Malaria is a disease caused by the protozoa Plasmodium and spread by a vector, the Anopheles mosquito. It is one of the most important diseases in the world in terms of mortality and morbidity. It is a particular problem in sub-Saharan Africa, but is also seen in South and South East Asia. Malaria deaths continue to rise at a time when non-malarial deaths are falling, mainly due to waning efficacy of available medicines, despite the arrival of new agents. Resistance continues to be a major problem and a vaccine remains elusive. The prevalence of fake medicines in endemic countries is another major problem.
Anopheles mosquitoes capable of carrying the disease exist in England, but the climate is currently too cool at some times of year for the malarial parasite to complete its lifecycle. As global warming bites, it may return to temperate areas such as Exeter, England, where in Roman times it was present.
Malaria has been with human beings for a long time in evolutionary terms, as seen in the numerous genetic mutations that occur for the express benefit of conferring partial immunity eg sickle cell trait, G6PD, hereditary spherocytosis. At the same time, the parasite has evolved multiple ways of avoiding the immune system, which is why developing a vaccine has proved so difficult. It is likely that our immune system has also evolved in response to pressure from the organism eg HLA B53 confers 40% protection vs severe malaria.
- Plasmodium falciparum - causes the most severe disease, predominates in Africa, widespread resistance, but no liver stage.
- Plasmodium vivax/ovale - cause less severe disease, predominates in Asia, resistance rare, liver stage
- Plasmodium malariae - causes less severe disease, predominates in Asia, resistance rare, but no liver stage
- Plasmodium knowlesi- a simian (eg macaque monkeys) reservoir parasite in Southeast Asia easy to misdiagnose
- Plasmodium cynomolgi- simian reservoir parasite in Malaysia morphologically identical to P. vivax
The parasite sporozoite form is injected with salivary secretions into the human host. It circulates until it reaches hepatocytes, where it replicates and forms clusters called schizonts. These release trophozoites into the blood stream, where red cells are infected by the merozoites after interaction with the membrane receptor basigin (at least with P. falciparum) and further replication occurs. Disease only appears once widespread haemolysis has occurred, usually 3 weeks or more after initial infection.
A proportion of trophozoites transform into gametocytes. When these are ingested along with human blood by another mosquito, they can then continue the life cycle in the mosquito. In P vivax and ovale, long lasting hypnozoites may persist in the liver, which can be responsible for late reactivation of disease. While P. knowlesi has long been known to have a monkey reservoir it was only in 2014 that the first Plasmodium cynomolgi infection in man was detected.
The Malaria Atlas Project (MAP) has produced estimates of the Plasmodium falciparum parasite rate (PfPR) for all countries to fair resolution. Global malaria deaths were about 1 million (95% CI 711,000—1,412,000) in 1980, peaked at 1,800,000 (1,430,000—2,366,000) in 2004 and had decreased to just over a million (929,000—1,685,000) in 2010, driven mostly by a decline in Africa.
In endemic areas, intermittent asymptomatic low level parasitaemia is seen commonly. Children are the most at risk of severe disease:
- cerebral malaria
- severe haemolysis
Even in adults with relative immunity, however, malaria causes recurrent, usually self-limiting, episodes of mild disease and is also responsible for chronic anaemia.
In non-endemic disease, particularly travelers or people who have lost their immunity by long term lack of exposure after emigration, the infection is more likely to manifest with disease and the disease is more likely to be severe. Symptoms develop at least 3 months after exposure, but suspect the diagnosis in those at risk for up to 1 year after exposure (although P. falciparum usually presents within 3 months).
Usually affects young children, who present febrile in coma, +/- seizures. But often multisystem dysfunction. Meningitis is the main differential.
Prognosis related to presence of recurrent seizures, raised intracranial pressure, metabolic derangement.
There is a need to identify at risk cases not just severe because high mortality before quinine is started.
- Mild malaria
- Present with fever, anaemia, splenomegaly. The periodicity of the fever depends on the species - falciparum tends to demonstrate daily spikes, P. vivax/ovale may spike every 2-3 days, P. malariae may spike every 4-5 days.
- Moderate risk
- Parasitaemia >5% (not very well correlated, and not really relevant for non-falciparum)
- Sickle cell disease (who have worse outcomes, despite being relatively protected!)
- High risk
- Asplenic or splenic dysfunction
- Acidosis (BE >-8)
- Hyperkalaemia (>5.5mmol/L)
- Impaired conscious level
Kussmaul breathing predicts acidosis & death.
Do not wait for the results of tests if symptoms/signs suggestive, since falciparum can be rapidly aggressive. Malarial retinopathy has recently been described and may turn out to be a useful diagnostic tool.
The blood smear is the classic test. Thin smears are best for identifying the particular type of malaria and the percentage parasitaemia (percentage of erythrocytes infected), but thick smears are more sensitive. Repeat testing is important - sensitivity is only 70% on a single smear, but rises to over 95% with 3 smears.
New molecular based tests are expensive but are less reliant on operator experience.
- HRP2 (histidine rich protein) is specific to P. falciparum.
- pLDH versions are available for P. falciparum and P. vivax.
- Aldolase is a pan-specific antigen, but probably not as sensitive as the others.
HRP2 alone is probably most appropriate for high prevalence area where non-falciparum tends to be co-infection.
See also UK malaria treatment guidelines.
- Surprisingly, shock usually responds to just 1 bolus of fluid. Excessive fluid resuscitation is likely to precipitate cardiac failure in severe anaemia, may exacerbate anaemia and raised intracranial pressure. Albumin appears to be superior to crystalloid.
- Oxygen for respiratory distress, glucose if hypoglycaemia.
- Poor evidence for exchange transfusion - consider for persistent acidosis or multiorgan failure, sickle cell.
- Seizures: follow standard guidelines. Partial, subtle seizures are common. No evidence to support prophylactic phenobarbitone.
The non-falciparum malarias are still mostly sensitive to chloroquine, which can be given orally for 3 days. G6PD deficiency should be excluded before chloroquine treatment is started in patients at risk. Treatment must also address eradication of liver stage hypnozooites, for which primaquine, the only presently active drug is usually given. In practice for optimal treatment this also needs point of care diagnostics for G6PD deficiency.
In falciparum malaria, quinine is the drug of choice unless the presentation is severe where there is now good evidence that artesunate is superior, at least in African children. It can be given orally but as it is extremely bitter compliance may not be good - use Malarone (proguanil + atovaquone), or Co-artemether (with lumefantrine = Riamet). Mefloquine resistance means that the BNF no longer recommends it. 7 days of quinine should be followed a single dose of Fansidar (if likely to be sensitive), or by 5 days clindamycin or 7 days doxycycline.
WHO now recommends use of the newer artemisin derivatives (originally discovered in China) which have proved to be much more effective in terms of rate of clearance of parasitaemia (they are active against all stages of the parasite life cycle) and can be given intramuscularly, rectally as well as by other routes.
In view of the problem of resistance, combination treatment is likely to be necessary for endemic areas. The rapid action of artemisin makes in less susceptible to the development of resistance, but reports of resistance in South-east Asia have already been reported.
Resistance to Malaria
Heterozygotes for haemoglobinopathies eg HbS have relative resistance to the Malarial parasite. This is due to the reduced lifespan of the red cells, and this relative resistance is also presumably the reason for the prevalence of hereditary spherocytosis etc, and G6PD deficiency.
Group O blood is less susceptible, group A blood more susceptible due to RBC surface compounds being less sticky for the parasite to gain entry. In Nigeria a preponderance of Group O is reported.
This has depended upon the twin strategies of effective insecticides to supplement the removal of stagnant water sources that reduce the local mosquito burden and effective treatments that disrupt the human transmission life cycle. Vaccines and several novel noninsecticidal intervention methods are under development targeting genetic or breeding weakness and inheritable bacterial endosymbionts such as Wolbachia but these are yet to be proved as large scale game changing sustainable interventions. The classic interventions can be effective and as of 2015 approximately 100 countries are malaria free, with Armenia, Morocco, Turkmeninstan and United Arab Emirates attaining this status since 2007. Local malaria transmission had been interrupted in Argentina, Egypt, Iraq, Georgia, Kyrgyzstan, Oman, Syria and Uzbekistan for at least 3 years and apart from minor reimported outbreaks in Azerbaijan, Costa Rica, Paraguay, Sri Lanka and Turkey. Indeed the 35 countries that since 2000 have adopted a goal of malaria elimination have reduced their disease burden by over 90% in 15 years. However for many such as Botswana, Namibia, South Africia and Swaziland it is the re-importation burden from neighbouring countries that for various reasons have not been able to adopt an eradication goal that is most challenging. Strategies such as replacing pyrethroids with more expensive organophosphate insecticides, more effective surveillance and population subgroup targeted interventions have helped but the evolution of resistance and lack of a single dose treatment for human disease or a mass drug administration approach that would target assymptomatic disease remain challenging.
Prevention of bites is the first step. Anopheles tend to bite in the evening. Skin should be covered, and repellent sprays/coils etc used. Eradication of mosquitoes with DDT was extremely successful in many areas.
Prophylaxis is recommended for those travelling to at-risk areas. The recommended combination of drugs varies according to location.
See HPA guidance.
There are several barriers:
- Antigens of the different life cycle stages differ
- Need to generate v high immune response
- Need to overcome escape mechanisms
The GlaxoSmithKline experimental malaria vaccine Mosquirix is expected to complete late-stage trials in 2011 involving 16,000 people. The company hopes to seek approval for the vaccine in 2012.. However WHO will require 30 month follow up data to change its recommendations which will not be until 2014.
RTS,S/AS02D was an early candidate vaccine showing an efficacy of about ~30%. A change in the adjuvant component appears to have improved efficacy in infants. Early reports of this newer candidate vaccine a hybrid of hepatitis B surface antigen fused with a recombinant antigen derived from part of the circumsporozoite protein, RTS,S/AS01E, has shown an efficacy of about 56% over a median follow-up period of 8 months.. Later phase 3 studies in older children are also favourable but the incidence of convulsions and unexpected incidence of meningitis need better understanding. If development does not have setbacks it may be available in 2015.
Sporozoite vaccine in Mozambique reduces clinical malaria by 22% only, and only for 2-3 months. PfEMP1 is main antigen for natural antibody but high levels of variation.
Probably best to go for T cell stimulating vaccine to knock out infected liver cells. Prime boost strategy = fowlpox vaccine first then modified viral vector eg adeno or smallpox. Current Kilifi trial.
Combination probably more effective but likely to be too expensive for Africa.
Regular treatment in pregnancy is beneficial.
- ↑ Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT, Rayner JC, Wright GJ. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum Nature 2011 doi:10.1038/nature10606
- ↑ Hay SI, Guerra CA, Gething PW, Patil AP, Tatem AJ, Noor AM, Kabaria CW, Manh BH, Elyazar IR, Brooker S, Smith DL, Moyeed RA, Snow RW. A world malaria map: Plasmodium falciparum endemicity in 2007. PLoS medicine. 2009 Mar 24; 6(3):e1000048.(Link to article – subscription may be required.)
- ↑ Murray CJL etal. Global malaria mortality between 1980 and 2010: a systematic analysis. The Lancet - 4 February 2012 ( Vol. 379, Issue 9814, Pages 413-431 ) DOI: 10.1016/S0140-6736(12)60034-8
- ↑ Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, et al. UK malaria treatment guidelines. J Infect 2007;54(2):111-21
- ↑ Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010 Nov 13; 376(9753):1647-1657.(Link to article – subscription may be required.)
- ↑ Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. The New England journal of medicine. 2009 Jul 30; 361(5):455-67.(Link to article – subscription may be required.)
- ↑ RIFINs are Adhesins Implicated in Severe Plasmodium falciparum Malaria Nature Medicine 9 March 2015; doi: 10.1038/nm.3812
- ↑ Hemingway J, Shretta R, Wells TN, Bell D, Djimdé AA, Achee N, Qi G. Tools and Strategies for Malaria Control and Elimination: What Do We Need to Achieve a Grand Convergence in Malaria? PLoS biology. 2016 Mar; 14(3):e1002380.(Epub) (Link to article – subscription may be required.)
- ↑ Chiodini P, Hill D, Lalloo D, Lea G, Walker E, Whitty C and Bannister B. Guidelines for malaria prevention in travellers from the United Kingdom. London, Health Protection Agency, January 2007.
- ↑ Pierson R, Kelland K. Glaxo Offers Free Malaria Research, Vaccine Nears. 2010; Updated Jan 20; Accessed: (2 February 2010): From Reuters Health Information (may require free subscription
- ↑ Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois MC, Demoitié MA, Stallaert JF, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Ballou WR, Cohen J, Riley EM, Lemnge MM, Marsh K, von Seidlein L. Efficacy of RTS,S/AS01E Vaccine against Malaria in Children 5 to 17 Months of Age. The New England journal of medicine. 2008 Dec 8.(Epub ahead of print) (Link to article – subscription may be required.)