Malaria

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Alison Leibowitz [3], Marjan Khan M.B.B.S.[4]

The symptoms of malaria, one of the oldest known infections, were initially believed to be caused by noxious elements. In 1880 Charles Louis Alphone Laveran discovered the Plasmodium parasite in blood smears of patients with malaria. The role of mosquitos in the transmission of malaria to humans was discovered a few years later. The entire life cycle of the Plasmodium parasite remained enigmatic until 1982.Although malaria has historically been treated using quinine, an alkaloid derived from barks of cinchona, the first synthetic quinine was produced in 1948.In 2014, the first candidate for anti-malarial vaccine was developed.

• Malaria is one of the earliest discovered global diseases, which continues to infect hundreds of million people worldwide. Frequently, it has been regarded as the most significant disease over the past three thousand years. Since antiquity, the malarial syndrome has been described in ancient China, India, Greece, and Egypt.^[1]
• Hippocrates, Homer, and other Greek and Roman physicians often referred to malaria as the “marsh fever”, “intermittent fever”, and “ague”.^[1][2]
• The name “malaria” was only coined in the mid-eighteenth century, derived from two Latin words that collectively translate to “bad air”.^[3]

• Malaria was originally believed to be an airborne noxious element or miasma from swamps. It was not until 1880, when Charles Louis Alphone Laveran, a French military physician, discovered an infectious parasite when he microscopically examined blood smears of 44 malaria patients and “noticed among the red corpuscles elements that seemed to be parasites”.^[4]
  • He was eventually rewarded the Nobel Prize for Physiology or Medicine in 1907 for his overall research on malaria.^[1]
  • In 1883, it was hypothesized that malarial transmission is by mosquito.^[3]
• Fourteen years later in 1897, Sir Ronald Ross, an Indian-born British bacteriologist, isolated malarial oocysts in Anopheles mosquitos and was able to prove that the culcine mosquito is the malarial vector for avian malaria.^[5]
  • Consequently, he also won the Nobel Prize for Physiology or Medicine in 1902 for his research on malarial transmission and life cycle.^[3]
  • Ross’s discovery was then followed by a similar discovery one year later for Anopheles mosquito and human malaria by Italian researchers Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Camillo Golgi, and Ettore Marchiafava.^[1]

• Malaria was mostly eliminated from the United States in the early 1950s.^[6]

• Between 1957 and 2011, in the United States, 63 outbreaks of locally transmitted mosquito-borne malaria occurred. In such outbreaks, local mosquitoes become infected by biting individuals carrying malaria parasites (acquired in endemic areas), subsequently transmitting malaria to local residents.^[6]

• Between 1963 and 2011, 97 cases of transfusion-transmitted malaria were reported in the United States. Approximately two thirds of these cases could have been prevented if the implicated donors had been deferred according to established guidelines.^[6]

• Robert Woodward and William vonEggers Doering developed the total synthesis of quinine in 1944.
• Paul Rabe and Karl Kindler’s report on converting d-quinotoxine into quinine in 1918.^[7][8]
• Originally, quinine is an alkaloid derived from barks of cinchona and Remijia tree species that were proven to be effective in the treatment of malaria.
• With Woodward and Doering’s discovery of the first artificial quinine, the first synthetic pharmacological agent to treat malaria was produced.^[8]

• In 1934, chloroquine (Resochin) was synthesized followed by Sontochin.^[9]
• These compounds belonged to a new class of antimalarials known as four-amino quinolines.
• Following World War II, chloroquine emerged as the principal weapons in the WHO’s ambitious “global eradication” malaria campaign.
• Chloroquine-resistant P. falciparum (CRPF) probably arose de novo from four independent geographic locations:

1. The Thai-Cambodian border around 1957.
2. Venezuela and the nearby Magdalena Valley of Colombia around 1960.
3. Port Moresby, Papua New Guinea, in the mid-1970s.
4. In Africa, CRPF was first found in 1978, spreading next to inland coastal areas and by 1983, to Sudan, Uganda, Zambia, and Malawi.

• Sulfadoxine-pyrimethamine (SP),the most widely used antifolate antimalarial combination today, was introduced in Thailand in 1967. Resistance to SP was reported in Thailand later that year.^[9]
• The pyrimidine derivative, proguanil, emerged from the antimalarial pipeline during World War II. it stimulated further study for making agents that block folate synthesis in parasites and bacteria, and resulted in the development of pyrimethamine.
• It became apparent that malaria parasites could quickly alter the target enzyme of the two drugs, leading to resistance.
• sulfonamides were then combined with proguanil or pyrimethamine for increasing efficacy, and forestalling or preventing the development of resistance.

• Mefloquine was a collaborative achievement of the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche.^[9]
• Mefloquine’s efficacy in preventing falciparum malaria was acknowledged in 1974.
• Mefloquine resistance began to appear in Asia around the time of the drug’s availability in 1985.

• Artemisinin is the antimalarial isolated by Chinese scientists in 1972 from Artemisia annua (sweet wormwood).^[9]
• The earliest report of its use appears in a Chinese book found in the Mawanhgolui Han dynasty tombs dating to 168 BC.
• Artemisinin and other Artemether-group drugs are the main line of treatment against drug-resistant malaria in many areas of southeast Asia.
• The number of Artemisinin-based combination therapy treatment courses procured from manufacturers increased globally from 187 million in 2010 to 409 million in 2016.^[10]
• Artemisinin partial resistance likely emerged prior to 2001.To date, it has been confirmed in 5 countries: Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam.^[10]

• Upon the understanding of malaria’s mode of transmission and mechanisms of disease, mosquito control and prompt diagnosis and treatment, allowed most European countries to eliminate malaria before the Second World War.^[11]
• In 1955, the Global Malaria Eradication Program was established in an effort to control and eliminate malaria, as well as to reduce the malarial burden in regions of moderate prevalence outside tropical Africa.
• The financial coverage and expertise to fight malaria further expanded to include global efforts, such as “Global Fund to Fight HIV, TB, and Malaria”, “U.S. President’s Malaria Initiative”, and “World Bank’s Booster Program”.^[11]
• In 2008, the World Health Organization (WHO) announced a multibillion-dollar initiative to eradicate malaria, partially funded by international donors.^[12]

• In 2005, with a grant funding from the Bill and Melinda Gates Foundation, PATH Malaria Vaccine Initiative (MVI), a non-profit organization, collaborated with Glaxosmithkline, to develop an anti-malarial vaccine. The vaccine has been administered, alongside other infant vaccines, through the Expanded Program on Immunization (EPI).
• In 2011, the first co-primary end point from the phase 3 trial of RTS, S/AS01 malaria vaccine was published, followed by a second co-primary end point in 2012.^[13]
• The vaccine was used to protect against uncomplicated and severe malaria in infants. In July 2014, Glaxosmithkline applied for approval to be the world’s first anti-malarial vaccine. Other malarial vaccines are currently being developed, but still require further validation of their clinical efficacy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Alison Leibowitz [2], Marjan Khan M.B.B.S.[3]

The classification of malaria can be established according to the strains of Plasmodium species. There are five common Plasmodium species that infect humans: P. falciparum, P. ovale, P. vivax, P. malariae, and P. knowlesi. Malaria can also be classified according to severity of infection: uncomplicated vs. severe.^[1][2]

The following Plasmodium strains are the most common strains implicated in human malarial infection.^[1][3]

The following table classifies malarial infections by severity.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

A plasmodium is also the macroscopic form of the protist known as a slime mould.

Plasmodium is a genus of parasitic protozoa. Infection with this genus is known as malaria. The parasite always has two hosts in its life cycle: a mosquito vector and a vertebrate host. At least ten species infect humans. Other species infect other animals, including birds, reptiles and rodents.

The genus Plasmodium was created in 1885 by Marchiafava and Celli and there are over 175 species currently recognized. New species continue to be described. ^[1]

The genus is currently (2006) in need of reorganization as it has been shown that parasites belonging to the genera Haemocystis and Hepatocystis appear to be closely related to Plasmodium. It is likely that other species such as Haemoproteus meleagridis will be included in this genus once it is revised.

Host range among the mammalian orders is non uniform. At least 29 species infect non human primates; rodents outside the tropical parts of Africa are rarely affected; a few species are known to infect bats, porcupines and squirrels; carnivores, insectivores and marsupials are not known to act as hosts.

In 1898 Ronald Ross demonstrated the existence of Plasmodium in the wall of the midgut and salivary glands of a Culex mosquito. For this discovery he won the Nobel Prize in 1902. However credit must also be given to the Italian professor Giovanni Battista Grassi, who showed that human malaria could only be transmitted by Anopheles mosquitoes. It is worth noting, however, that for some species the vector may not be a mosquito.

Mosquitoes of the genera Culex, Anopheles, Culiceta, Mansonia and Aedes may act as vectors. The currently known vectors for human malaria (> 100 species) all belong to the genus Anopheles. Bird malaria is commonly carried by species belonging to the genus Culex. Only female mosquitoes bite. Aside from blood both sexes live on nectar, but one or more blood meals are needed by the female for egg laying as the protein content of nectar is very low. The life cycle of Plasmodium was discovered by Ross who worked with species from the genus Culex.

The life cycle of Plasmodium is very complex. Sporozoites from the saliva of a biting female mosquito are transmitted to either the blood or the lymphatic system^[2] of the recipient. The sporozoites then migrate to the liver and invade hepatocytes. This latent or dormant stage of the Plasmodium sporozoite in the liver is called the hypnozoite.

The development from the hepatic stages to the erythrocytic stages has until very recently been obscure. In 2006^[3] it was shown that the parasite buds off the hepatocytes in merosomes containing hundreds or thousands of merozoites. These merosomes have been subsequently shown^[4] to lodge in the pulmonary capilaries and to slowly disintergrate there over 48-72 hours releasing merozoites. Erythrocyte invasion is enhanced when blood flow is slow and the cells are tightly packed: both of these conditions are found in the alveolar capilaries.

Within the erythrocytes the merozoite grow first to a ring-shaped form and then to a larger trophozoite form. In the schizont stage, the parasite divides several times to produce new merozoites, which leave the red blood cells and travel within the bloodstream to invade new red blood cells. Most merozoites continue this replicative cycle, but some merozoites differentiate into male or female sexual forms (gametocytes) (also in the blood), which are taken up by the female mosquito.

In the mosquito’s midgut, the gametocytes develop into gametes and fertilize each other, forming motile zygotes called ookinetes. The ookinetes penetrate and escape the midgut, then embed themselves onto the exterior of the gut membrane. Here they divide many times to produce large numbers of tiny elongated sporozoites. These sporozoites migrate to the salivary glands of the mosquito where they are injected into the blood of the next host the mosquito bites. The sporozoites move to the liver where they repeat the cycle.

Reactivation of the hypnozoites has been reported for up to 30 years after the initial infection in humans. The factors precipating this reactivation are not known. In the species Plasmodium malariae, Plasmodium ovale and Plasmodium vivax hypnozoites have been shown to occur. Reactivation does not occur in infections with Plasmodium falciparum. It is not known if hypnozoite reactivaction may occur with any of the remaining species that infect humans but this is presumed to be the case.

This life cycle is best understood in terms of its evolution.

The Apicomplexia – the phylum to which Plasmodium belongs – are thought to have originated within the Dinoflagellates – a large group of photosynthetic protozoa. It is currently thought that the ancestors of the Apicomplexia were originally prey organisms that evolved the ability to invade the intestinal cells and subsequently lost their photosynthetic ability. Some extant dinoflagelates, however, can invade the bodies of jellyfish and continue to photosynthesize, which is possible because jellyfish bodies are almost transparent. In other organisms with opaque bodies this ability would most likely rapidly be lost.

It is thought that Plasmodium evolved from a parasite spread by the orofaecal route which infected the intestinal wall. At some point this parasite evolved the ability to infect the liver. This pattern is seen in the genus Cryptosporidium to which Plasmodium is distantly related. At some later point this ancestor developed the ability to infect blood cells and to survive and infect mosquitoes. Once mosquito transmission was firmly established the previous orofecal route of transmission was lost.

Current (2007) theory suggests that the genera Plasmodium, Hepatocystis and Haemoproteus evolved from Leukocytozoon species. Parasites of the genus Leukocytozoan infect white blood cells (leukocytes), liver and spleen cells and are transmitted by ‘black flies’ (Simulium species) – a large genus of flies related to the mosquitoes.

Leukocytes, hepatocytes and most spleen cells actively phagocytose particulate matter making entry into the cell easier for the parasite. The mechanism of entry of Plasmodium species into erythrocytes is still very unclear taking as it does less than 30 seconds. It is not yet known if this mechanism evolved before mosquitoes became the main vectors for transmission of Plasmodium.

Plasmodium evolved about 130 million years ago. This period is coincidental with the rapid spread of the angiosperms (flowering plants). This expansion in the angiosperms is thought to be due to at least one genomic duplication event. It seems probable that the increase in the number of flowers led to an increase in the number of mosquitoes and their contact with vertebrates.

Mosquitoes evolved in what is now South America about 230 million years ago. There are over 3500 species recognised but to date their evolution has not been well worked out so a number of gaps in our knowledge of the evolution of Plasmodium remain.

Presently it seems probable that birds were the first group infected by Plasmodium followed by the reptiles – probably the lizards. At some point primates and rodents became infected. The remaining species infected outside these groups seem likely to be due to relatively recent events.

At the present time (2007) DNA sequences are available from fewer than sixty species and most of these are from species infecting either rodent or primate hosts. The evolution proposed here should be regarded as speculative and subject to revision as data becomes available.

The pattern of alternation of sexual and asexual reproduction which may seem confusing at first is a very common pattern in parasitic species. The evolutionary advantages of this type of life cycle were recognised by Mendel.

Under favourable conditions asexual reproduction is superior to sexual as the parent is well adapted to its environment and its descendents share these genes. Transferring to a new host or in times of stress, sexual reproduction is generally superior as this produces a shuffling of genes which on average at a population level will produce individuals better adapted to the new environment.

All the species examined to date have 14 chromosomes, one mitochondrion and one plastid. The chromosomes vary from 500 kilobases to 3.5 megabases in length. It is presumed that this is the pattern throughout the genus.

The plastid unlike those found in algae is not photosynthetic. Its function is not known but there is some suggestive evidence that it may be involved in reproduction.

On a molecular level, the parasite damages red blood cells using plasmepsin enzymes – aspartic acid proteases which degrade hemoglobin.

• Forms gamonts in erythrocytes
• Merogony occurs in erythrocytes and in other tissues
• Hemozoin is present
• Vectors are either mosquitos or sandflies
• Vertebrate hosts include mammals, birds and reptiles

Plasmodium belongs to the family Plasmodiidae (Levine, 1988), order Haemosporidia and phylum Apicomplexia. There are currently 450 recognised species in this order. Many species of this order are undergoing reexamination of their taxonomy with DNA analysis. It seems likely that many of these species will be re assigned after these studies have been completed.^[5][6] For this reason the entire order is outlined here.

Notes:

The genera Plasmodium, Fallisia and Saurocytozoon all cause malaria in lizards. All are carried by Dipteria (roughly speaking the flies). Pigment is absent in the Garnia. Non pigmented gametocytes are typically the only forms found in Saurocytozoon: pigmented forms may be found in the leukocytes occasionally. Fallisia produce non pigmented asexual and gametocyte forms in leukocytes and thrombocytes.

The full taxonomic name of a species includes the subgenus but this is often omitted. The full name indicates some features of the morphology and type of host species.

The only two species in the sub genus Laverania are P. falciparum and P. reichenowi.

Species infecting monkeys and apes (the higher primates) with the exceptions of P. falciparum and P. reichenowi are classified in the subgenus Plasmodium.

Parasites infecting other mammals including lower primates (lemurs and others) are classified in the subgenus Vinckeia.

The distinction between P. falciparum and P. reichenowi and the other species infecting higher primates was based on the morphological findings but have since been confirmed by DNA analysis. Vinckeia while previously considered to be something of a taxonomic ‘rag bag’ has been recently shown – perhaps rather surprisingly – to form a coherent grouping.

The remaining groupings here are based on the morphology of the parasites. Revisions to this system are likely to occur in the future as more species are subject to analysis of their DNA.

The four subgenera Giovannolaia, Haemamoeba, Huffia and Novyella were created by Corradetti et al^[7] for the known avian malarial species. A fifth – Bennettinia – was created in 1997 by Valkiunas.^[8] The relationships between the subgenera are the matter of current investigation. Martinsen et al ‘s recent (2006) paper outlines what is currently (2007) known.^[9]

P. juxtanucleare is currently (2007) the only known member of the subgenus Bennettinia.

Unlike the mammalian and bird malarias those affecting reptiles have been more difficult to classify. In 1966 Garnham classified those with large schizonts as Sauramoeba, those with small schizonts as Carinamoeba and the single then known species infecting snakes (Plasmodium wenyoni) as Ophidiella.^[10] He was aware of the arbitrariness of this system and that it might not prove to be biologically valid. Telford in 1988 used this scheme as the basis for the currently accepted (2007) system.^[11]

Classification criteria
Species in the subgenus Bennettinia have the following characteristics:

• Schizonts contain scant cytoplasm, are often round, do not exceed the size of the host nucleus and stick to it.
• Gametocytes while varying in shape tend to be round or oval, do not exceed the size of the nucleus and stick to it.

Species in the subgenus Giovanolaia have the following characteristics:

• Schizonts contain plentiful cytoplasm, are larger than the host cell nucleus and frequently displace it. They are found only in mature erythrocytes.
• Gametocytes are elongated.
• Exoerythrocytic schizogony occurs in the mononuclear phagocyte system.

Species in the subgenus Haemamoeba have the following characteristics:

• Mature schizonts are larger than the host cell nucleus and commonly displace it.
• Gametocytes are large, round, oval or irregular in shape and are substantially larger than the host nucleus.

Species in the subgenus Huffia have the following characteristics:

• Mature schizonts, while varying in shape and size, contain plentiful cytoplasm and are commonly found in immature erthryocytes.
• Gametocytes are elongated.

Species in the subgenus Novyella have the following characteristics:

• Mature schisonts are either smaller than or only slightly larger than the host nucleus. They contain scanty cytoplasm.
• Gametocytes are elongated. Sexual stages in this subgenus resemble those of Haemoproteus.
• Exoerythrocytic schizogony occurs in the mononuclear phagocyte system

Species in the subgenus Carinamoeba have the following characteristics:

• Infect lizards
• Schizonts normally give rise to less than 8 merozoites

Species in the subgenus Sauramoeba have the following characteristics:

• Infect lizards
• Schizonts normally give rise to more than 8 merozoites

Notes

• The erythrocytes of both reptiles and birds retain their nucleus, unlike those of mammals. The reason for the loss of the nucleus in mammalian erythocytes remains unknown.
• The presence of elongated gametocytes in several of the avian subgenera and in Laverania in addition to a number of clinical features suggested that these might be closely related. This is is no longer thought to be the case.

• Plasmodium falciparum (the cause of malignant tertian malaria)
• Plasmodium vivax (the most frequent cause of benign tertian malaria)
• Plasmodium ovale (the other, less frequent, cause of benign tertian malaria)
• Plasmodium malariae (the cause of benign quartan malaria)
• Plasmodium knowlesi
• Plasmodium brasilianum
• Plasmodium cynomolgi
• Plasmodium cynomolgi bastianellii
• Plasmodium inui
• Plasmodium rhodiani
• Plasmodium schweitzi
• Plasmodium semiovale
• Plasmodium simium

The first four listed here are the most common species that infect humans. With the use of the polymerase chain reaction additional species have been and are still being identified that infect humans.

One possible experimental infection has been reported with Plasmodium eylesi. Fever and low grade parasitemia were apparent at 15 days. The volunteer (Dr Bennett) had previously been infected by Plasmodium cynomolgi and the infection was not transferable to a gibbon (P. eylesi ‘s natural host) so this cannot be regarded as definitive evidence of its ability to infect humans. A second case has been reported that may have been a case of P. eylesi but the author was not certain of the infecting species.^[12]

A possible infection with Plasmodium tenue has been reported. ^[13] This report described a case of malaria in a three year old black girl from Georgia, USA who had never been outside the US. She suffered from both P. falciparum and P. vivax malaria and while forms similar to those described for P. tenue were found in her blood even the author was skeptical about the validity of the diagnosis. Confusingly Plasmodium tenue was proposed in the same year (1914) for a species found in birds. The human species is now considered to be likely to have been a misdiagnosis and the bird species is described on the Plasmodium tenue page.

Notes:

The only known host of P. falciparum are humans; neither is any other host currently known for P. malariae.

P. vivax will infect chimpanzees. Infection tends to be low grade but may be persistent and remain as source of parasites for humans for some time. P. vivax is also known to infect orangutans.^[14]

Like P. vivax, P. ovale has been shown to be transmittable to chimpanzees. P. ovale has a unusual distribution pattern being found in Africa, the Philippines and New Guinea. In spite of its admittedly poor transmission to chimpanzees given its discontigous spread, it is suspected that P. ovale may in fact be a zooenosis with an as yet unidentified host. If this is actually the case, the host seems likely to be a primate.

The remaining species capable of infecting humans all have other primate hosts.

Plasmodium shortii and Plasmodium osmaniae are now considered to be junior synonyms of Plasmodium inui

Species no longer recognised as valid

Taxonomy in parasitology until the advent of DNA based methods has always been a problem and revisions in this area are continuing. A number of synonoms have been given for the species infecting humans that are no longer recognised as valid.^[15] Since perusal of the older literature may be confusing some of these are listed here…

The species that infect primates other than humans include: P. bouillize, P. brasilianum, P. bucki, P. cercopitheci,P. coatneyi, P. coulangesi, P. cynomolgi, P. eylesi, P. fieldi, P. foleyi, P. fragile, P. girardi, P. georgesi, P. gonderi, P. hylobati, P. inui, P. jefferyi, P. joyeuxi,P. knowlesi, P. lemuris, P. percygarnhami, P. petersi, P. reichenowi, P. rodhaini, P. sandoshami, P. semnopitheci, P. silvaticum, P. simiovale, P. simium, P. uilenbergi, P. vivax and P. youngei.

Host records – Most if not all Plasmodium species infect more than one host: the host records shown here should be regarded as being incomplete.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]; Alison Leibowitz [3]

Malaria must be differentiated from other diseases that cause fever, chills, nausea, anemia and vomiting, such as Ebola, Typhoid fever, Shigellosis and Lassa fever.

The table below summarizes the findings that differentiate Malaria from other conditions, which also cause fever and vomiting:^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [3]

Worldwide, 3.4 billion people live in areas at risk of malaria transmission in 106 countries and territories. The World Health Organization estimates that in 2012 malaria caused 207 million clinical episodes, and 627,000 deaths. An estimated 91% of deaths in 2010 occurred in the African Region. The vast majority of cases of malaria occur in children under the age of 5 years. Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur. Malaria is present depending primarily on climatic factors such as temperature, humidity, and rainfall.

P. vivax is the most common cause of infection, responsible for about 80 % of all malaria cases. However, P. falciparum is the most important cause of disease, and responsible for about 15% of infections and 90% of deaths.^[1]

• The World Health Organization estimates that in 2012 malaria caused 207 million clinical episodes worldwide.^[2]
• In the United States, approximately 1,500–2,000 cases of malaria are reported every year, almost all in recent travelers. Reported malaria cases reached a 40-year high of 1,925 in 2011.^[2]

The vast majority of cases of malaria occurs in children under the age of 5 years.^[3]

• The World Health Organization estimates that in 2012 malaria caused 207 million clinical episodes, and 627,000 deaths. An estimated 91% of deaths in 2010 were in the African Region.^[2]

• Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur.^[4]
• The geographic distribution of malaria within large regions is complex, and malarial and malaria-free areas are often found close to each other.^[5]

• Shown below is an image depicting an approximation of the parts of the world where malaria transmission occurs (source: CDC).

• Malaria is more common in rural areas than in cities; this contrasts with dengue fever, where urban areas present the greater risk.^[7]
• The cities of the Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in many rural regions.^[8]

• In Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities.^[9]

• Malaria is found mainly on climatic factors such as temperature, humidity, and rainfall.
• Temperature is particularly critical. For example, at temperatures below 20°C (68°F), Plasmodium falciparum (which causes severe malaria) cannot complete its growth cycle in the Anopheles mosquito, and thus cannot be transmitted.

• In many malaria-endemic countries, malaria transmission does not occur in all parts of the country. Even within tropical and subtropical areas, transmission will not occur:
  • At very high altitudes
  • During colder seasons in some areas
  • In deserts (excluding the oases)
  • In some countries where transmission has been interrupted through successful control/elimination programs.

• Generally, in warmer regions closer to the equator transmission will be more intense and malaria is transmitted year-round. The highest transmission is found in Africa South of the Sahara and in parts of Oceania such as Papua New Guinea.

• In cooler regions, transmission will be less intense and more seasonal. There, P. vivax might be more prevalent because it tolerates better lower temperatures.

• Many temperate areas, such as western Europe and the United States, economic development and public health measures have succeeded in eliminating malaria. However, most of these areas have Anopheles mosquitoes that can transmit malaria, and the reintroduction of the disease is a constant risk.

• In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall.^[10]

• Malaria is not just a disease commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development.
• The disease has been associated with major negative economic effects on regions where it is widespread.
• A comparison of average per capita GDP in 1995, adjusted to give parity of purchasing power, between malarious and non-malarious countries demonstrates a fivefold difference (US$1,526 versus US$8,268).
• In countries where malaria is common, average per capita GDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries.^[11]
• Correlation does not imply causation, and the prevalence is at least partly because these regions do not have the financial capacities to prevent malaria. In its entirety, the economic impact of malaria has been estimated to cost Africa US$12 billion every year.
• The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.^[3]
• In some countries with a heavy malaria burden, the disease may account for as much as 40% of public health expenditure, 30-50% of inpatient admissions, and up to 50% of outpatient visits.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [3]; Alison Leibowitz [4]

Travel to endemic areas is a risk factor for malaria. For travelers, regions associated with the highest estimated relative risk of infection are West Africa and Oceania. Human behavior, often dictated by socioeconomic situations, can influence the risk of malaria for individuals and communities. In addition, children and pregnant women are at a higher risk of contracting malaria. Certain biologic characteristics can protect against particular types of malaria. Two genetic factors, the sickle cell trait and absence of Duffy blood group, have been shown to be epidemiologically significant.^[1]

Individuals who have the sickle cell trait (heterozygotes for the abnormal hemoglobin gene HbS) are relatively protected against P. falciparum malaria and thus possess a biologic advantage. Because P. falciparum malaria has historically been a leading cause of death in Africa, the sickle cell trait is found more frequently in Africa and in individuals of African ancestry, than in other population groups.

In general, the prevalence of hemoglobin-related disorders and other blood cell dyscrasias, such as Hemoglobin C, thalassemias, and G6PD deficiency, are more prevalent in malaria endemic areas and are thought to provide protection from malarial disease.^[1]

Individuals who are negative for the Duffy blood group possess red blood cells that are resistant to infection by P. vivax. Since the majority of Africans are Duffy negative, P. vivax is rare in Africa south of the Sahara, especially in West Africa. In that area, the niche of P. vivax has been taken over by P. ovale, a similar parasite that can infest Duffy-negative individuals.^[1]

Other genetic factors related to red blood cells can also influence malaria, but to a lesser extent. Various genetic determinants (such as the “HLA complex,” which plays a role in control of immune responses) may equally influence an individual’s risk of developing severe malaria.^[1]

In areas with high P. falciparum transmission (most of Africa south of the Sahara), newborns will be protected during the first few months of life, by maternal antibodies transferred to them through the placenta. As the transferred antibodies decrease with time, these young children become vulnerable to disease, and subsequent death, by malaria. If they survive repeated infections and reach an older age (2-5 years) they will develop a protective semi-immune status. In malaria-endemic areas, young children are at a high risk of developing malaria. For this reason, these young children are targeted preferentially by malaria control interventions.^[1]

In areas with lower transmission (such as Asia and Latin America), infections occur less frequently, resulting in a larger proportion of the older children and adults possesing no protective immunity. In such areas, malarial disease can be present in all age groups, and epidemics can occur.^[1]

Traveling to endemic areas is a risk factor for malaria. For travelers, regions associated with the highest estimated relative risk of infection are West Africa and Oceania. For these areas of intense transmission, exposure even for short time periods can result in transmission. For travelers, regions associated with a moderate estimated relative risk of infection are the other parts of Africa, South Asia, and South America.

First- and second-generation immigrants from malaria-endemic countries, returning to their native countries to visit friends and relatives, tend not to use appropriate malaria prevention measures and subsequently have an increased likelihood of developing malaria .^[2]

Pregnancy decreases immunity against many infectious diseases. Females who have developed protective immunity against P. falciparum frequently lose this protection upon pregnancy (especially during the first and second pregnancies). Malaria during pregnancy is harmful to the mothers and the fetus. Upon malarial infection, fetuses are at an increased risk of premature delivery, low birth weight, and mortality during the early months of life. For this reason pregnant women are targeted for protection by malaria control programs in endemic regions.^[1]

The Plasmodium Falciparum parasites adhere to the placental Chondroitin sulphate A and induce placental inflammation and dysregulated placental angiogenesis.This dysregulated angiogenesis of placenta leads to complications like placental insufficiency, preterm delivery, and low birth weight.

Human behavior, often dictated by socioeconomic situations, can influence the risk of malaria for individuals and communities. For example:^[1]

• Poverty-stricken rural populations in malaria-endemic areas, frequently cannot afford the housing and bed nets, which would protect them from exposure to mosquitoes. These individuals often are uninformed about the common manifestations of malaria and the importance of prompt and proper treatment. Often, cultural beliefs result in use of traditional, but ineffective, methods of treatment.
• Travelers from non-endemic areas may disregard the use of insect repellent or prophylactic malarial medicines, due to cost, inconvenience, or a lack of knowledge.
• Standing water in irrigation ditches or burrow pits can be breeding sites for larvae.
• Agricultural work, such as harvesting, may lead to an increased nighttime exposure to mosquito bites.
• Raising domestic animals near the household provides alternate blood sources for Anopheles mosquitoes, decreasing human exposure.
• War, migrations, and tourism may expose non-immune individuals to an environment with high malarial transmission.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2], Marjan Khan M.B.B.S.[3]

Screening of malaria is important in Sub-Saharan refugees and blood donors.^[1]

Screening for malaria infection is important in:^[1]

• Sub-Saharan refugees
  • A sub-optimal alternative to presumptive therapy is to test newly arriving for malaria infection.
  • Studies have demonstrated that a single malaria thick-and-thin blood smear lacks sensitivity for detecting asymptomatic or sub-clinical malaria in these populations.
  • Three separate blood films taken at 12 to 24 hour intervals, the standard recommendation for diagnosis of clinical malaria, has a greater sensitivity. However, this approach is rarely feasible for screening newly arriving refugee populations because of cost constraints and the need for multiple visits.
  • When a refugee does not receive presumptive therapy they should be monitored for signs or symptoms of disease, particularly during the initial 3 months after arrival, regardless of the post-arrival testing results.

• Blood donors
  • Studies using PCR test for the screening of malaria in blood donors are being conducted.^[2]

• In 1968, the World Health Organization published guidelines for the establishment of a screening program that can be summarized in 10 principles:

1. The disease should be an important health problem.
2. The natural history of the disease should be understood adequately.
3. A latent stage of the disease occurs.
4. A test for the disease is available.
5. The test is acceptable to the population.
6. Treatment for the disease exist.
7. facilities for diagnosis and treatment are available.
8. A policy about who to treat has been agreed on.
9. Case finding costs should be considered in relation to medical expenditure as a whole.
10. Case finding should be organized as an ongoing process rather than a one-time only project.

• These guidelines form the theoretic basis of most screening programs including malaria that are currently in use.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [3], Usama Talib, BSc, MD [4]

Following the infective bite of the Anopheles mosquito, a period of time goes by before the first symptoms appear, with the incubation period varying between 7 to 30 days depending on the immune status of the patient, type and strain of the plasmodium, the dose of sporozoites injected on the bite, and the presence of prophylactic drugs. The classical but rarely observed malaria attack lasts 6-10 hours, and it consists of a cold stage, hot stage, and sweating stage. Severe malaria is almost exclusively caused by P. falciparum infections and usually arises 6-14 days following infection.^[1] Complications of severe malaria include splenomegaly, severe headache, cerebral ischemia, hepatomegaly, hypotension, ARDS, and hemoglobinuria with renal failure. Severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases, fatality rates can exceed 20%, even with intensive care and treatment.^[2][3]

• Following the infective bite by the Anopheles mosquito, a period of time (the “incubation period“) goes by before the first symptoms appear.
• The incubation period in most cases varies from 7 to 30 days.
• The shorter periods are observed most frequently with P. falciparum and the longer ones with P. malariae.^[4]
• Antimalarial drugs taken for prophylaxis by travelers can delay the appearance of malaria symptoms by weeks or months, long after the traveler has left the malaria-endemic area. This can happen particularly with P. vivax and P. ovale, both of which can produce dormant liver stage parasites; the liver stages may reactivate and cause disease months after the bite of the infective mosquito. Such long delays between exposure and development of symptoms can result in misdiagnosis or delayed diagnosis because of reduced clinical suspicion by the health-care provider. Returned travelers should always remind their health-care providers of any travel in areas where malaria occurs, during the past 12 months.^[4]

The classical (but rarely observed) malaria attack lasts 6-10 hours. It consists of:^[4]

• A cold stage (sensation of cold, shivering)
• A hot stage (fever, headaches, vomiting; seizures in young children)
• A sweating stage (sweats, return to normal temperature, tiredness)

Classically (but infrequently observed) the attacks occur every second day with the “tertian” parasites (P. falciparum, P. vivax, and P. ovale) and every third day with the “quartan” parasite (P. malariae).^[4]

More commonly, the patient presents with a combination of any the following symptoms: fever, chills, sweats, headaches, nausea and vomiting, body aches, and general malaise.^[4]

In countries where cases of malaria are infrequent, these symptoms may be attributed to influenza, a cold, or other common infections, especially if malaria is not suspected. Conversely, in countries where malaria is frequent, residents often recognize the symptoms as malaria, and treat themselves without seeking diagnostic confirmation (“presumptive treatment”).^[4]

Severe malaria occurs when infections are complicated by serious organ failure or abnormalities in the patient’s blood or metabolism. Severe malaria is a medical emergency and should be treated urgently and aggressively.^[4]

Criterion Description for severe malaria :

Signs and symptoms:

Impaired consciousness  : A Glasgow coma score of <11 (range, 3 to 15; lower scores indicate lower levels of consciousness) in adults or a Blantyre coma score of <3 (range, 0 to 5; lower scores indicate lower levels of consciousness) in children.

Multiple convulsions  : More than two seizures within a 24-hr period.

Prostration  : Inability to sit, stand, or walk without assistance.

Clinically significant bleeding  : Recurrent or prolonged bleeding from the nose, gums, or venipuncture sites; hematemesis; or melena .

Shock or circulatory collapse :A systolic blood pressure of <80 mm Hg (<70 mm Hg in children), plus evidence of impaired perfusion (cool extremities or prolonged capillary . refill)

Laboratory and radiologic findings :

Acidosis :A base deficit of >8 meq/liter, a plasma bicarbonate level of <15 mmol/liter, or a venous plasma lactate level of ≥5 mmol/liter.

Anemia :A hemoglobin level of <7 g/dl or a hematocrit of <20% (≤5 g/dl or ≤15%, respectively, in children <12 yr of age) plus a parasite density of >10,000/μl.

Hypoglycemia : A plasma or serum glucose level of <40 mg/dl (<2.2 mmol/liter).

Parasitemia  : >10% (≥5% in nonimmune travelers).

Jaundice  : A plasma or serum bilirubin level of >50 μmol/liter (3 mg/dl) plus a parasite density of >100,000/μl.

Renal impairment: A plasma or serum creatinine level of >3 mg/dl or a blood urea level of >20 mmol/liter.

Pulmonary edema : Confirmed edema on radiologic examination or an oxygen saturation of <92% while breathing ambient air with a respiratory rate of >30 breaths/min.

In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks (“relapses”) after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites (“hypnozoites“) that may reactivate. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack.^[4]

• Severe malaria and its complications are associated with P. falciparum infection. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypotension, ARDS, and hemoglobinuria with renal failure may occur.

• Decreased fetal growth^[3]

• Thrombocytopenia^[5]
• Leukopenia^[5]
• High bilirubin^[5]
• Elevated creatinine^[5]
• Anemia^[5]

• Hypoglycemia^[6]
  • Increased turnover of glucose
  • Hyperinsulinemia secondary to treatment with quinine
• Lactic acidosis^[6]

• Spontaneous rupture of the spleen^[7]
• Hematoma^[7]
• Hyperreactive malarial syndrome^[7]
• Enlarged spleen^[7]
• Torsion^[7]
• Splenic cysts^[7]

• Cerebral malaria^[8]
  • Acute encephalopathy caused by infection with P. falciparum
  • Associated with 50% rate of mortality
  • Symptoms might be further exacerbated in case of hypoglycemia secondary to treatment with quinine
• Intracranial hemorrhage^[8]
• Cerebral artery occlusion^[8]
• Self limiting cerebral ataxia^[8]
• Epilepsy^[8]
• Transient psychiatric symptoms^[8]
• Transient extrapyramidal symptoms^[8]

• Pulmonary edema^[9]
  • Tachypnea
  • Dyspnea
• Hypoxemia^[9]
• Respiratory failure and intubation^[9]
• Acute respiratory distress syndrome (ARDS)^[9]

• Acute renal failure
• Blackwater fever (hemoglobin from lysed red blood cells leaks into the urine.)

• In endemic areas, the overall fatality rate for all cases of malaria can be as high as one in ten.^[10] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.^[11]

• Only in some individuals do malaria episodes progress to severe life-threatening disease, while in the majority the episodes are self-limiting. This is partly because of host genetic factors such as the sickle cell gene.^[12]

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