History of Malaria: Origin and Prehistoric Period Classical Period

History of malaria
The history of malaria stretches from its prehistoric origin as a

zoonotic disease in the primates of Africa through to the 21st
century. A widespread and potentially lethal human infectious
disease, at its peak malaria infested every continent, except
Antarctica.[1] Its prevention and treatment have been targeted in
science and medicine for hundreds of years. Since the discovery of
the Plasmodium parasites which cause it, research attention has
focused on their biology and as well as that of the mosquitoes
which transmit the parasites.
References to its unique, periodic fevers are found throughout

recorded history beginning in the first millennium BC in Greece
and China.[2][3]
For thousands of years, traditional herbal remedies have been used

to treat malaria.[4] The first effective treatment for malaria came
from the bark of the cinchona tree, which contains quinine. After
the link to mosquitos and their parasites was identified in the early Second World War poster "Keep out
twentieth century, mosquito control measures such as widespread malaria mosquitoes repair your torn
use of the insecticide DDT, swamp drainage, covering or oiling the screens". U.S. Public Health
Service, 1941–45
surface of open water sources, indoor residual spraying and use of
insecticide treated nets was initiated. Prophylactic quinine was
prescribed in malaria endemic areas, and new therapeutic drugs,
including chloroquine and artemisinins, were used to resist the scourge. Today, artemisinin is present in
every remedy applied in treatment of malaria. After introducing artemisinin as a cure administered together
with other remedies, malaria mortality in Africa decreased by half, though it later partially rebounded.[5]
Malaria researchers have won multiple Nobel Prizes for their achievements, although the disease continues
to afflict some 200 million patients each year, killing more than 600,000.
Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during
World War II, where about 500,000 men were infected.[6] According to Joseph Patrick Byrne, "Sixty
thousand American soldiers died of malaria during the African and South Pacific campaigns."[7]
At the close of the 20th century, malaria remained endemic in more than 100 countries throughout the
tropical and subtropical zones, including large areas of Central and South America, Hispaniola (Haiti and
the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania.
Resistance of Plasmodium to anti-malaria drugs, as well as resistance of mosquitos to insecticides and the
discovery of zoonotic species of the parasite have complicated control measures.
Contents
Origin and prehistoric period
Classical period
Middle Ages
European Renaissance
Spread to the Americas
Cinchona tree
Clinical indications
19th century
Antimalarial drugs
Cause: Identification of Plasmodium and Anopheles
Synthesis of quinine
20th century
Etiology: Plasmodium tissue stage and reproduction
Malariotherapy
Panama Canal and vector control
Antimalarial drugs
Insecticides
Research
A zoonotic malarial parasite
Notes
References
Further reading
External links
Origin and prehistoric period

The first evidence of malaria parasites was found in mosquitoes
preserved in amber from the Palaeogene period that are
approximately 30 million years old.[8] Malaria protozoa are
diversified into primate, rodent, bird, and reptile host lineages.[9][10]
The DNA of Plasmodium falciparum shows the same pattern of
diversity as its human hosts, with greater diversity in Africa than in
the rest of the world, showing that modern humans were suffering The mosquito and the fly in this
Baltic amber necklace are between
from the disease before they left Africa.[11] Humans may have
40 and 60 million years old.
originally caught P. falciparum from gorillas.[12] P. vivax, another
malarial Plasmodium species among the six that infect humans,
also likely originated in African gorillas and chimpanzees.[13] Another malarial species recently discovered
to be transmissible to humans, P. knowlesi, originated in Asian macaque monkeys.[14] While P. malariae is
highly host specific to humans, there is some evidence that low level non-symptomatic infection persists
among wild chimpanzees.[15]
About 10,000 years ago, malaria started having a major impact on human survival, coinciding with the start
of agriculture in the Neolithic revolution. Consequences included natural selection for sickle-cell disease,
thalassaemias, glucose-6-phosphate dehydrogenase deficiency, Southeast Asian ovalocytosis, elliptocytosis
and loss of the Gerbich antigen (glycophorin C) and the Duffy antigen on the erythrocytes, because such
blood disorders confer a selective advantage against malaria infection (balancing selection).[16] The three
major types of inherited genetic resistance (sickle-cell disease, thalassaemias, and glucose-6-phosphate
dehydrogenase deficiency) were present in the Mediterranean world by the time of the Roman Empire,
about 2000 years ago.[17]
Molecular methods have confirmed the high prevalence of P. falciparum malaria in ancient Egypt.[18] The
Ancient Greek historian Herodotus wrote that the builders of the Egyptian pyramids (circa 2700–1700
BCE) were given large amounts of garlic,[19] probably to protect them against malaria. The Pharaoh
Sneferu, the founder of the Fourth dynasty of Egypt, who reigned from around 2613–2589 BCE, used bed-
nets as protection against mosquitoes. Cleopatra VII, the last Pharaoh of Ancient Egypt, similarly slept
under a mosquito net.[20] However, whether the mosquito nets were used for the purpose of malaria
prevention, or for more mundane purpose of avoiding the discomfort of mosquito bites, is unknown. The
presence of malaria in Egypt from circa 800 BCE onwards has been confirmed using DNA-based
methods.[21]
Classical period
Malaria became widely recognized in ancient Greece by the 4th century BC, and is implicated in the
decline of many city-state populations. The term μίασμα (Greek for miasma): "stain, pollution", was coined
by Hippocrates of Kos who used it to describe dangerous fumes from the ground that are transported by
winds and can cause serious illnesses. Hippocrates (460–370 BC), the "father of medicine", related the
presence of intermittent fevers with climatic and environmental conditions and classified the fever
according to periodicity: Gk.:tritaios pyretos / L.:febris tertiana (fever every third day), and Gk.:tetartaios
pyretos / L.:febris quartana (fever every fourth day).[22][23]
The Chinese Huangdi Neijing (The Inner Canon of the Yellow Emperor) dating from ~300 BC – 200 AD
apparently refers to repeated paroxysmal fevers associated with enlarged spleens and a tendency to
epidemic occurrence.[24]
Around 168 BC, the herbal remedy Qing-hao ( 青蒿 ) (Artemisia annua) came
into use in China to treat female hemorrhoids (Wushi'er bingfang translated as "Recipes for 52 kinds of
diseases" unearthed from the Mawangdui).[25]
Qing-hao was first recommended for acute intermittent fever
episodes by Ge Hong as an effective medication in the 4th-century Chinese manuscript Zhou hou bei ji
fang, usually translated as "Emergency Prescriptions kept in one's Sleeve".[26] His recommendation was to
soak fresh plants of the artemisia herb in cold water, wring it out and ingest the expressed bitter juice in its
raw state.[27][28]
'Roman fever' refers to a particularly deadly strain of malaria that affected the Roman Campagna and the
city of Rome throughout various epochs in history. An epidemic of Roman fever during the fifth century
AD may have contributed to the fall of the Roman empire.[29][30] The many remedies to reduce the spleen
in Pedanius Dioscorides's De Materia Medica have been suggested to have been a response to chronic
malaria in the Roman empire.[31] Some so-called "vampire burials" in late antiquity may have been
performed in response to malaria epidemics. For example, some children who died of malaria were buried
in the necropolis at Lugnano in Teverina using rituals meant to prevent them from returning from the dead.
Modern scholars hypothesize that communities feared that the dead would return and spread disease.[32]
In 835, the celebration of Hallowmas (All Saints Day) was moved from May to November at the behest of
Pope Gregory IV, on the "practical grounds that Rome in summer could not accommodate the great
number of pilgrims who flocked to it", and perhaps because of public health considerations regarding
Roman Fever, which claimed a number of lives of pilgrims during the sultry summers of the region.[33]
Middle Ages
During the Middle Ages, treatments for malaria (and other diseases)
included blood-letting, inducing vomiting, limb amputations and
trepanning. Physicians and surgeons in the period used herbal
medicines like belladonna to bring about pain relief in afflicted
patients.[34][35]
European Renaissance
The name malaria derived from mal aria ('bad air' in Medieval
Italian). This idea came from the Ancient Romans who thought that
this disease came from pestilential fumes in the swamps. The word
malaria has its roots in the miasma theory, as described by historian
and chancellor of Florence Leonardo Bruni in his Historiarum
Florentini populi libri XII, which was the first major example of
Renaissance historical writing:[36]
Avuto i Fiorentini questo fortissimo castello e fornitolo

di buone guardie, consigliavano fra loro medesimi
fosse da fare. Erano alcuni a' quali pareva
Cinchona tree by Theodor Zwinger,
sommamente utile e necessario a ridurre lo esercito, e
1696
massimamente essendo affaticato per la infermità e per
la mala ariae per lungo e difficile campeggiare nel
tempo dell'autunno e in luoghi infermi, e vedendo
ancora ch'egli era diminuito assai per la licenza
conceduta a molti pel capitano di potersi partire:
perocchè, nel tempo che eglino erano stati lungamente
a quello assedio, molti, o per disagio del campo o per
paura d'infermità, avevano domandato e ottenuto
licenza da lui (Acciajuoli 1476).
After the Florentines had conquered this stronghold,

after putting good guardians on it they were discussing
among themselves how to proceed. For some of them
it appeared most useful and necessary to reduce the
army, more so as it was extremely stressed by disease
and bad air, and due to the long-lasting and difficult
camps in unhealthy places during the autumn. They
(the Florentines) further considered that the army was
reduced in numbers due to the leave permits granted to
many soldiers by their officers. In fact, during the
siege, many soldiers had asked and obtained leave
permits due to the camp hardships and fear of illness
[translated from medieval Italian, Toscanic dialect].
The coastal plains of southern Italy fell from international prominence when malaria expanded in the
sixteenth century. At roughly the same time, in the coastal marshes of England, mortality from "marsh
fever" or "tertian ague" (ague: via French from medieval Latin acuta (febris), acute fever) was comparable
to that in sub-Saharan Africa today.[37] William Shakespeare was born at the start of the especially cold
period that climatologists call the "Little Ice Age", yet he was aware enough of the ravages of the disease to
mention it in eight of his plays.[38] Malaria was commonplace in London and its marshes then and even
into the mid-Victorian era.[39]
Medical accounts and ancient autopsy reports state that tertian malarial fevers caused the death of four
members of the prominent Medici family of Florence [Note 1]. These claims have been confirmed with more
modern methodologies.[40]
Spread to the Americas

Malaria was not referenced in the "medical books" of the Mayans or Aztecs. European settlers and the
West Africans they enslaved likely brought malaria to the Americas in the 16th century.[41][42]
In the book 1493: Uncovering the New World Columbus Created, the author Charles Mann cites sources
that speculate that the reason African slaves were brought to the British Americas was because of their
resistance to malaria. The colonies needed low-paid agricultural labor, and large numbers of poor British
were ready to emigrate. North of the Mason–Dixon line, where malaria-transmitting mosquitoes did not
fare well, British indentured servants proved more profitable, as they would work toward their freedom.
However, as malaria spread to places such as the tidewater of Virginia and South Carolina, the owners of
large plantations came to rely on the enslavement of more malaria-resistant West Africans, while white
small landholders risked ruin whenever they got sick. The disease also helped weaken the Native American
population and make them more susceptible to other diseases.
Malaria caused huge losses to British forces in the South during the revolutionary war as well as to Union
forces during the Civil War.
Cinchona tree
Spanish missionaries found that fever was treated by Amerindians near Loxa (Ecuador) with powder from
Peruvian bark (later established to be from any of several trees of genus Cinchona).[43] It was used by the
Quechua Indians of Ecuador to reduce the shaking effects caused by severe chills.[44] Jesuit Brother
Agostino Salumbrino (1561–1642), who lived in Lima and was an apothecary by training, observed the
Quechua using the bark of the cinchona tree for that purpose. While its effect in treating malaria (and hence
malaria-induced shivering) was unrelated to its effect in controlling shivering from cold, it was nevertheless
effective for malaria. The use of the "fever tree" bark was introduced into European medicine by Jesuit
missionaries (Jesuit's bark).[45] Jesuit Bernabé de Cobo (1582–1657), who explored Mexico and Peru, is
credited with taking cinchona bark to Europe. He brought the bark from Lima to Spain, and then to Rome
and other parts of Italy, in 1632. Francesco Torti wrote in 1712 that only "intermittent fever" was amenable
to the fever tree bark.[46] This work finally established the specific nature of cinchona bark and brought
about its general use in medicine.[47]
It would be nearly 200 years before the active principles, quinine and other alkaloids, of cinchona bark
were isolated. Quinine, a toxic plant alkaloid, is, in addition to its anti-malarial properties, moderately
effective against nocturnal leg cramps.[48]
Clinical indications
In 1717, the dark pigmentation of a postmortem spleen and brain was published by the epidemiologist
Giovanni Maria Lancisi in his malaria text book De noxiis paludum effluviis eorumque remediis. This was
one of the earliest reports of the characteristic enlargement of the spleen and dark color of the spleen and
brain which are the most constant post-mortem indications of chronic malaria infection. He related the
prevalence of malaria in swampy areas to the presence of flies and recommended swamp drainage to
prevent it.[49]
19th century
In the nineteenth century, the first drugs were developed to treat
malaria and parasites were first identified as its source.
Antimalarial drugs
Quinine
French chemist Pierre Joseph Pelletier and French pharmacist Map of the United States showing
Joseph Bienaimé Caventou separated in 1820 the alkaloids the distribution of deaths from
cinchonine and quinine from powdered fever tree bark, allowing malaria. Census of 1880.
for the creation of standardized doses of the active ingredients.[50]
Prior to 1820, the bark was simply dried, ground to a fine powder
and mixed into a liquid (commonly wine) for drinking.[51]
An English trader, Charles Ledger, and his Amerindian servant spent four years collecting cinchona seeds
in the Andes in Bolivia, highly prized for their quinine but whose export was prohibited. Ledger managed
to get seeds out; in 1865, the Dutch government cultivated 20,000 trees of the Cinchona ledgeriana in Java
(Indonesia). By the end of the nineteenth century, the Dutch had established a world monopoly over its
supply.[52]
'Warburg's Tincture'
In 1834, in British Guiana, a German physician, Carl Warburg, invented an antipyretic medicine:
'Warburg's Tincture'. This secret, proprietary remedy contained quinine and other herbs. Trials were made
in Europe in the 1840s and 1850s. It was officially adopted by the Austrian Empire in 1847. It was
considered by many eminent medical professionals to be a more efficacious antimalarial than quinine. It
was also more economical. The British Government supplied Warburg's Tincture to troops in India and
other colonies.[53]
Methylene blue
In 1876, methylene blue was synthesized by German chemist Heinrich Caro.[54] Paul Ehrlich in 1880
described the use of "neutral" dyes – mixtures of acidic and basic dyes for the differentiation of cells in
peripheral blood smears. In 1891 Ernst Malachowski[55] and Dmitri Leonidovich Romanowsky[56]
independently developed techniques using a mixture of Eosin Y and modified methylene blue (methylene
azure) that produced a surprising hue unattributable to either staining component: a shade of purple.[57]
Malachowski used alkali-treated methylene blue solutions and Romanowsky used methylene blue solutions
which were molded or aged. This new method differentiated blood cells and demonstrated the nuclei of
malarial parasites. Malachowski's staining technique was one of the most significant technical advances in
the history of malaria.[58]
In 1891, Paul Guttmann and Ehrlich noted that methylene blue had a high affinity for some tissues and that
this dye had a slight antimalarial property.[59] Methylene blue and its congeners may act by preventing the
biocrystallization of heme.[60]
Cause: Identification of Plasmodium and

Anopheles
In 1848, German anatomist Johann Heinrich Meckel[62] recorded

black-brown pigment granules in the blood and spleen of a patient
who had died in a mental hospital. Meckel was thought to have
been looking at malaria parasites without realizing it; he did not
mention malaria in his report. He hypothesized that the pigment
was melanin.[63] The causal relationship of pigment to the parasite
was established in 1880, when French physician Charles Louis
Alphonse Laveran, working in the military hospital of Constantine,
Algeria, observed pigmented parasites inside the red blood cells of
malaria sufferers. He witnessed the events of exflagellation and
became convinced that the moving flagella were parasitic
In 1880, Charles Louis Alphonse
microorganisms. He noted that quinine removed the parasites from
Laveran observed pigmented
the blood. Laveran called this microscopic organism Oscillaria
parasites and the exflagellation of
malariae and proposed that malaria was caused by this
male gametocytes.[61]
protozoan.[64] This discovery remained controversial until the
development of the oil immersion lens in 1884 and of superior
staining methods in 1890–1891.
In 1885, Ettore Marchiafava, Angelo Celli and Camillo Golgi studied the reproduction cycles in human
blood (Golgi cycles). Golgi observed that all parasites present in the blood divided almost simultaneously at
regular intervals and that division coincided with attacks of fever. In 1886 Golgi described the
morphological differences that are still used to distinguish two malaria parasite species Plasmodium vivax
and Plasmodium malariae. Shortly after this Sakharov in 1889 and Marchiafava & Celli in 1890
independently identified Plasmodium falciparum as a species distinct from P. vivax and P. malariae. In
1890, Grassi and Feletti reviewed the available information and named both P. malariae and P. vivax
(although within the genus Haemamoeba.)[65] By 1890, Laveran's germ was generally accepted, but most
of his initial ideas had been discarded in favor of the taxonomic work and clinical pathology of the Italian
school. Marchiafava and Celli called the new microorganism Plasmodium.[66] H. vivax was soon renamed
Plasmodium vivax. In 1892, Marchiafava and Bignami proved that the multiple forms seen by Laveran
were from a single species. This species was eventually named P. falciparum. Laveran was awarded the
1907 Nobel Prize for Physiology or Medicine "in recognition of his work on the role played by protozoa in
causing diseases".[67]
Dutch physician Pieter Pel first proposed a tissue stage of the malaria parasite in 1886, presaging its
discovery by over 50 years. This suggestion was reiterated in 1893 when Golgi suggested that the parasites
might have an undiscovered tissue phase (this time in endothelial cells).[68] Pel in 1896 supported Golgi's
latent phase theory.[69]
The establishment of the scientific method from about the mid-19th century on demanded testable
hypotheses and verifiable phenomena for causation and transmission. Anecdotal reports[Note 2], and the
discovery in 1881 that mosquitos were the vector of yellow fever,[73] eventually led to the investigation of
mosquitoes in connection with malaria.
An early effort at malaria prevention occurred in 1896 in
Massachusetts. An Uxbridge outbreak prompted health officer Dr.
Leonard White to write a report to the State Board of Health, which
led to a study of mosquito-malaria links and the first efforts for
malaria prevention. Massachusetts state pathologist, Theobald
Smith, asked that White's son collect mosquito specimens for
further analysis, and that citizens add screens to windows, and
drain collections of water.[74]
Britain's Sir Ronald Ross, an army surgeon working in

Secunderabad India, proved in 1897 that malaria is transmitted by
mosquitoes, an event now commemorated via World Mosquito
Day.[75] He was able to find pigmented malaria parasites in a
mosquito that he artificially fed on a malaria patient who had
crescents in his blood. He continued his research into malaria by
showing that certain mosquito species (Culex fatigans) transmit
malaria to sparrows and he isolated malaria parasites from the
salivary glands of mosquitoes that had fed on infected birds.[76] He
The notebook in which Ronald Ross
reported this to the British Medical Association in Edinburgh in
first described pigmented malaria
1898.
parasites in stomach tissues of an
Anopheles mosquito, 20 and 21
Giovanni Battista Grassi, professor of Comparative Anatomy at
August 1897
Rome University, showed that human malaria could only be
transmitted by Anopheles (Greek anofelís: good-for-nothing)
mosquitoes.[77] Grassi along with coworkers Amico Bignami, Giuseppe Bastianelli and Ettore Marchiafava
announced at the session of the Accademia dei Lincei on 4 December 1898 that a healthy man in a non-
malarial zone had contracted tertian malaria after being bitten by an experimentally infected Anopheles
claviger specimen.
In 1898–1899, Bastianelli, Bignami and Grassi were the first to observe the complete transmission cycle of
P. falciparum, P. vivax and P. malaria from mosquito to human and back in A. claviger.[78]
A dispute broke out between the British and Italian schools of malariology over priority, but Ross received
the 1902 Nobel Prize for Physiology or Medicine for "his work on malaria, by which he has shown how it
enters the organism and thereby has laid the foundation for successful research on this disease and methods
of combating it".[79]
Synthesis of quinine
William Henry Perkin, a student of August Wilhelm von Hofmann at the Royal College of Chemistry in
London, unsuccessfully tried in the 1850s to synthesize quinine in a commercial process. The idea was to
take two equivalents of N-allyltoluidine (C10 H13 N) and three atoms of oxygen to produce quinine
(C20 H24 N2 O2 ) and water. Instead, Perkin's mauve was produced when attempting quinine total synthesis
via the oxidation of N-allyltoluidine.[80] Before Perkin's discovery, all dyes and pigments were derived
from roots, leaves, insects, or, in the case of Tyrian purple, molluscs.
Quinine wouldn't be successfully synthesized until 1918. Synthesis remains elaborate, expensive and low
yield, with the additional problem of separation of the stereoisomers. Though quinine is not one of the
major drugs used in treatment, modern production still relies on extraction from the cinchona tree.
20th century
Etiology: Plasmodium tissue stage and

reproduction
Relapses were first noted in 1897 by William S. Thayer, who

recounted the experiences of a physician who relapsed 21 months
after leaving an endemic area.[81] He proposed the existence of a
tissue stage. Relapses were confirmed by Patrick Manson, who
allowed infected Anopheles mosquitoes to feed on his eldest
son.[82] The younger Manson then described a relapse nine months
Malaria map of British India, 1927
after his apparent cure with quinine.[83]
Also, in 1900 Amico Bignami and Giuseppe Bastianelli found that

they could not infect an individual with blood containing only gametocytes.[84] The possibility of the
existence of a chronic blood stage infection was proposed by Ronald Ross and David Thompson in
1910.[85]
The existence of asexually-reproducing avian malaria parasites in cells of the internal organs was first
demonstrated by Henrique de Beaurepaire Aragão in 1908.[86]
Three possible mechanisms of relapse were proposed by Marchoux in 1926 (i) parthenogenesis of
macrogametocytes: (ii) persistence of schizonts in small numbers in the blood where immunity inhibits
multiplication, but later disappears and/or (iii) reactivation of an encysted body in the blood.[87] James in
1931 proposed that sporozoites are carried to internal organs, where they enter reticuloendothelial cells and
undergo a cycle of development, based on quinine's lack of activity on them.[88] Huff and Bloom in 1935
demonstrated stages of avian malaria that transpire outside blood cells (exoerythrocytic).[89] In 1945 Fairley
et al. reported that inoculation of blood from a patient with P. vivax may fail to induce malaria, although the
donor may subsequently exhibit the condition. Sporozoites disappeared from the blood stream within one
hour and reappeared eight days later. This suggested the presence of forms that persist in tissues.[90] Using
mosquitoes rather than blood, in 1946 Shute described a similar phenomenon and proposed the existence of
an 'x-body' or resting form.[91] The following year Sapero proposed a link between relapse and a tissue
stage not yet discovered.[92] Garnham in 1947 described exoerythrocytic schizogony in Hepatocystis
(Plasmodium) kochi.[93] In the following year Shortt and Garnham described the liver stages of P.
cynomolgi in monkeys.[94] In the same year a human volunteer consented to receive a massive dose of
infected sporozoites of P. vivax and undergo a liver biopsy three months later, thus allowing Shortt et al. to
demonstrate the tissue stage.[95] The tissue form of Plasmodium ovale was described in 1954 and that of P.
malariae in 1960 in experimentally infected chimpanzees.
The latent or dormant liver form of the parasite (hypnozoite), apparently responsible for the relapses
characteristic of P. vivax and P. ovale infections,[96][97] was first observed in the 1980s.[64][98] The term
hypnozoite was coined by Miles B. Markus while a student. In 1976, he speculated: "If sporozoites of
Isospora can behave in this fashion, then those of related Sporozoa, like malaria parasites, may have the
ability to survive in the tissues in a similar way."[99] In 1982, Krotoski et al reported identification of P.
vivax hypnozoites in liver cells of infected chimpanzees.[98]
Malariotherapy
In the early twentieth century, before antibiotics, patients with tertiary syphilis were intentionally infected
with malaria to induce a fever; this was called malariotherapy. In 1917, Julius Wagner-Jauregg, a Viennese
psychiatrist, began to treat neurosyphilitics with induced Plasmodium vivax malaria.[100] Three or four
bouts of fever were enough to kill the temperature-sensitive syphilis bacteria (Spirochaeta pallida also
known as Treponema pallidum). P. vivax infections were then terminated by quinine. By accurately
controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. While about
15% of patients died from malaria, this was preferable to the almost-certain death from syphilis.[101]
Therapeutic malaria opened up a wide field of chemotherapeutic research and was practised until
1950.[102] Wagner-Jauregg was awarded the 1927 Nobel Prize in Physiology or Medicine for his discovery
of the therapeutic value of malaria inoculation in the treatment of dementia paralytica.[103]
Henry Heimlich advocated malariotherapy as a treatment for AIDS,[104] and some studies of
malariotherapy for HIV infection have been performed in China.[105] The United States Centers for
Disease Control and Prevention does not recommend the use of malariotherapy for HIV.[105]
Panama Canal and vector control
In 1881, Dr. Carlos Finlay, a Cuban-born physician of Scottish ancestry, theorized that yellow fever was
transmitted by a specific mosquito, later designated Aedes aegypti.[106] The theory remained controversial
for twenty years until confirmed in 1901 by Walter Reed.[107] This was the first scientific proof of a disease
being transmitted exclusively by an insect vector, and demonstrated that control of such diseases necessarily
entailed control or eradication of its insect vector.
Yellow fever and malaria among workers had seriously delayed construction of the Panama Canal.
Mosquito control instituted by William C. Gorgas dramatically reduced this problem.[108]
Antimalarial drugs
Chloroquine
Johann "Hans" Andersag[109] and colleagues synthesized and

tested some 12,000 compounds, eventually producing Resochin as
a substitute for quinine in the 1930s.[110][111] It is chemically
related to quinine through the possession of a quinoline nucleus and
the dialkylaminoalkylamino side chain. Resochin (7-chloro-4- 4-
(diethylamino) – 1 – methylbutyl amino quinoline) and a similar
compound Sontochin (3-methyl Resochin) were synthesized in
1934.[112] In March 1946, the drug was officially named
Chloroquine.[113] Chloroquine is an inhibitor of hemozoin
production through biocrystallization. Quinine and chloroquine
affect malarial parasites only at life stages when the parasites are
forming hematin-pigment (hemozoin) as a byproduct of
hemoglobin degradation.
Chloroquine-resistant forms of P.
falciparum emerged only 19 years later.[114] The first resistant
strains were detected around the Cambodia‐Thailand border and in
Colombia, in the 1950s.[115] In 1989, chloroquine resistance in P.
Protocol for the synthesis of vivax was reported in Papua New Guinea. These resistant strains
Resochin, Hans Andersag 1934 spread rapidly, producing a large mortality increase, particularly in
Africa during the 1990s.[116]
Artemisinins
Systematic screening of traditional Chinese medical herbs was carried out by Chinese research teams,
consisting of hundreds of scientists in the 1960s and 1970s.[117] Qinghaosu, later named artemisinin, was
cold-extracted in a neutral milieu (pH 7.0) from the dried leaves of Artemisia annua.[26][118]
Artemisinin was isolated by pharmacologist Tu Youyou (Nobel Prize in Physiology or Medicine, 2015). Tu
headed a team tasked by the Chinese government with finding a treatment for chloroquine-resistant malaria.
Their work was known as Project 523, named after the date it was announced – 23 May 1967. The team
investigated more than 2000 Chinese herb preparations and by 1971 had made 380 extracts from 200
herbs. An extract from qinghao (Artemisia annua) was effective but the results were variable. Tu reviewed
the literature, including Zhou hou bei ji fang (A handbook of prescriptions for emergencies) written in 340
BC by Chinese physician Ge Hong. This book contained the only useful reference to the herb: "A handful
of qinghao immersed with two litres of water, wring out the juice and drink it all." Tu's team subsequently
isolated a nontoxic, neutral extract that was 100% effective against parasitemia in animals. The first
successful trials of artemisinin were in 1979.[119]
Artemisinin is a sesquiterpene lactone containing a

peroxide group, which is believed to be essential for its
anti-malarial activity. Its derivatives, artesunate and
artemether, have been used in clinics since 1987 for the
treatment of drug-resistant and drug-sensitive malaria,
especially cerebral malaria. These drugs are
characterized by fast action, high efficacy and good
tolerance. They kill the asexual forms of P. berghei and
P. cynomolgi and have transmission-blocking
activity.[120] In 1985, Zhou Yiqing and his team
combined artemether and lumefantrine into a single Artemisia annua being grown as a field crop in
West Virginia for the production of artemisinin,
tablet, which was registered as a medicine in China in
2005
1992. Later it became known as "Coartem".[121]
Artemisinin combination treatments (ACTs) are now
widely used to treat uncomplicated falciparum malaria,
but access to ACTs is still limited in most malaria-endemic countries and only a minority of the patients
who need artemisinin-based combination treatments receive them.[122]
In 2008 White predicted that improved agricultural practices, selection of high-yielding hybrids, microbial
production, and the development of synthetic peroxides would lower prices.[123][124]
Insecticides
Efforts to control the spread of malaria suffered a major setback in 1930: entomologist Raymond Corbett
Shannon discovered imported disease-bearing Anopheles gambiae mosquitoes living in Brazil (DNA
analysis later revealed the actual species to be A. arabiensis).[125] This species of mosquito is a particularly
efficient vector for malaria and is native to Africa.[126] In 1938, the introduction of this vector caused the
greatest epidemic of malaria ever seen in the New World. However, complete eradication of A. gambiae
from northeast Brazil and thus from the New World was achieved in 1940 by the systematic application of
the arsenic-containing compound Paris green to breeding places, and of pyrethrum spray-killing to adult
resting places.[127]
DDT
Austrian chemist Othmar Zeidler is credited with the first synthesis of DDT
(DichloroDiphenylTrichloroethane) in 1874.[128] The insecticidal properties of DDT were identified in
1939 by chemist Paul Hermann Müller of Geigy Pharmaceutical. For his discovery of DDT as a contact
poison against several arthropods, he was awarded the 1948 Nobel Prize in Physiology or Medicine.[129]
In the fall of 1942, samples of the chemical were acquired by the United States, Britain and Germany.
Laboratory tests demonstrated that it was highly effective against many insects.
Rockefeller Foundation studies showed in Mexico that DDT remained effective for six to eight weeks if
sprayed on the inside walls and ceilings of houses and other buildings.[130] The first field test in which
residual DDT was applied to the interior surfaces of all habitations and outbuildings was carried out in
central Italy in the spring of 1944. The objective was to determine the residual effect of the spray upon
Anopheline density in the absence of other control measures. Spraying began in Castel Volturno and, after a
few months, in the delta of the Tiber. The unprecedented effectiveness of the chemical was confirmed: the
new insecticide was able to eradicate malaria by eradicating mosquitoes.[131] At the end of World War II, a
massive malaria control program based on DDT spraying was carried out in Italy. In Sardinia – the second
largest island in the Mediterranean – between 1946 and 1951, the Rockefeller Foundation conducted a
large-scale experiment to test the feasibility of the strategy of "species eradication" in an endemic malaria
vector.[132] Malaria was effectively eliminated in the United States by the use of DDT in the National
Malaria Eradication Program (1947–52). The concept of eradication prevailed in 1955 in the Eighth World
Health Assembly: DDT was adopted as a primary tool in the fight against malaria.
In 1953, the World Health Organization (WHO) launched an antimalarial program in parts of Liberia as a
pilot project to determine the feasibility of malaria eradication in tropical Africa. However, these projects
encountered difficulties that foreshadowed the general retreat from malaria eradication efforts across
tropical Africa by the mid-1960s.[133]
DDT was banned for agricultural uses in the US in 1972 (DDT has never been banned for non-agricultural
uses such as malaria control[134]) after the discussion opened in 1962 by Silent Spring, written by
American biologist Rachel Carson, which launched the environmental movement in the West. The book
catalogued the environmental impacts of indiscriminate DDT spraying and suggested that DDT and other
pesticides cause cancer and that their agricultural use was a threat to wildlife. The U.S. Agency for
International Development supports indoor DDT spraying as a vital component of malaria control programs
and has initiated DDT and other insecticide spraying programs in tropical countries.[135]
Pyrethrum
Other insecticides are available for mosquito control, as well as

physical measures, such as draining the wetland breeding grounds
and the provision of better sanitation. Pyrethrum (from the
flowering plant Chrysanthemum [or Tanacetum] cinerariaefolium)
is an economically important source of natural insecticide.
Pyrethrins attack the nervous systems of all insects. A few minutes
after application, the insect cannot move or fly, while female
Pyrethrum field (Chrysanthemum
mosquitoes are inhibited from biting.[136] The use of pyrethrum in
cinerariaefolium) Lari Hills, Nairobi,
insecticide preparations dates to about 400 BCE. Pyrethrins are
Kenya, in 2010
biodegradable and break down easily on exposure to light. The
majority of the world's supply of pyrethrin and Chrysanthemum
cinerariaefolium comes from Kenya. The flower was first introduced into Kenya and the highlands of
Eastern Africa during the late 1920s. The flowers of the plant are harvested shortly after blooming; they are
either dried and powdered, or the oils within the flowers are extracted with solvents.
Research
Avian, mouse and monkey models
Until the 1950s, screening of anti-malarial drugs was carried out on avian malaria. Avian malaria species
differ from those that infect humans. The discovery in 1948 of Plasmodium berghei in wild rodents in the
Congo[137] and later other rodent species that could infect laboratory rats transformed drug development.
The short hepatic phase and life cycle of these parasites made them useful as animal models, a status they
still retain.[64] Plasmodium cynomolgi in rhesus monkeys (Macaca mulatta) were used in the 1960s to test
drugs active against P. vivax.
Growth of the liver stages in animal-free systems was achieved in the 1980s when pre-erythrocytic P.
berghei stages were grown in wI38, a human embryonic lung cell line (cells cultured from one
specimen).[138] This was followed by their growth in human hepatoma line HepG2.[139] Both P.
falciparum and P. vivax have been grown in human liver cells; partial development of P. ovale in human
liver cells was achieved; and P. malariae was grown in chimpanzee and monkey liver cells.[140]
The first successful continuous malaria culture was established in 1976 by William Trager and James B.
Jensen, which facilitated research into the molecular biology of the parasite and the development of new
drugs. By using increasing volumes of culture medium, P.falciparum was grown to higher parasitemia
levels (above 10%).[141]
Diagnostics
The use of antigen-based malaria rapid diagnostic tests (RDTs) emerged in the 1980s.[142] In the twenty-
first century Giemsa microscopy and RDTs became the two preferred diagnostic techniques. Malaria RDTs
do not require special equipment and offer the potential to extend accurate malaria diagnosis to areas
lacking microscopy services.[143]
A zoonotic malarial parasite
Plasmodium knowlesi has been known since the 1930s in Asian macaque monkeys and as experimentally
capable of infecting humans. In 1965 a natural human infection was reported in a U.S. soldier returning
from the Pahang Jungle of the Malaysian peninsula.[144]
Notes
1. Eleonora of Toledo (1522–1562), Cardinal Giovanni (1543–1562), Don Garzia (1547–1562)
and Grand Duke Francesco I (1531–1587)
2. Giovanni Maria Lancisi, John Crawford,[70] Patrick Manson,[71] Josiah C. Nott, Albert
Freeman Africanus King[72] and Laveran developed theories that malaria was caused by
mosquito bites, but little evidence supported this idea.
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Further reading
Packard RM (2007). The Making of a Tropical Disease: A Short History of Malaria (https://bo
oks.google.com/books?id=B_V1Xj6wH7IC). Johns Hopkins Biographies of Disease. JHU
Press. ISBN 978-0-8018-8712-3.
Shah S (2010). The Fever: How Malaria Has Ruled Humankind for 500,000 Years (https://bo
oks.google.com/books?id=4jUjPh64X9UC). Macmillan. ISBN 978-0-374-23001-2. excerpt
and text search (https://www.amazon.com/Fever-Malaria-Ruled-Humankind-Years/dp/03742
30013/)
External links
Alphonse Laveran Nobel Lecture: Protozoa as causes of disease (http://nobelprize.org/nobe
l_prizes/medicine/laureates/1907/laveran-lecture.html)
Paul H Müller Nobel Lecture 1948: Dichloro-diphenyl-trichloroethane and newer
insecticides (http://nobelprize.org/nobel_prizes/medicine/laureates/1948/muller-lecture.pdf)
Ronald Ross Nobel Lecture (http://nobelprize.org/nobel_prizes/medicine/laureates/1902/ros
s-lecture.pdf)
Julius Wagner-Jauregg Nobel Lecture: The Treatment of Dementia Paralytica by Malaria
Inoculation (http://nobelprize.org/nobel_prizes/medicine/laureates/1927/wagner-jauregg-lect
ure.html)
Grassi versus Ross: Who solved the riddle of malaria? (http://www.im.microbios.org/0901/09
01069.pdf)
Malaria and the Fall of Rome (https://www.bbc.co.uk/history/ancient/romans/malaria_01.sht
ml)
Malaria Around the North Sea (http://www.xs4all.nl/~ottoknot/werk/Malaria.html)
Malariasite: History (https://web.archive.org/web/20140619212323/http://www.malariasite.co
m/malaria/History.htm)
Centers for Disease Control: History of Malaria (https://www.cdc.gov/malaria/about/history/)
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History of Malaria: Origin and Prehistoric Period Classical Period

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History of Malaria: Origin and Prehistoric Period Classical Period

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History of malaria

The history of malaria stretches from its prehistoric origin as a

References to its unique, periodic fevers are found throughout

For thousands of years, traditional herbal remedies have been used

Origin and prehistoric period

Avuto i Fiorentini questo fortissimo castello e fornitolo

After the Florentines had conquered this stronghold,

Spread to the Americas

Cause: Identification of Plasmodium and

In 1848, German anatomist Johann Heinrich Meckel[62] recorded

Britain's Sir Ronald Ross, an army surgeon working in

Etiology: Plasmodium tissue stage and

Relapses were first noted in 1897 by William S. Thayer, who

Also, in 1900 Amico Bignami and Giuseppe Bastianelli found that

Panama Canal and vector control

Johann "Hans" Andersag[109] and colleagues synthesized and

Artemisinin is a sesquiterpene lactone containing a

Other insecticides are available for mosquito control, as well as

Avian, mouse and monkey models

A zoonotic malarial parasite

Nerlich AG, Schraut B, Dittrich S, Jelinek T, Zink AR (2008). "Plasmodium falciparum in

Knottnerus O S (2002). "Malaria Around the North Sea: A Survey" (http://www.xs4all.nl/~otto

Poser CM, Bruyn GW (1999). An Illustrated History of Malaria (https://books.google.com/boo

Woronzoff-Dashkoff KK. (2002). "The wright-giemsa stain. Secrets revealed" (https://www.re

Schuster FL (2002). "Cultivation of Plasmodium spp" (https://www.ncbi.nlm.nih.gov/pmc/artic

Retrieved from "https://en.wikipedia.org/w/index.php?title=History_of_malaria&oldid=1074743415"

This page was last edited on 1 March 2022, at 23:10 (UTC).

Text is available under the Creative Commons Attribution-ShareAlike License 3.0;

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