History of Malaria
Malaria is a protozoal disease transmitted by the Anopheles mosquito, caused by minute parasitic protozoa of the genus Plasmodium, which infect human and insect hosts alternatively. It is a very old disease and prehistoric man is thought to have suffered from malaria. It probably originated in Africa and accompanied human migration to the Mediterranean shores, India and South East Asia. In the past it used to be common in the marshy areas around Rome and the name is derived from the Italian, (mal-aria) or "bad air"; it was also known as Roman fever. Today some 500 hundred million people in Africa, India, South East Asia and South America are exposed to endemic malaria and it is estimated to cause two and a half million deaths annually, one million of which are children.
Fishermen and traders, long before British colonisation, probably introduced the disease into northern Australia and in the past malaria was not uncommon in the northern parts of the country. In Western Australia an explosive outbreak of falciparum malaria occurred at Fitzroy Crossing in 1934 which at first was mistaken for influenza and resulted in 165 deaths. WHO declared Australia free of malaria in 1981, however since that time 9 patients have contracted locally acquired malaria.
The so called "airport malaria" has become a problem in recent years. A publican working in an establishment close to London's Heathrow Airport became acutely ill and was found to be suffering from falciparum malaria; he had never been out of the country. A lady driving her car past the same airport became ill with malaria although she too had never been out of the country. Four workers unloading a cargo plane at Amsterdam airport became infected with malaria. It is assumed that infected mosquitoes were carried on planes from Africa and released at the destination airport.
World Distribution of Malaria
While it was recognised that the Anopheles mosquito played a key role in the transmission of the disease, it was not until 1948 that all the stages in its life cycle were identified. The parasite undergoes a development stage in the mosquito and the female of the species requires a blood meal to mature her eggs. She bites a human and injects material from her salivary glands, which contains primitive malarial parasites called sporozoites, before feeding. These sporozoites circulate in the blood for a short time and then settle in the liver where they enter the parenchymal cells and multiply; this stage is known as pre-erythrocytic schizogony. After about 12 days there may be many thousands of young parasites known as merozoites in one liver cell, the cell ruptures and the free merozoites enter red blood cells. The blood stages of the four species of malaria can be seen in the section on diagnosis. In the case of P. vivax, and P.ovale the liver cycle continues and requires a course of primaquine to eliminate it. P.falciparum on the other hand does not have a continuing liver cycle.
In the red blood cells the parasites develop into two forms, a sexual and an asexual cycle. The sexual cycle produces male and female gametocytes, which circulate in the blood and are taken up by a female mosquito when taking a blood meal. The male and female gametocytes fuse in the mosquito's stomach and form o÷cysts in the wall of the stomach. These o÷cysts develop over a period of days and contain large numbers of sporozoites, which move to the salivary glands and are ready to be injected into man when the mosquito next takes a meal. In the asexual cycle the developing parasites form schizonts in the red blood cells which contain many merozoites, the infected red cells rupture and release a batch of young parasites, merozoites, which invade new red cells. In P.vivax, P.ovale and probably P.malariae, all stages of development subsequent to the liver cycle can be observed in the peripheral blood. However, in the case of P.falciparum only ring forms and gametocytes are usually present in the peripheral blood. Developing forms appear to stick in the blood vessels of the large organs such as the brain and restrict the blood flow with serious consequences.
While all four species have a haemolytic component ie. when a new brood of parasites break out of the red blood cell, this is usually of little consequence. The exception is falciparum malaria where the parasites multiply very rapidly and may occupy 30% or more of the red blood cells causing a very significant level of haemolysis. One reason for this is that P.falciparum invades red cells of all ages whereas P.vivax and P.ovale prefer younger red cells, while P.malariae seeks mature red cells.
Life Cycle of the Malarial Parasite
History of Treatment and Prophylaxis
Antimalarial drugs fall into several chemical groups and it is useful to have some knowledge of their chemistry. The aim here is to give a brief outline of anti-malarial drugs and their usefulness today, when drug resistant strains of malaria have become a major problem. It is not a comprehensive history nor does it include a number of drugs which are no longer used.
Quinine has been used for more than three centuries and until the 1930's it was the only effective agent for the treatment of malaria. It is one of the four main alkaloids found in the bark of the Cinchona tree and is the only drug which over a long period of time has remained largely effective for treating the disease. It is now only used for treating severe falciparum malaria partly because of undesirable side effects. In Africa in the 1930's and 40's it was known for people to take quinine when they thought they had "a touch of malaria" and the association of repeated infections with falciparum malaria and inadequate treatment with quinine, resulted in the development in some of acute massive intravascular haemolysis and haemoglobinuria ie. black water fever.
This drug is a 9-amino-acridine developed in the early 1930's. It was used as a prophylactic on a large scale during the Second World War (1939-45) and was then considered a safe drug. It had a major influence in reducing the incidence of malaria in troops serving in South East Asia. It is now considered to have too many undesirable side effects and is no longer used .
A very effective 4-amino-quinoline both for treatment and prophylaxis. It was first used in the 1940s shortly after the Second World War and was effective in curing all forms of malaria, with few side effects when taken in the dose prescribed for malaria and it was low in cost. Unfortunately most strains of falciparum malaria are now resistant to chloroquine and more recently chloroquine resistant vivax malaria has also been reported.
This drug falls into the biguanide class of antimalarials and was first synthesised in 1946. It has a biguanide chain attached at one end to a chlorophenyl ring and it is very close in structure to pyrimethamine. The drug is a folate antagonist and destroys the malarial parasite by binding to the enzyme dihydrofolate reductase in much the same way as pyrimethamine. It is still used as a prophylactic in some countries.
In 1998 a new drug combination was released in Australia called Malarone. This is a combination of proguanil and atovaquone. Atovaquone became available 1992 and was used with success for the treatment of Pneumocystis carrinii. When combined with proguanil there is a synergistic effect and the combination is at the present time a very effective antimalarial treatment. The drug combination has undergone several large clinical trials and has been found to be 95% effective in otherwise drug resistant falciparum malaria. How long it will be before resistant strains of malaria appear remains to be seen. It has been claimed to be largely free from undesirable side effects but it should be noted that proguanil is an antifolate. This is not likely to be a problem with a single treatment course of the drug but some caution should be exercised when using it for prophylaxis. At present it is a very expensive drug.
A combination of dapsone and pyrimethamine. Resistance to this drug is now widespread and its use is no longer recommended.
This is a combination drug, each tablet containing sulphadoxine 500mg. and pyrimethamine 25mg. It acts by interfering with folate metabolism. Resistance to Fansidar is now widespread and serious side effects have been reported. It is no longer recommended.
First introduced in 1971, this quinoline methanol derivative is related structurally to quinine. The compound was effective against malaria, resistant to other forms of treatment when first introduced and because of its long half life was a good prophylactic, but widespread resistance has now developed and this together with undesirable side effects have resulted in a decline in its use.
Because of its relationship to quinine the two drugs must not be used together. There have been reports of various undesirable side effects including several cases of acute brain syndrome, which is estimated to occur in 1 in 10,000 to 1 in 20,000 of the people taking this drug. It usually develops about two weeks after starting mefloquine and generally resolves after a few days.
This belongs to a class of compound called the phenanthrene-methanols and is not related to quinine. It is an effective antimalarial introduced in the 1980s, but due to its short half life of 1 to 2 days, is therefore not suitable for use as a prophylactic. Unfortunately resistant forms are increasingly being reported and there is some concern about side effects. Halofantrin has been associated with neuropsychiatric disturbances. It is contraindicated during pregnancy and is not advised in women who are breastfeeding. Abdominal pain, diarrhoea, puritus and skin rash have also been reported.
This is derived from a Chinese herbal remedy and covers a group of products. The two most widely used are artesunate and artemether. While they are widely used in Southeast Asia they are not licensed in much of the so called "Western World", including Australia. A high rate of treatment failures has been reported and it is now being combined with mefloquine for the treatment of falciparum malaria.