species infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. A fifth species, Plasmodium knowlesi normally parasitizes monkeys but sometimes causes fatal human infections. In addition, there are rare case reports of people becoming infected by species of Plasmodium that normally parasitize other animals. In most vertebrate hosts, Plasmodium parasites are not particularly pathogenic but in humans, they cause the disease malaria. Historical literature usually refers to it as the ague or marsh fever. The word ague derives from the Latin for sharp (acutus) because it manifests as a sharp fever (febris acuta) whilst living in a marshy district has long been associated with ill health – although this was attributed to the bad air (hence mal aria) rather than the anopheline mosquitoes flying in it.
Plasmodium falciparum, P. vivax, P. ovale and P. malariae exhibit marked differences in their biology, and molecular evidence suggests that they evolved from separate lineages. That is, they are more closely related to Plasmodium species that parasitise other animals than they are to one another. Interestingly, molecular evidence indicates that P. falciparum originated in gorillas and humans recently acquired the disease in a single cross‐species transmission. Therefore, contrary to previous assumptions, P. falciparum does not derive from chimpanzees nor did it originate in primitive human ancestors (Liu et al. 2010). It is also now apparent that P. vivax originated in Africa millions of years ago among chimpanzees, gorillas, and ancestral humans (Loy et al. 2017).
Malaria causes a higher human mortality than any other parasitic disease although the situation is improving in many countries. Between 2000 and 2017, there were significant reductions in both the number of cases and the mortality associated with malaria https://www.afro.who.int/health‐topics/malaria. In 2000, there were 233 million cases of malaria resulting in 985,000 deaths, but by 2017, the figures had declined to 219 million cases and 435,000 deaths. Although malaria transmission occurs in 91 countries and approximately 50% of the world’s population is at risk of contracting the disease, most cases occur in just 15 countries with Nigeria accounting for 27% of them and the Democratic Republic of Congo for 10%. Indeed, approximately 90% of the fatal cases occur in sub‐Saharan Africa and involve children less than 5‐years‐old. Even within a country, there can be big differences in the risks of contracting malaria. In Nigeria (population ~201 million), 76% of people live in malaria prone areas, whilst the remaining 24% live in areas of low transmission. Similarly, in Kenya (population ~47.6 million), there is virtually no risk of the disease in some regions, whilst in others the risk is high, and it is a major cause of childhood mortality. Unfortunately, at the time of writing (2021), efforts to make further reductions appear to have stalled. Regardless of whether it causes fatal disease, wherever malaria is common amongst a community it has serious socioeconomic consequences and contributes to poverty. This is because illness prevents people from working and/or they are less productive. In addition, because the disease is particularly severe in young children, they are unable to attend school and gain the education that would improve their chances in life. Some estimates suggest that the direct costs of malaria are US$12 billion per year and the indirect costs resulting from reduced economic growth substantially more. However, the causes of poverty are complex and whilst malaria undoubtedly causes immense hardship, it is not the main reason that so many people in the developing countries remain poor (Utzinger and Tanner 2013).
How Malaria Has Influenced the Course of History
Malaria has influenced the course of history for thousands of years and remains relevant today. The distinctive symptoms of chronic and repeated infections of malaria can be identified with almost complete certainty from historical descriptions from ancient civilisations of Egypt, Sumeria, China, and India. For example, a Chinese medical text, the Nei Cheng, written in approximately 2700 BC refers to epidemics of the ‘Mother of Fevers’ that is undoubtedly malaria. The authors describe the cyclical fevers and an enlarged spleen that are features of malaria. Similarly, the symptoms of malaria can be identified from the writings of Hippocrates in Ancient Greece (~500 BC). Some authors have suggested that the decline of the Ancient Greek and Roman civilisations was associated with effects of malaria epidemics (Poser and Bruyn 1999). More recently, during WW2, an outbreak of malaria among allied troops in 1943 seriously compromised their attempts to invade Sicily. American troops suffered similar problems with malaria during the Vietnam war in the 1960s. Although malaria caused only about 0.2% of fatalities among the American troops, the debilitating effects reduced the combat strength of some units by up to 50%. The Viet Cong were aware of the problems that malaria caused the American troops and intentionally sabotaged local mosquito and malaria control programmes. They were successful in undermining malaria control over large areas, but consequently the combat strength of their own troops was also severely compromised (Drisdelle 2011).
Today, malaria is considered a tropical disease, but it was once a common disease in many of the temperate regions of the world. Malaria was a major cause of mortality in parts of Italy and Greece as late as the 1920s (Snowdon 2006). Malaria existed in the United Kingdom until the early years of the twentieth century, particularly in the fenland regions (Reiter 2000). The potentially fatal consequences of the ague are alluded to in works by Geoffrey Chaucer (c1343–1400) and William Shakespeare (1564–1616), so the disease was obviously common enough for their audiences to be familiar with it. Samuel Pepys (1633–1703) describes suffering from the ague in his diaries and historical accounts state that Oliver Cromwell (1599–1658) died from an attack of the ‘tertian ague’.
3.4.1.1 Plasmodium Life Cycle
The Plasmodium species that infect humans have a complex life cycle that involves both asexual and sexual reproductive stages (Figure 3.10). They are all transmitted by Anopheline mosquitoes and multiplication takes place in both humans and the mosquito vector. Only female mosquitoes feed on blood, as they require nutrients contained within it to produce their eggs. Male mosquitoes feed on nectar and other sugary solutions, and therefore, only female mosquitoes transmit malaria.
Figure 3.10 Life cycle of Plasmodium falciparum. 1: An infected mosquito injects sporozoites into the blood stream and these travel to the liver. The sporozoites invade the hepatocytes and undergo exoerythrocytic schizogony to produce numerous merozoites. 2: Merozoites leave the liver cells, enter the circulation, and infect red blood cells. They transform into ring‐shaped trophozoites that develop into schizonts (erythrocytic schizogony), which then form numerous merozoites. The parasites export proteins that re‐model the cell membrane of infected red blood cells so that ‘knobs’ are formed. When an infected cell dies, it releases merozoites that reinfect other red blood cells. 3: At some point, merozoites develop into male and female gametocytes. Those of P. falciparum have a characteristic banana shape that deforms the host red blood cell. 4: After ingestion by a mosquito, the male and female gametocytes are released from the red blood cells and fuse to form a zygote. 5: The zygote differentiates into an ookinete that invades a mosquito gut cell within which it forms an oocyst. The oocyst undergoes sporogony to form numerous sporozoites that are released into the haemolymph. 6: The sporozoites penetrate the mosquito salivary glands and are transmitted within mosquito’s saliva when it feeds. Drawings not to scale.
We contract malaria when a female mosquito harbouring the sporozoite stage of the parasite bites us. The sporozoites enter our body with her saliva and the blood stream transports them to the liver where they penetrate the hepatocytes (liver cells). Within the hepatocytes, the sporozoites change their morphology and multiply asexually by ‘exoerythrocytic schizogony’ to form thousands of merozoites. The term exoerythrocytic indicates that the reproduction takes place in cells other than the red blood cells. Schizogony is a form
