Human malaria can be caused by four species of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, P. malariae. Ocassionally other species of malaria usually found in primates can affect man. Malaria probably originated from animal malarias in central Africa, but was spread around the globe by human migration. Public health measures and changes in land use have eradicated malaria in most developed countries, although the potential for malaria transmission still exists in many areas. Five hundred million people are infected every year, and over one million die yearly. Twenty five thousand international travellers per year are infected
Epidemiology
Malaria is transmitted by the bite of female anopheline mosquitoes. The parasite undergoes a temperature-dependent cycle of development in the gut of the insect, and its geographical range therefore depends on the presence of the appropriate mosquito species and on adequate temperature. The disease occurs in endemic or epidemic form throughout the tropics and subtropics except for areas above 2000 m: Australia, the USA, and most of the Mediterranean littoral are also malaria-free. In hyperendemic areas (51-75% rate of parasitaemia, or palpable spleen in children 2-9 years of age) and holoendemic areas (> 75% rate) where transmission of infection occurs year round, the bulk of the mortality is seen in infants. Those who survive to adulthood acquire significant immunity; low-grade parasitaemia is still present, but causes few symptoms. In mesoendemic areas (11-50%) there is regular seasonal transmission of malaria. Mortality is still mainly seen in infants, but older children and adults may develop chronic ill health due to repeated infections. In hypoendemic areas (0-10%), where infection occurs in occasional epidemics, little immunity is acquired and the whole population is susceptible to severe and fatal disease.
Malaria can also be transmitted in contaminated blood transfusions. It has occasionally been seen in injecting drug users sharing needles and as a hospital-acquired infection related to contaminated equipment. Rare cases are acquired outside the tropics when mosquitoes are transported from endemic areas ('airport malaria'), or when the local mosquito population becomes infected by a returning traveller.
Parasitology
The female mosquito becomes infected after taking a blood meal containing gametocytes, the sexual form of the malarial parasite. The developmental cycle in the mosquito usually takes 7-20 days (depending on temperature), culminating in infective sporozoites migrating to the insect's salivary glands. The sporozoites are inoculated into a new human host, and those which are not destroyed by the immune response are rapidly taken up by the liver. Here they multiply inside hepatocytes as merozoites: this is pre-erythrocytic (or hepatic) sporogeny. After a few days the infected hepatocytes rupture, releasing merozoites into the blood from where they are rapidly taken up by erythrocytes. In the case of P. vivax and P. ovale, a few parasites remain dormant in the liver as hypnozoites. These may reactivate at any time subsequently, causing relapsing infection.
Inside the red cells the parasites again multiply, changing from merozoite, to trophozoite, to schizont, and finally appearing as 8-24 new merozoites. The erythrocyte ruptures, releasing the merozoites to infect further cells. Each cycle of this process, which is called erythrocytic schizogony, takes about 48 hours in P. falciparum, P. vivax and P. ovale, and about 72 hours in P. malariae. P. vivax and P. ovale mainly attack reticulocytes and young erythrocytes, while P. malariae tends to attack older cells; P. falciparum will parasitize any stage of erythrocyte.
A few merozoites develop not into trophozoites but into gametocytes. These are not released from the red cells until taken up by a feeding mosquito to complete the life cycle.
Causes of anaemia in malaria infection
Haemolysis of infected red cells
Haemolysis of non-infected red cells (blackwater fever)
Dyserythropoiesis
Splenomegaly and sequestration
Folate depletion
After repeated infections partial immunity develops, allowing the host to tolerate parasitaemia with minimal ill effects. This immunity is lost if there is no further infection for a couple of years. Certain genetic traits also confer some immunity to malaria. People who lack the Duffy antigen on the red cell membrane (a common finding in West Africa) are not susceptible to infection with P. vivax. Certain haemoglobinopathies (including sickle cell trait) also give some protection against the severe effects of malaria: this may account for the persistence of these otherwise harmful mutations in tropical countries. Iron deficiency may also have some protective effect. The spleen appears to play a role in controlling infection, and splenectomized people are at risk of overwhelming malaria. Some individuals appear to have a genetic predisposition for developing cerebral malaria following infection with P. falciparum. Pregnant women are especially susceptible to severe disease.
Clinical features
Typical malaria is seen in non-immune individuals. This includes children in any area, adults in hypoendemic areas, and any visitors from a non-malarious region.
he normal incubation period is 10-21 days, but can be longer. The most common symptom is fever, although malaria may present initially with general malaise, headache, vomiting, or diarrhoea. At first the fever may be continual or erratic: the classical tertian or quartan fever only appears after some days. The temperature often reaches 41°C, and is accompanied by rigors and drenching sweats.
P. vivax or P. ovale infection
The illness is relatively mild. Anaemia develops slowly, and there may be tender hepatosplenomegaly. Spontaneous recovery usually occurs within 2-6 weeks, but hypnozoites in the liver can cause relapses for many years after infection. Repeated infections often cause chronic ill health due to anaemia and hyperreactive splenomegaly.
P. malariae infection
This also causes a relatively mild illness, but tends to run a more chronic course. Parasitaemia may persist for years, with or without symptoms. In children, P. malariae infection is associated with glomerulonephritis and nephrotic syndrome.
This causes, in many cases, a self-limiting illness similar to the other types of malaria, although the paroxysms of fever are usually less marked. However it may also cause serious complications and the vast majority of malaria deaths are due to P. falciparum. Patients can deteriorate rapidly, and children in particular progress from reasonable health to coma and death within hours. A high parasitaemia (> 1% of red cells infected) is an indicator of severe disease, although patients with apparently low parasite levels may also develop complications. Cerebral malaria is marked by diminished consciousness, confusion, and convulsions, often progressing to coma and death. Untreated it is universally fatal. Blackwater fever is due to widespread intravascular haemolysis, affecting both parasitized and unparasitized red cells, giving rise to dark urine.
Some features of severe falciparum malaria
CNS
Cerebral malaria (coma convulsion)
Renal
Haemoglobinuria (blackwater fever)
Oliguria
Uraemia (acute tubular necrosis)
Blood
Severe anaemia (haemolysis and dyserythropoiesis)
Disseminated intravascular coagulation (DIC)
Respiratory
Acute respiratory distress syndrome
Metabolic
Hypoglycaemia (particularly in children)
Metabolic acidosis
Gastrointestinal/liver
Diarrhoea
Jaundice
Splenic rupture
Other
Shock - hypotensive
Hyperpyrexia
Diagnosis
Malaria should be considered in the differential diagnosis of anyone who presents with a febrile illness in, or having recently left, a malarious area. Falciparum malaria is unlikely to present more than 3 months after exposure, even if the patient has been taking prophylaxis, but vivax malaria may cause symptoms for the first time up to a year after leaving a malarious area.
Diagnosis is usually made by identifying parasites on a Giemsa-stained thick or thin blood film (thick films are more difficult to interpret, and it may be difficult to speciate the parasite, but they have a higher yield). At least three films should be examined before malaria is declared unlikely. An alternative microscopic method is quantitative buffy coat analysis (QBC), in which the centrifuged buffy coat is stained with a fluorochrome which 'lights up' malarial parasites. A number of antigen-detection methods for identifying malarial proteins and enzymes have been developed. Some of these are available in card or dipstick form, and are potentially suitable for use in resource-poor settings. Serological tests are of no diagnostic value.
Parasitaemia is common in endemic areas, and the presence of parasites does not necessarily mean that malaria is the cause of the patient's symptoms. Further investigation, including a lumbar puncture, may be needed to exclude bacterial infection.
Management
Drug treatment of uncomplicated malaria in adults
Type of malaria
Drug treatment
Plasmodium vivax, P. ovale, P. malariae, CQ-sensitive P. falciparum
Chloroquine:600 mg
300 mg 6 hours later
300 mg 24 hours later
300 mg 24 hours later
CQ-resistant, SP-sensitive P. falciparum Fansidar (SP): 3 tablets as single dose
CQ- and SP-resistant P. falciparum Quinine: 600 mg 3 times daily for 7 days plus
Tetracycline: 500 mg 4 times daily for 7 days or Fansidar (SP): 3 tablets as single dose
Alternative therapies
Mefloquine: 20 mg/kg in 2 doses 8 hours apart or Malarone: 4 tablets daily for 3 days or Coartemether: 4 tablets 12-hourly for 3 days or Lapdap (chlorproguanil/dapsone)
ollowing successful treatment of P. vivax or P. ovale malaria, it is necessary to give a 2- to 3-week course of primaquine (15 mg daily) to eradicate the hepatic hypnozoites and prevent relapse. This drug can precipitate haemolysis in patients with G6PD deficiency
Prevention and control.
Area visited Prophylactic regimen Alternatives
No chloroquine resistance Chloroquine 300 mg weekly Proguanil 200 mg daily
Limited chloroquine resistance
Significant chloroquine resistance
Chloroquine 300 mg weekly plus
Proguanil 200 mg daily
Mefloquine 250 mg weekly Doxycycline 100 mg daily
Or
Mefloquine 250 mg weekly
Doxycycline 100 mg daily
Or
Malarone 1 tablet daily
