● Malaria 361 ● Trypanosomal infection 364 MALARIA CHAPTER 47 MALARIA AND OTHER PARASITIC INFECTIONS It estimated that malaria infects 300–500 million humans per year throughout the world, and up to 2 million (mainly children) die annually. Approximately 40% of the world population live in malarious areas, particularly in equatorial regions. Malaria is transmitted to humans in the saliva of the anopheles mosquito and is caused by protozoan organisms of the genus Plasmodium. There are four major species, namely P. falciparum, P. vivax, P. ovale and P. malariae. P. falciparum is the most lethal form. Malaria is one of the most common causes of serious illness in the returning traveller. At least 2000 cases are imported into the UK (10 000 in Europe) per year. Air travel and the incubation period of the disease have raised the awareness of diagnosing and appropriately treating malaria even in areas where it is not endemic (e.g. hospitals near international airports in Western Europe and the USA). Female anopheline mosquito Sporozoites (in salivary gland) Oocyst Zygote Microgamete and macrogamete BITE Erythrocytic stages Schizogony BITE Schizonts Human Hepatic Pre-erythrocyte phase Merozoites Trophozoites Microgametocyte and macrogametocyte �ve �ve �ve �ve �ve ● Helminthic infection 364 Visitors to endemic areas must be warned of the infection risk and advised that prophylactic drug therapy should be taken, but that it is not 100% effective. They should also be advised to wear long-sleeved clothing to cover extremities (especially in the evenings, when mosquitos feed) to use mosquito-repellent sprays, to sleep in properly screened rooms with mosquito nets (impregnated with pyrethroids) around the bed and/or to burn and vapourize synthetic pyrethroids during the night. In addition to chemoprophylactic drug therapy, travellers to remote areas should be advised to carry standby antimalarial drug treatment with quinine. Where there is doubt concerning the suitability of drug therapy for malaria prophylaxis or treatment, the malaria reference laboratory at the London School of Hygiene and Tropical Medicine has advice and guidance (Tel. 020 7636 3924 for health professionals and Tel. 09065 508908 for the general public, regarding malaria prophylaxis: website www.hpa.org.uk/srmd/malaria). Figure 47.1 illustrates the Plasmodium life cycle and the therapeutic targets. Drug therapy Suppressive (quinacrine, pyrimethamine) Clinical cure (chloroquine, quinine, amodiaquine, pyrimethamine, mefloquine, halofantrine) Atovaquone Artemesinin Gametocidal (pyrimethamine) Radical cure (primaquine) Figure 47.1: Malaria life cycle and type of drug treatment.
362 MALARIA AND OTHER PARASITIC INFECTIONS Key points The malaria parasite • Plasmodium falciparum infection has the highest mortality and causes cerebral malaria. • P. malariae, P. ovale and P. vivax cause more benign disease. • The hepatic forms of P. ovale and P. vivax cause relapses. • Antimalarial drugs act at different stages of the malaria parasite’s life cycle. • Resistance, especially of P. falciparum, to chloroquine, sulfadoxine–pyrimethamine and mefloquine is an increasing problem world-wide. MALARIA PROPHYLAXIS Malaria prophylaxis is relative and the agents are chosen mainly on the basis of the susceptibility patterns of the local Plasmodium species. The arylaminoalcohols (e.g. mefloquine), 4-aminoquinolines (e.g. chloroquine) and the antifolate agents (e.g. pyrimethamine and proguanil) are the major prophylactic drugs. Prophylaxis must start at least one week (and preferably two weeks) before entering a malaria endemic region, and must continue for four weeks afterwards. Chloroquine is only used as a prophylactic in regions where falciparum malaria is not chloroquine resistant. Drugs for the prophylaxis of chloroquine-resistant falciparum malaria are shown below; items 3 and 4 appear to be well tolerated. 1. mefloquine, weekly; 2. chloroquine, weekly plus proguanil daily; 3. doxycycline daily; 4. atovaquone and proguanil daily. Key points Malaria prophylaxis • All travellers to an endemic area should be made aware of the risks. • Use appropriate measures to avoid mosquito bites (e.g. repellents, appropriate cover at night, mosquito nets). • The choice of chemoprophylaxis regimen is dependent on the dominant local parasite species and its drug resistance profile. • Chemoprophylaxis must start before, and continue after, travel to and from an endemic area. • Full compliance with the chemoprophylaxis regimen is necessary. • Drug choice and doses may need to be altered in patients with renal or hepatic dysfunction. • Prophylaxis is not 100% effective. PREVENTION OF MALARIA IN PREGNANCY Chloroquine or mefloquine (in chloroquine-resistant areas) are believed to be the most effective and safest antimalarial drugs for chemoprophylaxis in pregnancy. DRUG TREATMENT OF ACUTE MALARIA THE 4-AMINOQUINOLINES (E.G. CHLOROQUINE) CHLOROQUINE Uses Chloroquine is still one of the most commonly used antimalarial drugs world-wide, but increasing resistance (especially P. falciparum) has reduced its efficacy. It is used in: • acute malaria – chloroquine is effective in terminating an acute attack of benign vivax malaria, but is not radically curative because it does not eradicate the latent hepatic forms of the parasite, and relapses can occur subsequently. If given intravenously, chloroquine can cause encephalopathy. Following a course of chloroquine, primaquine may be given for 14–21 days to achieve a radical cure (i.e. to eliminate hepatic forms and prevent relapse). Before starting primaquine, the possibility of glucose-6-phosphate dehydrogenase (G6PD) deficiency should be considered (Chapter 14). • malaria prophylaxis (see above); • rheumatoid arthritis or systemic lupus erythematosis may be treated with chloroquine or hydroxychloroquine (Chapter 26). Antimalarial mechanism of action The erythrocyte stages of Plasmodium are sensitive to chloroquine. At this stage of its life cycle, the parasite digests haemoglobin in a food vacuole to provide energy for the parasite. The food vacuole is acidic and the weak base chloroquine is concentrated within it by diffusion ion-trapping. Chloroquine and other 4-aminoquinolines are believed to inhibit the malarial haem polymerase within the food vacuole of the plasmodial parasite, thereby inhibiting the conversion of toxic haemin (ferriprotoporphyrin IX) to haemozoin (a pigment which accumulates in infected cells and is not toxic to the parasite). Ferriprotoporphyrin IX accumulates in the presence of chloroquine and is toxic to the parasite, which is killed by the waste product of its own appetite (‘hoist with its own petard’). Adverse effects Short-term therapy These include the following: 1. mild headache and visual disturbances; 2. gastro-intestinal upsets; 3. pruritus. Prolonged therapy These include the following: 1. retinopathy, characterized by loss of central visual acuity, macular pigmentation (‘bull’s-eye’ macula) and retinal artery constriction. Progressive visual loss is halted by stopping the drug, but is not reversible; 2. lichenoid skin eruption; 3. bleaching of hair; 4. weight loss; 5. ototoxicity (cochleovestibular paresis in fetal life).