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The History of Malaria

  • Writer: FibonacciMD
    FibonacciMD
  • 19 hours ago
  • 8 min read

Few diseases have shaped human history as profoundly as malaria, which still remains one of the world’s most deadly diseases.  In 2024, the World Health Organization (WHO) estimated that malaria infected 282 million people and caused 610,000 deaths, with 95% of these infections occurring in Africa.  


Malaria is a life-threatening illness caused by a protozoan parasite and transmitted to humans through the bites of infected female Anopheles mosquitoes.  There are five distinct species of Plasmodium that can cause malaria, with Plasmodium falciparum and Plasmodium vivax posing the greatest threats.  Symptoms typically begin 10-15 days after a bite, commonly beginning with fever, headache, and chills. The parasite initially travels to the liver where it reproduces.  It then leaves the liver to infect red blood cells, which is where more parasites are released.  In some people, the infection is partially controlled, and symptoms improve until more parasites are released from infected red blood cells, restarting the cycle.  If an Anopheles mosquito feeds on a person with circulating parasites, it may pass the infection on to the next person they bite.  In severe cases, the parasites can cause convulsions, respiratory distress, bleeding, as well as other significant health issues.  Some people can develop partial immunity to the parasite, and in others the parasite may reside dormant in the liver and reactivate at a later date. 



Historical Timeline and Impact 

Ancient writings attest to the length of time malaria has infected humans.  Mesopotamian clay tablets contain writings of a febrile disease suggestive of malaria.  Malaria antigens have been discovered in ancient Egyptian remains.  In ancient Indian texts, malaria is called the “king of diseases.” The ancient Greeks also wrote about the disease.  


Malaria arrived in Rome in the first century AD, possibly via Greek traders who traveled to Africa.  It has been suggested by some historians that malaria epidemics may have played a part in the fall of the Roman Empire, as in 79 AD, a malaria epidemic led farmers to abandon their fields around Rome, reducing agricultural productivity.  Roman soldiers and traders spread malaria further throughout Europe.  The disease was also reported in India and China. 


Malaria was once known as Roman fever.  Because diseases at that time were thought to arise from miasmas or evil vapors, the name was later derived from Medieval Italian, mal aria (bad air). 


Malaria may have come to the Americas with early explorers, but it also was later brought in with the transatlantic slave trade from Africa.  Both Abraham Lincoln and George Washington reportedly suffered bouts of malaria during their lives.  During the Civil War, many soldiers were infected.  Malaria continued to plague the South long after the war and it was not until the 1930s, after the Tennessee Valley Authority brought hydroelectric power and modernization to the rural U.S. South, that malaria was controlled there.  During World War II, soldiers fighting in the Pacific region also suffered from significant malaria cases.  


It was in Africa where malaria claimed most of its victims.  Indigenous populations were exposed throughout their lives, and those who survived developed a form of partial immunity.  European colonists in the 18th century did not possess this immunity and consequently parts of West Africa were commonly referred to as “the White man’s grave” due to malaria and other tropical diseases.


In 1946, the Malaria Control in War Areas program, which had successfully kept the southeastern states malaria-free during World War II, was reorganized as the Communicable Disease Center (CDC), which later became the Centers for Disease Control and Prevention.


Discovery of the Cause of Malaria

In 1880, a French army doctor, Charles Louis Alphonse Laveran, theorized that malaria was caused by a “germ”.  While looking at blood from an infected soldier, he noticed pigments in red blood cells caused by hemoglobin digestion by the Plasmodium parasite.  He then examined blood smears from more patients with malaria and found the parasite in the majority of patients.  Laveran received the Nobel Prize in 1907 for discovering that Plasmodium parasites caused malaria.


Malaria Parasites in Red Blood Cells
Malaria Parasites in Red Blood Cells

In 1886, Camillo Golgi linked the fevers seen in malaria with the release of malaria parasites in the blood.

In 1897, Surgeon-Major Ronald Ross of the British Indian Medical Service discovered that the malaria parasites develop within mosquitoes.  Ross received the Nobel Prize for demonstrating that mosquitoes transmit malaria.


In 1948, Henry Edward Shortt and Percy Cyril Claude Garnham, doctors and researchers, discovered that after infecting a host, the malaria parasite’s early development occurs in the human liver.


Sickle Cell Trait and Malaria

It is thought that sickle cell anemia and trait are genetic adaptations to resist malarial infections.  Sickle cell trait is found in approximately 10 to 40% of Africans.  Unlike sickle cell anemia, where the gene is inherited from both parents and causes severe disease, people with sickle cell trait inherit one normal hemoglobin gene and one sickle hemoglobin gene.  Trait carriers are generally healthy unless subjected to extreme physiological stress, such as a low oxygen environment.  Under severe stress, red blood cells in people with the trait will also sickle.  It is thought that the malaria parasite entering a red blood cell in a person with sickle cell trait consumes oxygen and nutrients which causes the cell to sickle.  Sickled cells make it harder for the parasite to survive.  Sickled cells are eliminated by the body before the red blood cells full of malarial parasites can rupture and continue the spread of the infection.  Thus, people who carry sickle cell trait generally experience lower rates of severe malaria and malaria-related mortality.



Treatments 

According to legend, a Native South American accidentally discovered that the bark of the cinchona tree (Cinchona officinalis) was a treatment for malaria.  When ill with a fever, he drank from a pool of bitter, stagnant water surrounded by cinchona trees and recovered.  The bark contains quinine and other alkaloids, which can treat malaria.  


The Journey of Quinine from Peru to Europe

The Spanish discovered that indigenous inhabitants of Peru were using cinchona bark in the 1600s.  It then also became known as “Jesuit’s bark” and became a favorite European medicine for treating malaria.  The bark was dried and grounded down to a powder to produce quinine.


In 1820, French chemists Joseph Pelletier and Jean Bienaimé Caventou isolated quinine from cinchona bark.  Quinine then became a therapy for malaria throughout the world. 


The gin and tonic was said to have originated during British rule in India, in the mid-1800s when soldiers mixed gin with quinine-containing tonic water to make the bitter antimalarial medication more palatable.


Malaria and the World Wars 

The Dutch engineered a hardy form of cinchona and eventually produced 80% of the world's quinine on the Indonesian island of Java.  During World War I the Allies controlled Java and much of the world’s quinine supply, and the Germans were unable to access antimalarial drugs which reportedly caused illness in their troops.  After the war, the Germans wanted to avoid being unable to access antimalarial drugs again, so they commissioned the chemical company I.G. Farben to develop new alternatives.  They subsequently  synthesized pamaquine and later quinacrine, although toxic side effects limited their use.  In 1934 they synthesized chloroquine (called Resochin) and 3-methyl chloroquine but overestimated their toxicity and did not do further research on the compounds.  


During World War II, the Allies were deprived of quinine by the German occupation of Holland and the Japanese occupation of Java.  French soldiers reportedly raided a supply of German-manufactured 3-methyl chloroquine in Tunis and handed it over to American investigators who made minor modifications to the formulation and named it chloroquine.  It was later recognized that the compound the Germans had called Resochin was chloroquine.  After World War II chloroquine was used extensively throughout the world to treat malaria, although some strains started to develop resistance to the drug.


Later Therapy Advances 

Sulfadoxine-pyrimethamine (Fansidar, Swidar and Amalar). This medication is most commonly used in the treatment and prevention, first used in 1967, is a combination of two drugs that block folate production required by the malaria parasite.


Mefloquine (Lariam) was produced as a replacement for chloroquine and started being used first as a prophylactic drug before being used to treat malaria in the mid-1970s. It is administered weekly and may be taken for over a year for malaria prevention as long as it is well tolerated.


Malarone (a combination of atovaquone and proguanil) is generally well tolerated and has largely replaced mefloquine as the drug of choice for malaria prophylaxis. It is taken daily and may be taken for as long as six to twelve months. Malarone is also a highly effective, treatment of acute, uncomplicated Plasmodium falciparum malaria.


Daily oral doxycycline is another option for malaria prophylaxis. Generally, it is less well tolerated than Malarone (more drug-drug interactions, increased sun sensitivity, and Category D if pregnant), but it is a cheaper, effective option.  Duration of administration should be considered carefully.


Artemisinin, derived from wormwood, has been used in Chinese medicine for thousands of years.  In 1979, scientists published a study demonstrating its effectiveness and today artemisinin-derived drugs, typically combined with a longer-acting medication, are used as first-line drugs for drug-resistant malaria.  

There are a number of medications that travelers to endemic areas may take to prevent getting malaria, although none are 100% effective.  


There are currently two vaccines approved for malaria: RTS,S/AS01 (approved in 2021) and R21/Matrix-M (approved in 2023).  Malaria vaccines may reduce uncomplicated malaria by approximately 40%, severe malaria by approximately 30%, and all-cause mortality by 13%.  They are currently recommended for children living in areas where malaria is endemic. 


The vaccines mimic the surface of the malaria sporozoite, helping the recipient produce antibodies against it.  Vaccinated individuals can then eliminate sporozoites injected into the bloodstream by mosquitoes before the parasites settle in the liver and reproduce. They also stimulate T-cell immunity that can help destroy any organisms not picked up by the immediately available circulating antibodies. 


Genetically Modified Mosquitoes 

Some regions of the world have introduced genetically modified Anopheles mosquitoes in an effort to control malaria.  Scientists insert a gene that prevents female offspring from surviving to adulthood.  Genetically modified mosquito eggs are released into a target area, and after hatching, the resulting males pass the gene to their offspring.  This reduces the Anopheles mosquito population, particularly the females responsible for transmitting malaria.  Using gene-drive technology, the inserted gene can be copied onto both chromosomes, allowing it to be inherited by nearly 100% of offspring and spread more rapidly through successive generations. 


Summary

Malaria has afflicted the human race since antiquity, and despite present-day vaccines, medications, and mosquito control measures, it still persists, adversely affecting millions of people each year. 


If you liked this article, you may also enjoy reading The Creation of the Gin and Tonic; a Medical Odyssey , which also discusses malaria treatment. 


You may also find these other FibonacciMedicine history of medicine articles interesting:

References



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