Malaria

This disease is notifiable in the UK under the Public Health (Infectious Diseases) Regulations 1988.

Malaria has been recognised as a human disease for thousands of years and remains one of the most common diseases affecting humans worldwide. Its impact falls almost entirely on developing countries, with the heaviest toll in Africa. It is estimated that by 2010, over half the world's population will be exposed to the risk of contracting malaria.¹ As well as its direct health cost, it carries a significant economic burden in countries where there is endemic disease:²

• Malaria is thought to take off 1.3% from the economic growth of some African countries.
• In some countries it accounts for 40% of public health expenditure, 30-50% of inpatient admissions, and 50% of outpatient visits.
• Malaria deters investment, tourism, and labour intensive cash-crops.

During the 1960s and 70s, there was optimism that malaria could be eradicated. The 1980s and 90s saw serious setbacks:

• The development of resistance to commonly used drugs.
• The development of resistance to commonly used insecticides.
• The breakdown of control programmes and local primary health services, often in the context of regional political and economic collapse.

Child deaths due to malaria doubled in subSaharan Africa in the 1990s and malaria remerged in Central Asia, Eastern Europe and previously clear areas of South East Asia. Political will to tackle malaria has picked up over the last decade, accompanied by ambitious international targets (for example, the Roll Back Malaria partnership aims to halve malaria deaths worldwide by 2010). The emphasis now is not on eradication, rather on control of what is a preventable and treatable disease.³

Malaria is a parasitic disease caused by infection from one of the four species of Plasmodium:

Humans acquire malaria after being bitten by an infected mosquito. The sporozoites in the mosquito saliva then travel via the blood stream 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.

Malaria occurs almost exclusively in the tropics and subtropics⁵ 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.²

Risk factors

The groups most at risk of developing developing severe disease are:⁶

• The poor (60% of malaria deaths 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)

Outside endemic areas, returning travellers from these regions can develop malaria. Malaria is the commonest imported tropical disease to the UK with 1500-2000 cases reported every year.⁷ A large number of cases of malaria occur in non-UK born people and their families after visiting Africa or South Asia. The reason for the higher incidence in this group is higher rates of travel and a significantly lower uptake of antimalarial prophylaxis - this is thought to be due to their underestimating risk and overestimating protection afforded by having been brought up in a malaria-endemic country.⁴
Risk of contracting malaria in travellers to these areas is proportional to the number of potentially infectious mosquito bites they receive. Risk factors for malaria in travellers, therefore, include:⁴

• Travel to areas of high humidity and ambient temperature between 20-30°C (there is no malarial transmission <16°C or at altitudes >200 m above sea level)
• Travel at times of high seasonal rainfall
• Visits to rural locations (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

There are occasional cases of malaria (<2 per annum) reported in individuals who have never been in a malarious area or having come in contact with infected blood (eg blood transfusion or IV drug abuse). Such cases usually occur around airports and seaports - such "airport malaria" is presumably caused by infected mosquitos hitching a ride from endemic regions in aircraft, ships, containers, luggage or buses. Always consider malaria a possibility in individuals working or living close to such airports and ports.⁸

Spread of drug resistance to P. falciparum

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-based combination therapies (ACTs) are life-saving in areas of high resistance. In order to preserve the efficacy of artemisinins, WHO has called for a ban on the use of oral artemisinin monotherapies.
[See also the Map of Drug Resistance in the Internet and Further Reading section below. ]

In view of the life-cycle of the malaria parasite, symptoms may occur from 6 days of naturally acquired infection to many months later. Most patients with falciparum infection present in the first month or months of infection. P.Vivax or ovale infections commonly present later than 6 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 malaria infections are wrongly diagnosed as non-specific viral infections, influenza, gastroenteritis or hepatitis. Children, in particular, are more likely to present with non-specific symptoms (fever, lethargy, malaise, somnolence) and to have gastro-intestinal 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)

As the initial presenting symptoms are non-specific, 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:

• Typhoid
• Hepatitis
• Dengue fever
• Avian influenza
• SARS
• HIV
• Meningitis/encephalitis
• Viral haemorrhagic fevers

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

Diagnostic investigations include:

• 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 lab in under an hour. If there is potential for delay, refer the patient to hospital for testing.⁷ Where the blood film is negative, at least 2 further films should be obtained over the next 48 hours, before excluding the diagnosis. Be aware that an individual can have malaria despite negative films. This is particularly the case in pregnancy where parasite biomass can be sequestered in the placenta - seek expert help early if concerned.
• 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. These tests may have uses in remote areas without formal medical facilities but there is a risk that travellers use them incorrectly and delay treatment as a consequence.⁴
• PCR is becoming available, but remains expensive and requires specialist equipment.

All cases of malaria should be notified to public health authorities and a blood specimen sent to the Malaria Reference Laboratory for confirmation.
Other investigations frequently performed include:

• Full blood count - typically reveals thrombocytopenia and anaemia. Leukocytosis is rarely seen but is an indicator of a poor prognosis when present.
• Liver function tests - often abnormal.
• Urea and electrolytes - may show lowered Na⁺ and increased creatinine.
• Low blood glucose may be present in severe disease.

Ill patients may also require:

• Blood gases
• Blood cultures
• Clotting studies
• Urine and stool culture
• CXR
• Lumbar puncture

The management of malaria depends not only on the severity of the disease, but also the strain of Plasmodium involved. 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 co-morbidities. G6PD activity should be measured in vivax or ovale infections as the primaquine (which is necessary to eliminate the dormant hypnozoites and prevent recurrence) can cause haemolysis in those with G6PD deficiency.

Falciparum malaria

Current guidelines⁷ suggest all patients with falciparum malaria should be admitted to hospital initially. Some specialist units in the UK and Europe treat certain groups with falciparum malaria as out-patients - but caution is advocated since 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 despite appropriate treatment.

Drugs

The choice of anti-malarial agent used will depend on the strain of Plasmodium, and the degree of resistance that it exhibits. Vivax and ovale may produce a dormant form in the liver that requires eradication if the disease is not to recur.
The local infectious diseases unit will be able to give advice and initiate appropriate treatment in line with the current UK guidelines.

Treatment of non-falciparum malaria

Current UK guidelines⁷ recommend:

• Chloroquine (20 mg/kg) 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 vivax malaria can be treated with quinine, co-artem or atovaguone-proguanil as for uncomplicated falciparum malaria.
• Prevention of relapse:
  • For treatment of P.ovale 15 mg primaquine/day for 14 days is recommended
  • Some strains of P.vivax require higher doses to prevent relapse so 30 mg primaquine/day for 14 days is suggested.
  • Expert help should be enlisted in treating those with G6PD deficiency.

Treatment for uncomplicated falciparum malaria

Current UK guidelines⁷ suggest possible alternative regimens for adults as:

1. Oral quinine sulphate 600 mg/8 h for 5-7 days plus doxycycline 200 mg daily (or clindamycin 450 mg/8 h for pregnant women) for 7 days
2. Atovaquone-proguanil (Malarone®): 4 standard tablets daily for 3 days
3. Co-artem (Riamet®): if weight>35 kg, 4 tablets stat and then further 4 tablets at 8, 24, 36, 48 and 60 hours

Clinical experience of co-artem and atovaquone-proguanil is relatively limited but the advantages of these regimens are that they are shorter and not associated with the common side-effects of nausea, deafness and ringing in the ears associated with quinine.

Treatment of severe or complicated falciparum malaria

Current UK guidelines⁷ suggest:

1. Intravenous quinine dihydrochloride is the first line antimalarial. A loading dose of 20 mg/kg over 4 hours, followed by 10 mg/kg 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.
2. Oral quinine sulphate 600 mg tds should be substituted once the patient is well enough to complete a 5-7 day course in total.
3. A second drug should always accompany quinine. 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.
4. Artesunate regimen - adults only, on expert advise. 2.4 mg/kg given as an IV injection and repeated at 12 and 24 hours and daily thereafter. Rectal formulations also exist but tend to be used in resource-poor settings where intravenous therapy is not possible. It should be accompanied by a 7 day course of doxycycline. Note, 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.

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

If left untreated, or treatment is delayed, malaria may be fatal, there are still 10-20 deaths in the UK⁷ and an estimated 1.5-2.7 million deaths worldwide⁶ from malaria every year. Cerebral malaria has a mortality rate of about 20%.

Use of effective chemoprophylaxis and insecticide treated nets prevents about 90% of malaria.⁴ Travellers can protect themselves from infection with malaria by taking sensible precautions:

• The use of a prophylactic regime appropriate to their travel itinerary. Note,travellers should be aware that this is not a guarantee against infection.
• Avoiding outdoor activity after sunset.
• Wearing long sleeved shirts, and trousers.
• Using insecticide-treated bed nets (ITNs), remembering to keep the netting clear of the bed as mosquitoes will bite through netting and clothing if still and touching the netting! (the reviewer has personal experience of a badly bitten knee as proof). Take needle and thread for netting repairs.
• Using insect repellent, for yourself, clothing, and re-treating netting.

Encourage non-UK born travellers to use precautions - 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.

For those living in malaria endemic countries, limited resources frequently makes malaria prevention very difficult to implement. Vector control (reducing the breeding grounds by spraying or destruction of habitat) has only had very limited success. More successful recent strategies include:³

• Use of ITNs
• Targeted chemoprophylaxis for those most at risk - for example, treating pregnant women twice during pregnancy improves maternal and infant outcomes.
• Indoor residual spraying

Hopes for the future include:⁶

• The development of vaccines.
• The development of new antimalarial drugs for prophylaxis and treatment (the Malaria Genome project will hopefully provide new targets for both drugs and vaccines).
• Molecular manipulation of the mosquito genome to produce transgenic mosquitoes that cannot infect humans.
• Reducing poverty and improving access to health care in malaria endemic regions.

The story of the human struggle to control malaria is not recent:

• Malaria has its origins in the dramatic climate change in Africa 7-12,000 years ago (increase in temperature and humidity creating new water sources and the start of agriculture in the Middle East and NE 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 2700BC (or BCE - before common era, for non-christians), and described the use of the Qinghoa 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.
• Malaria is Italian for "bad air", as it was noted that by 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 S 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 synthesized 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 naming the last of the four in 1922, P. ovale.
• 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 Andersag, though it was not recognised as an effective and safe antimalarial until 1946.
• A German chemistry student synthesized DT for his thesis in 1874, though its insecticidal properties were not recognised until 1939 by Muller, who won the Nobel Prize for Medicine in 1948.
• Lest we forget, malaria was endemic in the marshes of southern and eastern England from the 16th to 19th centuries (species vivax and malariae), and briefly reappeared after both the First and Second World Wars.

The number of Nobel Prizes awarded to work on malaria is testimony to its global importance and human impact.

The author is grateful to Dr David Ward for this historical section.