Clinical Review - Malaria

Contributed by Dr Charlie Easmon specialist adviser in travel medicine and medical director at The Number One Health Group Ltd, London

Section 1: Epidemiology and aetiology
Malaria parasites are single-celled hermaphrodites that can reproduce both asexually and sexually.

Ten types are known to infect humans but only four are of practical importance: Plasmodium falciparum, P vivax, P malariae and P ovale.

Their life cycle requires two stages - a mosquito vector and a vertebrate host. Human red blood cells or liver cells become infected before the sexual forms (gametocytes) are sucked up by a female anopheline mosquito, which feeds on humans. The mosquito, which feeds at dusk and dawn, then goes on to transmit to another person or animal.

Malaria parasite within a human red blood cell

The geographical spread of malaria has reduced over the centuries, partly because of public health measures (Mussolini drained the Pontine Marshes in Rome) and improved economies (in India malaria can now be regarded as both seasonal and regional).

Malaria is still a common and life-threatening disease in many tropical and subtropical areas. It is currently endemic in over 100 countries, which are visited by more than 125 million international travellers every year.

Incidence
Each year over 10,000 travellers are reported to fall ill after returning home. Due to under-reporting, the real figure may be as high as 30,000.

The heaviest burden is in areas with high levels of anopheline mosquito breeding sites such as green leaf vegetation cover.1

P falciparum is the most deadly form of malaria. It causes cerebral malaria, pulmonary oedema and end-organ failure. It can be thought of as 'kill or cure' in tourists to endemic areas because no recurrence of the same infection has been reported for this disease.

P falciparum is estimated to account for 80 per cent of all human malarial infections and 90 per cent of the deaths. It is more prevalent in sub-Saharan Africa than in other regions.

The other three plasmodia listed all have liver phases where the parasite lays dormant (hypnozoites). The longest recorded recurrence of the same infection is more than 30 years.

P vivax causes far fewer deaths than P falciparum but has been estimated to cause up to 80 million clinical cases annually in Latin America, the Indian subcontinent, the south-western Pacific and southeast Asia. 2

Inadequate advice
Sadly, many studies show that advice to travellers to protect themselves against malaria is universally poor.

An airport survey found that a third of Spanish travellers to sub-Saharan Africa had received no malaria prophylaxis at all.3

A German study showed similarly low correct chemoprophylaxis rates (35-53 per cent).4

In the UK we could reduce imported malaria by ensuring those who visit their friends and relatives in Africa or India are better informed.5

Section 2: Diagnosis
Fever with a flu-like illness and relevant travel within the past 12 months should be considered as malaria until proven otherwise.

A travel history should be an essential part of the GP consultation.

Malaria can start as a mild malaise. A common myth is to rely on the presence or absence of fever but malaria symptoms may be simple headache, diarrhoea, cough, vomiting and abdominal cramps.6

Because the parasite can multiply rapidly and, in the case of P falciparum cause death within 24 hours, do not wait to see if a fever develops. Symptoms prior to death can include all aspects of organ failures, severe headache, vomiting and coma.

So-called 'semi-immunity' requires frequent exposure to infecting bites and is progressively lost after an undefined time in a non-endemic area.

The clinical manifestations in semi-immune patients may be milder disease and quicker recovery - faster fever clearance time and faster parasite clearance time.7

Most UK residents who visit friends and relatives in Africa should not consider themselves semi-immune because this level of protection soon wanes after a lack of exposure to the parasite.

How soon is not known but some have estimated a period as short as six months.

It is worth noting that malaria can still occur in people who correctly used chemoprophylaxis and repellents, estimated to be 90 per cent effective.

Investigations
The gold standard is a thick and thin blood film performed by a laboratory competent to recognise the strain and the severity of the parasite load. If you have doubts about the experience of your local lab ask them for a second opinion from The Hospital for Tropical Diseases or the Liverpool School of Tropical Medicine.

The blood test can be taken at any time; do not wait for a fever.

Malaria antigens can also be tested for by an FDA-approved test (see box). This rapid whole blood immunochromatographic qualitative test costs approximately £25 per case and has a high level of accuracy for P falciparum and also tests for the other three types of malaria.

Two antibodies are tested for: 1) specific for the histidine-rich protein II antigen of P falciparum, 2) specific for an antigen common to all four types.

However, note that the test will still read positive for P falciparum for several days after the parasites have been cleared.

Urgent investigations required

  • Thick and thin blood films and malaria rapid antigen tests - ask lab for a result within one hour.
  • FBC, LFTs, U&Es, blood glucose.
  • Blood cultures for typhoid and other bacteraemia.
  • Urine dipstick and culture, and faeces if patient has diarrhoea.
  • Chest radiograph to exclude community-acquired pneumonia.

Source: British Infection Society and Health Protection Agency algorithm for initial Assessment and management

Section 3: Management

Prevention is of course better than cure. The ABCD rule applies.8

A - Awareness

B - Bite avoidance

C - Compliance/adherence9 with anti-malaria medication

D - Diagnosis

International advice varies about the duration and safety of the different types of chemoprophylaxis. UK doctors advising long-term travellers should read the Advisory Committee on Malaria Prevention in UK Travellers guidance and not rely on the standard advice for short-term travellers.10

No prophylactic, apart from primaquine (which is rarely used in this capacity), has the same level of efficacy against P vivax and P ovale as for P falciparum.

In practical terms, this means that, despite prophylaxis, always be on the alert for the possibility of an illness within 12 months of travel being caused by P vivax or P ovale.11

This is important as the level of protection is less than 90 per cent but is offset by the fact that neither P vivax nor P ovale carries a high risk of death in UK tourists.

Current treatments
The diagnosis and management of malaria are well summarised by an algorithm produced by the British Infection Society (BIS)and the Health Protection Agency.12

Careful management is required for P falciparum, and some controversy exists as to whether such cases are best managed in a specialist centre, or whether milder cases could be treated as outpatients.

The French Speaking Society of Infectious Diseases13 has recommended conditions for outpatient treatment and a study refines this to suggest that those likely to have fast parasite clearance times could indeed be treated as outpatients.14

Patients with severe malaria, admission temperature greater than or equal to 40 degsC, GI signs, higher initial parasitaemia or platelet count lower than 50,000 should be treated in hospital.

If the infective species is not known, or if the infection is mixed, initial treatment should be as for P falciparum malaria.

Treatment options

In P falciparum or mixed infections treatment for adults is:

Quinine with either doxycycline or clindamycin

OR

Proguanil with atovaquone (Malarone)

OR

Artemether with lumefantrine (Riamet).

Chloroquine may be used for benign malarial infections.

In most parts of the world P falciparum is now resistant to chloroquine so this is no longer suitable for treatment. Mefloquine is now rarely used for treatment because of concerns about resistance.

In seriously ill patients who are unable to take tablets quinine should be given by IV infusion. Specialist advice should be sought in difficult cases (see BIS algorithm).12

Children and pregnant women with malaria are best managed by specialists. P falciparum malaria is particularly dangerous in pregnancy, especially in the last trimester.

Benign malarias
Benign malaria is usually caused by P vivax and less commonly by P ovale and P malariae. Chloroquine is the first-line treatment of benign malarias, but chloroquine-resistant P vivax infection has been reported from Indonesia, New Guinea and some adjacent islands.

Chloroquine alone is suitable for P malariae infections.

In the case of P vivax and P ovale, the parasites in the liver need to be destroyed in order to prevent relapses.

This is achieved with 14 days of primaquine given after chloroquine at a dose of 30mg daily for P vivax and 15mg daily for P ovale.

In pregnancy, the adult treatment doses of chloroquine can be given for benign malaria. In the case of P vivax or P ovale, however, primaquine should be postponed until the pregnancy is over. Chloroquine may be used instead at a dose of 300 mg per week during the pregnancy.15

Section 4: The future of malaria
Malaria has fortunately disappeared from many areas - one of the best examples is from the fenlands of the UK.

In some parts of the world malaria has been controlled by residual dichloro-diphenyl-trichloroethane (DDT) spraying but recurred with a vengeance when this was stopped in many countries because of environmental concerns.

Four tools are needed for a country to control malaria:

  • Insecticide-treated bed nets;
  • Treatment of malaria cases;
  • Intermittent prophylaxis for the vulnerable (pregnant women and intermittent preventive treatment for infants);
  • Spraying to reduce the mosquito count.

Fortunately, more funding, focus and determination is now available from the public and the private sector.

CRISTINA PEDRAZZINI / SCIENCE PHOTO LIBRARY

Insecticide-treated bed nets are key to controlling malaria spread

Malaria vaccine
Because malaria is so prevalent, even a low efficacy vaccine would be of benefit in reducing illness and death. Hopefully, with continued investment and research, a vaccine will come to play a key role in the future battle to control malaria.

Various vaccines are currently in development. Approaches involve finding a suitable antigen and a way of synthesising it. The antigen also needs to be combined with a potent, easily reproducible adjuvant.

The Malaria Vaccine Initiative and GlaxoSmithKline are currently in phase II trials in several African countries (Kenya, Tanzania, Mozambique, Ghana, Gabon and Burkina Faso) with a candidate vaccine called RTS,S which contains parts of the circumsporozoite protein combined with hepatitis B surface antigen.

Another vaccine candidate aims to block the receptors for P vivax malaria (ICGEB PvRII). A third candidate involves live but attenuated P falciparum sporozoites (Sanaria Pf SPZ).

 

Further resources

References

1. Machault V, Orlandi-Pradines E, Michel R et al. Remote sensing and malaria risk for military personnel in Africa. J Travel Med. 2008 15: 216-20.

2. Dao N, Cuong B, Ngoa N et al. Vivax malaria: preliminary observations following a shorter course of treatment with artesunate plus primaquine. Trans R Soc Trop Med Hyg 2007; 101: 534-9.

3. Lopez-Velez R, Bayas J M. Spanish Travelers to High-Risk Areas in the Tropics. J Travel Med 2007; 14: 297-305.

4. Ropers G, Du Ry van Beest Holle M, Wichmann O, et al. Determinants of malaria prophylaxis among German travelers to Kenya, Senegal, and Thailand. J Travel Med 2008; 15 : 162-71.

5. Smith A D, Bradley D J, Smith V et al. Imported malaria and high risk groups. BMJ 2008 3;337: a120.

6. Freedman D O, Malaria Prevention in short-term travellers. N Engl J Med 2008; 359: 603-12.

7. Mascarello M, Allegranzi B, Angheben A, et al. Imported Malaria in Adults and Children: Epidemiological and Clinical Characteristics of 380 Consecutive Cases Observed in Verona, Italy. J Travel Med. 2008; 15: 229-36.

8. British Infection Society www.britishinfectionsociety.org/documents/malariapreventionBIS07.pdf

9. Berg J, Visser L G. Expatriate Chemoprophylaxis Use and Compliance. J Travel Med 2007; 14: 357-8.

10. van Genderen P J, Koene H R, Spong K, Overbosch D. The safety and tolerance of atovaquone/proguanil for the long-term prophylaxis of plasmodium falciparum malaria in non-immune travelers and expatriates (corrected title). J Travel Med 2007; 14: 92-5.

11. Maguire J D, Llewellyn D M. Relapsing Vivax Malaria After 6 Months of Daily Atovaquone/Proguanil in Afghanistan. J Travel Med 2007; 14: 411-14.

12. British Infection Society www.britishinfectionsociety.org/documents/MalariaAlgorithm07.pdf

13. The 12th Consensus Conference of Anti-infectious Therapy of the French-speaking Society of Infectious Diseases, 14 April 1999. Management and prevention of imported Plasmodium falciparum malaria. Arch Pediatr 2000; 7: 201-8.

14. Briand V, Bouchaud O, Tourret J. Hospitalization Criteria in Imported Falciparum Malaria. J Travel Med 2007; 14: 306-11.

15. British National Formulary 55, London; BMJ Group, March 2008.

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