counts often rise between the first and second days even with effective treatment. A patient with non-falciparum malaria (vivax, ovale, malariae) can generally be managed as an outpatient, unless they are clinically unwell or unable to take oral drugs.
for malaria may have other potentially serious infections, including HIV-related ones (see Assessment of returning travellers with fever on pages 66e72 of this issue).
Diagnostic tests Recent decades have seen an expansion in malaria diagnostics, particularly the use of rapid diagnostic tests. Despite this, microscopy of thick and thin blood films remains the mainstay of diagnosis (Figure 1). All malaria diagnostic tests are intended to detect blood-stage disease; there are no reliable tests for dormant malaria in an asymptomatic patient. Rapid diagnostic tests: rapid diagnostic tests (RDTs) for malaria are now widely available.12 Table 3 summarizes the strengths and limitations of RDTs along with the alternative diagnostic methods. They are particularly useful as an additional test in laboratories with relatively few cases in a year, but do not give information on the parasite density (which has prognostic value). They are a useful adjunct to malaria films for diagnosis in a non-endemic setting, but should not be used as a substitute for blood films.
Management of patient with severe falciparum malaria The essential step in managing a patient with severe malaria is to give an appropriate parenteral antimalarial, at an effective dose, quickly. Two antimalarials e quinine and artesunate e are recommended for parenteral treatment and both are effective, but artesunate is associated with lower mortality. However, it is better to start quinine immediately than delay whilst waiting for artesunate if it is not available. All cases of severe malaria should be discussed with clinicians experienced in managing the disease (see Practice points). Evidence from two large randomized controlled trials demonstrates that intravenous artesunate is superior to quinine in terms of mortality in adults in Asia and children in Africa.14,15 The AQUAMAT trial, which enrolled over 5000 children in nine African countries, demonstrated a 22.5% (95% confidence interval 8.1e36.9) relative reduction in mortality from severe falciparum malaria.15 A recent Cochrane review reported a risk ratio in adults of 0.61 (95% confidence interval 0.5e0.75) for artesunate in comparison to quinine in severe malaria.16 The dose is 2.4 mg/kg at 0, 12 hours and 24 hours, then once daily. Patients with severe malaria should have a minimum of three doses. All patients should receive follow-on therapy to avoid recrudescence (see below). The benefits of artesunate include a rapid reduction in parasitaemia and a relatively favourable adverse effect profile, particularly in patients in whom the adverse effects of quinine (cardiac arrhythmias or hypoglycaemia) are likely to be problematic. Despite this, access to intravenous artesunate is limited in Europe and the USA due to a restricted supply of stock. With more widespread use, reports of previously unrecognized adverse effects of parenteral artesunate are emerging, including neutropenia and late unexplained haemolysis.17 Quinine remains an effective antimalarial and should be used for severe falciparum malaria when a supply of intravenous artesunate is not immediately available. Unless quinine or mefloquine has been taken in the preceding 12 hours, or there is a clear acute cardiac history, a loading dose of quinine is required for the first dose (Table 4).18 The dose of quinine is 10 mg/kg by slow infusion three times a day after an initial loading dose of 20 mg/kg. ECG monitoring is recommended in elderly patients or those with a cardiac history. All patients treated with intravenous therapy (artesunate or quinine) should be given a full course of treatment with oral antimalarials once they are able to tolerate oral medication. Any of the options given in Table 5 is appropriate.
Polymerase chain reaction (PCR): detection of Plasmodiumspecific nucleic acid sequences by PCR is highly sensitive. This method is however limited by speed, cost and availability of technology, and is currently not used routinely in clinical practice. Serology: serological (antibody) tests have no place in the clinical diagnosis of acute malaria.
Treatment General principles Once malaria has been identified the two key questions are: is this falciparum or non-falciparum? if falciparum, is it severe (sometimes called complicated) or non-severe (Table 2)?
Figure 1 Malaria blood slide (reproduced courtesy of the Hospital for Tropical Diseases).
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Diagnostic tests for malaria Test Blood films Thick
Thin Rapid diagnostic tests
PCR
Strengths
Limitations
Practical implications
Highly sensitive (up to 50 parasites per microlitre blood/0.001% parasitaemia) Specificity, speciation, quantification of degree of parasitaemia Sensitivity (reported 84e100% for falciparum malaria)9
Does not allow accurate quantification of degree of parasitaemia
Gold standard diagnostic test for clinical practice
High degree of sensitivity. Accurate speciation including knowlesi malaria
Less sensitive than thick film as smaller volume of blood examined. Less sensitive for diagnosis and speciation of non-falciparum forms. Remains positive for variable duration following treatment (<1 month for HRP-2), unsuitable for monitoring response to therapy.
High cost of equipment and maintenance
Potential role in developing world, where confidence in microscopy is variable, is currently being established. In UK, a useful adjunct to blood slide microscopy in hospitals where malaria is uncommonly seen and on-call staff have little experience in microscopy Not used routinely in clinical practice outside of specialist settings
PCR, polymerase chain reaction.
Table 3
that aggressive fluid management may be detrimental.19 The implications of this for the management of adult imported malaria are not clear. However, in adults with severe malaria pulmonary oedema may occur, and this may be precipitated by excessive intravenous hydration. Pre-renal failure may be assessed with small fluid boluses, and fluid replaced cautiously if required. Antibiotic therapy is indicated in patients presenting with shock or other evidence of bacterial co-infection. Shock is uncommon in adults with severe malaria, so its occurrence suggests a concurrent diagnosis of sepsis. Bacterial co-infection with malaria in children in malaria endemic settings is common, under-recognized and may complicate imported malaria in an intensive care setting.5,20 Thrombocytopenia is common and often severe, but is rarely associated with bleeding and needs treatment only when bleeding occurs. ARDS usually presents late, often after the parasitaemia has been cleared. Management of ARDS, disseminated intravascular coagulation (DIC) and acute renal failure in malaria are as for other causes. Renal failure almost invariably resolves, although this may take days or weeks on renal support. The use of exchange blood transfusion or haemophoresis (in which blood is drawn off whilst uninfected blood is transfused) is controversial. Theoretical benefits include reduction in parasite load. No large randomized controlled trial has been performed but a meta-analysis failed to show any overall impact on mortality.21 However, it is not recommended where artesunate is used as parasite clearance is much more rapid.
Adjunctive treatments in the early management of severe malaria: supportive treatment for severe malaria is similar to that for other diseases. Intravenous fluids and blood transfusion for severe anaemia may be indicated. Fluid resuscitation in severe malaria is controversial. A recent randomized controlled trial of fluid management in severe febrile illness in children in Kenya, 57% of whom had malaria parasitaemia, has suggested
Summary of treatment options for severe falciparum malaria Drug
Dose
Artesunate (IV) 2.4 mg/kg at 0, 12 hours, and 24 hours then 2.4 mg/kg once daily Quinine (IV) Slow infusion: loading dose 20 mg/kg then 10 mg/kg three times per day
Notes Minimum treatment course: three doses
Adverse effects include hypoglycaemia and cardiac arrhythmias. Electrocardiographic monitoring recommended if elderly or history of cardiac arrhythmias
Key points: 1) Start treatment as soon as possible. 2) Both treatment options are effective. 3) Artesunate is preferable when available. 4) Follow IV therapy with a full course of oral treatment for falciparum malaria (see Table 5, ‘Summary of pharmacotherapy for non-severe malaria’).
Management of patients with non-severe falciparum malaria Severe malaria should be excluded. If there is no indication for parenteral treatment, the patient should be admitted to hospital
Table 4
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Summary of pharmacotherapy for non-severe malaria in adults Drugs used in treatment of malaria (adult doses given except where specified) Indication
Drug
Side effects/contraindications
Non-severe falciparum (initial treatment): choice of three regimens
For adults: quinine sulphate 600 mg every 8 hours for 5e7 days For children: 10 mg/kg quinine salt every 8 hours for 7 days D second agent as follow-on (see below)
Mild adverse effects: tinnitus, hearing loss, dizziness, nausea, blurring vision Unpleasant taste Hypoglycaemia Can induce arrhythmias in context of preexisting cardiac disease Serious cardiovascular and neurological adverse effects occur rarely West Africans often report previous itching but this is usually associated with chloroquine Not in early pregnancy e insufficient data
Atovaquoneeproguanil (MalaroneÒ) 4 ‘standard’ tablets daily for 3 days Weight <40 kg requires reduced dose Artemetherelumefantrine (RiametÒ). Doses at 0, 8, 24, 36, 48 and 60 hours >35 kg: 4 tablets per dose 25e35 kg: 3 tablets per dose 14e24 kg: 2 tablets per dose 5e14 kg: 1 tablet per dose Second agent for follow-on treatment: choice of three agents
Non-falciparum
Eradicating hypnozoites (additional treatment for ovale, vivax and mixed infection)
Doxycycline 200 mg orally daily for 7 days
Clindamycin For adults: 450 mg every 8 hours for 7 days For children: 7e13 mg/kg/dose every 8 hours for 7 days Sulphadoxineepyrimethamine (FansidarÒ) In children only e single dose: Up to 4 years (>5 kg) ½ tablet 5e6 years 1 tablet 7e9 years 1 ½ tablets 10e14 years 2 tablets 15e18 years 3 tablets In adults: chloroquine 600 mg base orally followed by 300 mg at 6, 24 and 48 hours D treatment for hypnozoites to prevent relapse in vivax and ovale (see below) Primaquine 15 mg (ovale) or 30 mg (vivax) per day orally for 14 days Children require weight-related dosing. If G6PD deficient, seek expert advice.
Use worldwide as first-line treatment for nonsevere malaria in adults and children Not currently licensed in the UK for use in children <12 years Avoid in early pregnancy Relatively contraindicated in combination with rifampicin May cause gastritis, photosensitivity and complications of antibiotic use Contraindicated in pregnancy and children <12 years Choice in pregnancy and children <12 years, but liquid formulation difficult to obtain
May cause skin rashes and (rarely) Stevens eJohnson syndrome Can be taken safely whilst breastfeeding, in absence of other co-morbidities
Occasional treatment failures with vivax malaria, especially cases from East Asia, Papua New Guinea. Second-line agents e as for falciparum. Contraindicated in pregnancy Screening for G6PD deficiency required before use e primaquine causes haemolysis in patients with G6PD deficiency and is contraindicated
G6PD, glucose-6-phosphate dehydrogenase.
Table 5
Management of non-falciparum malaria Non-falciparum malaria is rarely severe but care should be taken to avoid missing a mixed infection, where P. falciparum is also present. Where there is any uncertainty, treat as falciparum
for at least 24 hours and given oral anti-malarial therapy as described in Table 5. No routine follow-up is required, but the opportunity should be taken to discuss improved preventative strategies.
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malaria can occur it is advisable to get the most up-to-date advice. For the UK this is available at the Public Health England Malaria Reference Laboratory (http://www.hpa. org.uk/Topics/InfectiousDiseases/InfectionsAZ/Malaria/ Guidelines/mala10guidelinesPrevention/) and the National Travel Health Network and Centre (NaTHNaC, http://www.nathnac.org/pro/index.htm); in the USA the CDC also publishes regularly updated advice. Chloroquinebased regimens are no longer effective. Seek early medical attention if you have fever or other symptoms in Africa or malaria-endemic Asia or South America, and for up to 12 months after return. No traveller is immune to malaria.
malaria. Chloroquine remains the mainstay of treatment for nonfalciparum malaria, followed by primaquine to eradicate hypnozoites of ovale and vivax (Table 5). Primaquine can cause severe haemolysis in some patients with glucose-6dehydrogenase (G6PD) deficiency e its use should be deferred until the results of screening for this enzyme are available. Where a diagnosis of G6PD deficiency has been established, advice should be sought (see Practice Points below). Management of mixed species infection In mixed infection patients should be treated for falciparum malaria; quinine and artesunate are effective in all species, whereas resistance to chloroquine in P. falciparum is widespread. Additional treatment is required to eradicate dormant hypnozoites if there is co-infection with vivax or ovale.
A
Malaria in pregnancy The management of malaria in pregnancy can be complicated and is beyond the scope of this article; specialist advice is recommended both for falciparum and non-falciparum malaria and for febrile pregnant women returning from endemic areas who have an initial negative test for malaria.22 In addition to increasing the likelihood of severe malaria and reducing the sensitivity of diagnostic tests, malaria presents a significant risk to the pregnancy. There is a very small theoretical risk of teratogenicity from some antimalarials but, as in all instances of malaria, rapid treatment with an effective antimalarial is the key to good management.
REFERENCES 1 World malaria report 2012. Geneva: World Health Organization, 2012. 2 Dondorp AM, Fairhurst RM, Slutsker L, et al. The threat of artemisininresistant malaria. N Engl J Med 2011; 365: 1073e5. 3 Gautret P, Schlagenhauf P, Gaudart J, et al. Multicenter EuroTravNet/GeoSentinel study of travel-related infectious diseases in Europe. Emerg Infect Dis 2009; 15: 1783e90. 4 Checkley AM, Smith A, Smith V, et al. Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study. Br Med J 2012; 344: e2116. 5 Marks ME, Armstrong M, Suvari MM, et al. Severe imported falciparum malaria among adults requiring intensive care: a retrospective study at the hospital for tropical diseases, London. BMC Infect Dis 2013; 13: 118. 6 Jelinek T. Imported falciparum malaria in Europe: 2007 data from TropNetEurop. Euro Surveill 2008; 13, pii; 18895. 7 Miller LH, Ackerman HC, Su XZ, Wellems TE. Malaria biology and disease pathogenesis: insights for new treatments. Nat Med 2013; 19: 156e67. 8 Riley EM, Stewart VA. Immune mechanisms in malaria: new insights in vaccine development. Nat Med 2013; 19: 168e78. 9 Nic Fhogartaigh C, Hughes H, Armstrong M, et al. Falciparum malaria as a cause of fever in adult travellers returning to the United Kingdom: observational study of risk by geographical area. QJM 2008; 101: 649e56. 10 WHO. Guidelines for the treatment of Malaria. 2nd edn. Geneva: World Health Organization, 2010. 11 Newman RD, Parise ME, Barber AM, Steketee RW. Malaria-related deaths among U.S. travelers, 1963-2001. Ann Intern Med 2004; 141: 547e55. 12 Murray CK, Gasser Jr RA, Magill AJ, Miller RS. Update on rapid diagnostic testing for malaria. Clin Microbiol Rev 2008; 21: 97e110. 13 Lalloo DG, Shingadia D, Pasvol G, et al. UK malaria treatment guidelines. J Infect 2007; 54: 111e21. 14 Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717e25. 15 Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376: 1647e57.
Drug-resistant malaria Falciparum malaria is now almost entirely resistant to chloroquine, and resistance to sulphadoxineepyrimethamine (FansidarÒ) is widespread. Although most non-falciparum malaria remains chloroquine sensitive, vivax malaria treatment failures with chloroquine are reported in parts of Asia.1 Resistance to artemisinins is emerging in South East Asia although fortunately this rarely results in clinical failure.
Prevention This is the area of imported malaria where the greatest impact could be made. A recent retrospective analysis of malaria deaths in returned travellers in the UK reported that appropriate malaria chemoprophylaxis had been taken by fewer than 40% of patients with malaria4 and similar results are found in the USA.11 Travellers visiting friends and relatives in endemic areas from which their families originally came constitute a large proportion of malaria cases overall and are the least likely to take chemoprophylaxis.23 Take every opportunity to give the following four key messages. Avoid mosquito bites by covering up with clothing and using insect repellent, and sleep under treated mosquito nets; most malaria transmission occurs after midnight, especially in Africa. Chemoprophylaxis is essential when travellers are going to high-transmission countries, especially in Africa. Since malaria drug resistance patterns change and outbreaks of
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16 Sinclair D, Donegan S, Isba R, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2012. Issue 6. Art. No.: CD005967. 17 Eder M, Farne H, Cargill T, Abbara A, Davidson RN. Intravenous artesunate versus intravenous quinine in the treatment of severe falciparum malaria: a retrospective evaluation from a UK centre. Pathogens Glob Health 2012; 106: 181e7. 18 British National Formulary 65. London: BMJ Publishing Group Ltd and Royal Pharmaceutical Society, 2013. 19 Maitland K, Babiker A, Kiguli S, Molyneux E. The FEAST trial of fluid bolus in African children with severe infection. Lancet 2012; 379: 613. author reply 13e14. 20 Nadjm B, Mtove G, Amos B, et al. Severe febrile illness in adult hospital admissions in Tanzania: a prospective study in an area of high malaria transmission. Trans R Soc Trop Med Hyg 2012; 106: 688e95. 21 Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 2002; 34: 1192e8. 22 Takem EN, D’Alessandro U. Malaria in pregnancy. Mediterr J Hematol Infect Dis 2013; 5: e2013010.
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23 Smith AD, Bradley DJ, Smith V, et al. Imported malaria and high risk groups: observational study using UK surveillance data 1987e2006. Br Med J 2008; 337: a120.
Practice points C
C
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Malaria is common, and up to one in five travellers from Africa, and a significant number from Asia and Latin America who present with fever, will have it. Always do a blood film For severe malaria, artesunate is the drug of choice but if this is not available locally use parenteral quinine For advice on difficult clinical cases contact the on-call registrar at The Hospital for Tropical Diseases (020 3456 7890) or Liverpool School of Tropical Medicine (0151 705 3100) Prophylaxis advice can be obtained from: http://www.hpa.org. uk/Topics/InfectiousDiseases/InfectionsAZ/Malaria/Guidelines/ mala10guidelinesPrevention/
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