- Malaria slows economic growth in Africa, fuelling the vicious cycle which perpetuates poverty.
- In Africa, it accounts for 40% of public health expenditure and 25% of the household income.
- Malaria deters investment, tourism and labour-intensive cash-crops.
Political will to tackle malaria has picked up over the last decade, accompanied by ambitious international targets. The last five-year period has seen a concerted effort by endemic countries and donors to tackle malaria but this is unlikely to be sustained in the face of the global economic downturn.
Consider
malaria in every febrile patient returning from a malaria-endemic area
within the last year, especially in the previous three months,
regardless of whether they have taken chemoprophylaxis, as prompt
recognition and appropriate treatment will improve prognosis and prevent
deaths.
Aetiology
Malaria is a parasitic disease caused by infection by species of the genus Plasmodium:| Clinical features | UK cases 2011 | |
| Plasmodium falciparum | Responsible for severe disease and malaria-related deaths. Incubation 7-14 days (up to 1 year if semi-immune); most travellers present within 8 weeks. Classical tertian and subtertian periodicity (paroxysms at 48- and 36-hour intervals) are rare; daily (quotidian) or irregular are more common. | 1,149 |
| Plasmodium vivax | Causes benign tertian malaria - fever every third day. Incubation period of 12-17 days. Relapse due to dormant parasites in the liver. | 416 |
| Plasmodium ovale | Relapsing course as with P. vivax. Incubation period of 15-18 days. | 77 |
| Plasmodium malariae | Causes benign quartan malaria - fever every 4th day, but this is frequently not observed, particularly in early infection. Long incubation period (18-40 days). Parasites can remain dormant in the blood. 5-10% present over a year after infection. With chronic infection, can cause nephrotic syndrome. | 31 |
Humans acquire malaria after being bitten by an infected mosquito. The sporozoites in the saliva of the mosquito then travel via the bloodstream to the liver where they mature or, in certain species, may lie dormant (when they are known as hypnozoites). The mature organisms then rupture to release further organisms (merozoites) into the blood, where they invade red blood cells and undergo asexual reproduction. Feeding mosquitoes ingest these in a blood meal and in the mosquito gut they undergo sexual reproduction to produce thousands of infective sporozoites, and the cycle continues
Epidemiology
Malaria occurs almost exclusively in the tropics and subtropics and approximately 40% of the world's population, mostly those living in the world's poorest countries, are at risk of malaria. Every year, more than 500 million people become severely ill with malaria - most cases and deaths occur within sub-Saharan Africa.Risk factors
The groups most at risk of developing severe disease are:- The poor (60% of deaths from malaria worldwide occur in the poorest 20% of the population, due to lack of access to effective treatment).
- Young children and infants.
- Pregnant women (especially primigravidae).
- Elderly people.
- Non-immune people (eg, travellers, foreign workers).
The risk of contracting malaria in travellers is proportional to the number of potentially infectious mosquito bites they receive. Therefore, risk factors for malaria in travellers include:
- Travel to areas of high humidity and ambient temperature between 20-30°C (there is no malarial transmission <16°C or at altitudes >2000 m above sea level).
- Travel at times of high seasonal rainfall.
- Visits to rural locations (the risk of contracting malaria in African villages is eight times that in its urban areas).
- Staying in cheap backpacker accommodation.
- Being outdoors between dusk and dawn.
- Longer durations of travel.
Spread of drug resistance
Resistance to antimalarial drugs has spread rapidly over the past few decades - monitoring and surveillance has had to become more intensive to enable early detection of changing patterns of resistance so that national malaria treatment policies can be revised as necessary. There are currently no effective alternatives to artemisinins for the treatment of resistant P. falciparum malaria. Artemisinin, derived from wormwood leaves, has been used in traditional Chinese medicine for centuries to treat malaria and other conditions but its use beyond China has only really happened in the last decade. Synthetic derivatives such as artemether and artesunate have greater bioavailability than artemisinin. Artemisinin-based combination therapies (ACTs) are life-saving in areas of high resistance. In order to preserve the efficacy of artemisinins, the World Health Organization (WHO) has called for a ban on the use of oral artemisinin monotherapies. Despite this, artemisinin-resistant cases have been reported in the Cambodia-Thailand border region. Genome-based research is currently being conducted to determine why artemisinins have been effective and what can be done to develop alternative therapies.Presentation
In view of the life cycle of the malaria parasite, symptoms may occur from six days of naturally acquired infection to many months later. Most patients with P. falciparum infection present in the first month or within the first six months of infection. P. vivax or P. ovale infections commonly present later than six months after exposure and sometimes after years.There are no specific symptoms of malaria - so it is critical to consider the possibility of the diagnosis. Most missed malarial infections are wrongly diagnosed as nonspecific viral infections, influenza, gastroenteritis or hepatitis. Children, in particular, are more likely to present with nonspecific symptoms (fever, lethargy, malaise, somnolence) and to have gastrointestinal symptoms.
Where malaria is a possibility:
- Take a careful exposure history (countries and areas of travel including stopovers and date of return, etc).
- Determine what prophylaxis has been taken - drug(s), dose and adherence, date of cessation.
- Pursue diagnostic tests urgently.
Symptoms
- Fever, often recurring
- Chills
- Rigors
- Headache
- Cough
- Myalgia
- Gastrointestinal upset
Signs
- Fever
- Splenomegaly
- Hepatomegaly
- Jaundice
- +/- abdominal tenderness
Signs of severe disease (usually P. falciparum)
- Impaired consciousness
- Shortness of breath
- Bleeding
- Fits
- Hypovolaemia
- Hypoglycaemia
- Renal failure
- Nephrotic syndrome
- Acute respiratory distress syndrome (during treatment)
Differential diagnosis
As the initial presenting symptoms are nonspecific, there are many alternative diagnoses that could be considered; however, in any returning traveller, these should only be investigated once the possibility of malaria has been excluded, due to the serious consequences of a delay in diagnosis. Other travel-related infections that may present with similar symptoms include:Investigations
Prompt and accurate diagnosis of malaria is vital for effective case management:- To ensure appropriate drug treatment.
- To prevent presumptive treatment of malaria (widespread in endemic areas).
- To help reduce the mortality rate associated with the disease.
- Thick and thin blood smears stained with Giemsa stain remain the 'gold standard'. Advantages include low cost and high sensitivity and specificity when used by well-trained staff. Where there is suspicion of malaria, a venous blood specimen in an EDTA tube should be sent to the laboratory in under an hour. If there is potential for delay, refer the patient to hospital for testing.Where the blood film is negative, at least two further films should be obtained over the subsequent 48 hours, before excluding the diagnosis. Be aware that an individual can have malaria despite a negative film. This is particularly the case in pregnancy where parasite biomass can be sequestered in the placenta - seek expert help early if concerned. See separate article Malaria in Pregnancy.
- Rapid diagnostic tests (or 'dipstick' tests) which detect parasite antigens are available and are easier to use for staff without microscopy training, have less waiting time and indirect costs but have been relatively more expensive.
- Nucleic acid-based tests are emerging as a viable point of care option.
- FBC - typically reveals thrombocytopenia and anaemia. Leukocytosis is rarely seen but is an indicator of a poor prognosis when present.
- G6PD activity - prior to giving primaquine (see 'Treatment of non-falciparum malaria', below).
- LFTs - often abnormal.
- U&Es - may show lowered Na+ and increased creatinine.
- Low blood glucose may be present in severe disease.
- Blood gases
- Blood cultures
- Clotting studies
- Urine and stool culture
- CXR
- Lumbar puncture
Management
The management of malaria depends not only on the severity of the disease but also the strain of Plasmodium involved and the degree of resistance that it exhibits. All cases should be discussed with infectious disease specialists - the local infectious diseases unit will be able to give advice and initiate appropriate treatment in line with the current UK guidelines. Admission is usual for:- Severely unwell patients.
- Patients with P. falciparum malaria.
- Patients with mixed infections.
- Patients in whom the strain cannot be identified.
Non-falciparum malaria
This is usually managed on an outpatient basis, unless the patient has other comorbidities. G6PD activity should be measured in P. vivax or P. ovale infections, as the primaquine (which is necessary to eliminate the dormant hypnozoites and prevent recurrence) can cause haemolysis in those with G6PD deficiency.Treatment of non-falciparum malaria
Current UK guidelines recommend:
- Chloroquine as the drug of choice for the treatment of all non-falciparum malaria - it is highly effective against P. malariae and P. ovale and most strains of P. vivax.
- Where chloroquine fails, resistant P. vivax malaria can be treated with quinine, artemether with lumefantrine or atovaquone-proguanil as for uncomplicated falciparum malaria.
- Prevention of relapse - primaquine is used to destroy liver stage parasites (unlicensed use):
- For treatment of P. ovale 15 mg primaquine/day for 14 days.
- Some strains of P. vivax require higher doses to prevent relapse, so 30 mg primaquine/day for 14 days.
- Expert help should be enlisted in treating those with G6PD deficiency.
Falciparum malaria
Current guidelines suggest all patients with falciparum malaria should be admitted to hospital initially - even semi-immune patients may worsen quickly. High-quality supportive management is important in patients with severe or complicated malaria: HDU management should be available with facilities for transfer to ICU if further deterioration occurs despite appropriate treatment.Treatment for uncomplicated falciparum malariaCurrent UK guidelines suggest as possible alternative regimens for adults:
- Oral quinine sulfate 600 mg/8 hours for 5-7 days plus doxycycline 200 mg daily (or clindamycin 450 mg/8 hours for pregnant women) for 7 days.
- Atovaquone-proguanil (Malarone®): 4 standard tablets daily for 3 days.
- Artemether with lumefantrine (Riamet®): if weight >35 kg, 4 tablets stat and then a further 4 tablets at 8, 24, 36, 48 and 60 hours.
Treatment of severe or complicated falciparum malariaCurrent UK guidelinuggest:
- IV quinine dihydrochloride is the first-line antimalarial drug. A loading dose of 20 mg/kg (to a maximum of 1.4 g) over 4 hours, followed by 10 mg/kg (to a maximum of 700 mg) every 8 hours for the first 48 hours or until the patient can swallow is usual to reach high therapeutic blood levels quickly, although alternative regimens exist. ECG monitoring is required.
- Oral quinine sulfate 600 mg tds should be substituted once the patient is well enough to complete a 5- to 7-day course in total.
- Artesunate regimen - for named adult patient use only, on expert advice. This is usually given as an IV injection, repeated at 12 and 24 hours and daily thereafter. Rectal formulations also exist but tend to be used in resource-poor settings where IV therapy is not possible
- NB: intravenous artesunate has not been licensed in the European Union but there is accumulating evidence that it offers a significant benefit over quinine where patients have very severe malaria or high parasite counts. A Cochrane review suggests that IV artesunate is the drug of choice for adults with severe malaria, particularly if acquired in Asia.
- A second drug should always accompany these regimes. Current recommendations are for doxycycline 200 mg od (or clindamycin 450 mg tds for pregnant women) for a total of 7 days from when the patient can swallow.
Complications
Complications are almost always associated with P. falciparum infection and include:- Impaired consciousness or seizures (cerebral malaria).
- Renal impairment.
- Acidosis.
- Hypoglycaemia.
- Pulmonary oedema or acute respiratory distress syndrome.
- Anaemia.
- Splenic rupture.
- Disseminated intravascular coagulopathy.
- Shock secondary to complicating bacteraemia/septicaemia (algid malaria).
- Haemoglobinuria ('black water fever').
- Multiple organ failure.
- Death.
Prognosis
If left untreated, or where treatment is delayed, malaria may be fatal. There were still 8 deaths in the UK in 2011. Globally, there were 660,000 deaths in the year 2010 but it has been calculated that over the period of a decade 1.1 million deaths were averted by intervention. Cerebral malaria has a mortality rate of about 20%.Prevention
See separate article Malaria Prophylaxis.Use of effective chemoprophylaxis and insecticide-treated nets (ITNs) prevents about 90% of malaria. Travellers should be encouraged to use a prophylactic regime appropriate to their travel itinerary but they should be aware that this is not a guarantee against infection.
Other behavioural modifications, such as avoiding outdoor activity after sunset, wearing long-sleeved shirts and trousers, using ITNs and insect repellant must also be recognised as important.
Encouraging migrant travellers visiting family and friends to take prophylactic medication should be a priority - any immunity to malaria accrued by growing up in a malarious country is rapidly lost on emigration and second-generation family members will have no immunity, rendering them (and particularly children) vulnerable.
Historical
The story of the human struggle to control malaria is not recent:- Malaria has its origins in the dramatic climate change in Africa 7,000-12,000 years ago (increase in temperature and humidity creating new water sources and the start of agriculture in the Middle East and North East Africa (forest-clearing and pools of water).
- The occurrence and spread of malaria can be traced by the evolution of the G6PD, thalassaemia and sickle cell mutations, which in the carrier state gives humans resistance to malaria. The appearance of one variant suggests the spread of malaria by the army of Alexander the Great.
- Described first by the Chinese in the Nei Ching (the Canon of Medicine) in 2700 BC (or BCE - 'before common era', for non-Christians) and then, also described, the use of the qing hoa plant (annual or sweet wormwood) for fever in 340 AD (or CE - 'common era'). The active ingredient, artemisinin, was identified in 1971 and is in modern use as an antimalarial drug.
- Malaria is Italian for 'bad air', as it was noted that shuttering up the houses and not going out in the evening reduced the risk from the gases of the swamp.
- The bark of the Cinchona tree (containing quinine) in South America was found to be effective in treatment; legend describes taking its name from the countess of Chinchon, wife of a Peruvian viceroy who was cured of fever in 1658. It appeared in the British Pharmacopoeia in 1677 and later became known as 'Jesuit's powder' or 'Jesuit's bark' from those who first used it. The Dutch smuggled seeds from Bolivia and successfully grew this in their Indonesian colonies, obtaining a world monopoly on the supply, beating earlier attempts by themselves and the British using a different species which had poor yields.
- Quinine was successfully synthesised in 1944.
- Alphonse Laveran, a French military physician, discovered the protozoan parasite in 1880, whilst working in Algeria (he was later awarded the Nobel Prize for this in 1907).
- The Italians, Grassi and Filetti, named P. vivax and P. malariae in 1890 and an American, Welch, named P. falciparum in 1897. Stephens named the last of the four, P. ovale, in 1922.
- Ronald Ross, an officer in the Indian Medical Service, demonstrated the transmission of malaria by mosquito from bird to bird in 1897, earning the Nobel Prize in 1902.
- Chloroquine was discovered in 1934 by the German Hans Andersag, although it was not recognised as an effective and safe antimalarial until 1946.
- A German chemistry student synthesised DDT for his thesis in 1874, although its insecticidal properties were not recognised until 1939 by Müller, who won the Nobel Prize for Medicine in 1948.
- It should not be forgotten that malaria was endemic in the marshes of Southern and Eastern England from the 16th to 19th centuries (species P. vivax and P. malariae) and briefly reappeared after both the First and Second World Wars.
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