Plasmodium falciparum

Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species (also called malignant or falciparum malaria) is the most dangerous form of malaria, with the highest rates of complications and mortality. As of 2006, there were an estimated 247 million human malarial infections (98% in Africa, 70% being 5 years or younger). It is much more prevalent in sub-Saharan Africa than in many other regions of the world; in most African countries, over 75% of cases were due to P. falciparum, whereas in most other countries with malaria transmission, other, less virulent plasmodial species predominate. Almost every malarial death is caused by P. falciparum.

A human parasite causing the malignant form of tertian (pernicious or malignant ) malaria, found in all continents.

Malaria is caused by an infection with protozoa of the genus Plasmodium. The name malaria, from the Italian mala aria, meaning «bad air», comes from the linkage suggested by Giovanni Maria Lancisi (1717) of malaria with the poisonous vapours of swamps. This species name comes from the Latin falx, meaning «sickle», and parere meaning «to give birth». The organism itself was first seen by Laveran on November 6, 1880 at a military hospital in Constantine, Algeria, when he discovered a microgametocyte exflagellating. Patrick Manson (1894) hypothesised that mosquitoes could transmit malaria. This hypothesis was experimentally confirmed independently by Giovanni Battista Grassi and Ronald Ross in 1898. Grassi (1900) proposed an exerythrocytic stage in the life cycle, later confirmed by Short, Garnham, Covell and Shute (1948), who found Plasmodium vivax in the human liver.

Around the world, malaria is the most significant parasitic disease of humans, and claims the lives of more children worldwide than any other infectious disease . Since 1900, the area of the world exposed to malaria has been halved, yet two billion more people are presently exposed. Morbidity, as well as mortality, is substantial. Infection rates in children in endemic areas are of the order of 50%: Chronic infection has been shown to reduce school scores by up to 15%. Reduction in the incidence of malaria coincides with increased economic output.

While there are no effective vaccines for any of the six or more species that cause human malaria, drugs have been employed for centuries. In 1640, Huan del Vego first employed the tincture of the cinchona bark for treating malaria; the native Indians of Peru and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this «Jesuits’ bark» to England. Its first recorded use there was by Dr John Metford of Northampton in 1656. Morton (1696) presented the first detailed description of the clinical picture of malaria and of its treatment with cinchona. Gize (1816) studied the extraction of crystalline quinine from the cinchona bark, and Pelletier and Caventou (1820) in France extracted pure quinine alkaloids, which they named quinine and cinchonine.

The life cycle of all Plasmodium species is complex. Infection in humans begins with the bite of an infected female Anopheles mosquito. Sporozoites released from the salivary glands of the mosquito enter the bloodstream during feeding, quickly invading liver cells (hepatocytes). Sporozoites are cleared from the circulation within 30 minutes. During the next 14 days in the case of P. falciparum, the liver-stage parasites differentiate and undergo asexual multiplication, resulting in tens of thousands of merozoites that burst from the hepatocyte. Individual merozoites invade red blood cells (erythrocytes) and undergo an additional round of multiplication, producing 12-16 merozoites within a schizont. The length of this erythrocytic stage of the parasite lifecycle depends on the parasite species: irregular cycle for P. falciparum, 48 hours for P. vivax and P. ovale, and 72 hours for P. malariae.[6] The clinical manifestations of malaria, fever, and chills are associated with the synchronous rupture of the infected erythrocytes. The released merozoites go on to invade additional erythrocytes. Not all of the merozoites divide into schizonts; some differentiate into sexual forms, male and female gametocytes. These gametocytes are taken up by a female Anopheles mosquito during a blood meal. Within the mosquito midgut, the male gametocyte undergoes a rapid nuclear division, producing eight flagellated microgametes that fertilize the female macrogamete. The resulting ookinete traverses the mosquito gut wall and encysts on the exterior of the gut wall as an oocyst. Soon, the oocyst ruptures, releasing hundreds of sporozoites into the mosquito body cavity, where they eventually migrate to the mosquito salivary glands.

Plasmodium falciparum causes severe malaria via a distinctive property not shared by any other human malaria, that of sequestration. Within the 48-hour asexual blood stage cycle, the mature forms change the surface properties of infected red blood cells, causing them to stick to blood vessels (a process called cytoadherence). This leads to obstruction of the microcirculation and results in dysfunction of multiple organs, typically the brain in cerebral malaria.

Etiology

Five species of genus Plasmodium are known to cause malaria in humans. The vector for Plasmodium spp. is a female Anopheles mosquito that inoculates sporozoites contained in her salivary glands into the puncture wound when feeding.[3] Sporozoites enter peripheral bloodstream and are uptaken by hepatocytes, where they undergo an asexual pre-erythrocytic liver-stage as liver schizonts lasting up to 2 weeks before the onset of the blood stage.[3][4] As they replicate within hepatocytes, they form motile merozoites that are subsequently released into the bloodstream, where they invade red blood cells (RBC). The process continues through serial cycles of asexual replication of merozoites that go through ring, trophozoite, and schizont stages before forming and releasing new invasive daughter merozoites that consequently infect new RBC, therefore causing a rise in parasite numbers.[3][5] P. falciparum produces high levels of blood-stage parasites and is known to modify the surface of the infected RBC, creating an adhesive phenotype, e.g. (sticky cell) causing RBC sequestration inside small and middle-sized vessels, removing the parasite from the circulation for nearly half of the asexual cycle.[6] Sequestration leads to splenic parasite clearance avoidance, host cell endothelial damage, and microvascular obstruction.[5][6] A small fraction of intra-erythrocytic parasites switch to sexual development, producing morphologically distinct male and female gametocytes that reach the host’s dermis and are ingested by a mosquito, rendering it infectious to humans.[3][4][5] After ingestion by a female Anopheles mosquito, the male micro-gametocytes go through a process of ex-flagellation in the mosquito’s midgut, fusing with female macro-gametes to form a zygote. The zygote then reaches the stage of ookinete that migrates through a thin wall, matures into oocyst, producing and upon rupturing, releasing numerous sporozoites that are dispersed throughout mosquitos body, including salivary glands, therefore completing the lifecycle. Gametocytes are hence of vital importance to the transmission cycle of malaria.[2][4][7] The clinical symptoms are, however, predominantly a result of the asexual stages of parasite replication in human blood.[5]

Morfologia

Em geral

Em geral, Plasmodium (que parasitam os seres humanos) formam quatro estágios de desenvolvimento no homem: esquizontes hepáticos, trofozoítos, esquizontes e gamontos ou gametócitos intraeritrocitários. Eles também têm três estágios de desenvolvimento em mosquitos: oocinetos, oocistos e esporozoítos.

Em humanos

Os esquizontes hepáticos aparecem como grupos de pequenos corpos basofílicos localizados dentro dos hepatócitos do hospedeiro. Eles medem entre 40-80 μm de diâmetro quando amadurecem.

Os estágios intraeritrocíticos consistem em pequenos trofozoítos em forma de anel medindo entre 1 e 2 µm de diâmetro. Os esquizontes amorfos multinucleados medem até 7 ou 8 μm de comprimento. E os gametócitos micro- (♂) e macro- (♀), que variam em comprimento de 7 a 14 μm.

Outras características morfológicas que os distinguem de outros protozoários, é que durante o seu desenvolvimento em humanos os microgametocitos têm um núcleo maior e difuso, enquanto os macrogametocitos têm um citoplasma de coloração mais escura.

Em mosquitos

Durante o desenvolvimento de Plasmodium nos mosquitos, os microgametes são longos e finos, entre 15 a 25 µm de comprimento. Os ookinetos móveis são 15-20 x 2-5 μm. Oócitos ovais podem medir até 50 mm de diâmetro na superfície externa.

Plasmodium falciparum

A morfologia desta espécie de parasita varia dependendo de seu estágio no sangue. Neste caso, a descrição morfológica desta espécie será utilizada quando se desenvolver em humanos:

—Ring: citoplasma delicado, com 1-2 pequenos pontos cromáticos, às vezes com formas de renda.

—Trofozoítos: eles são dificilmente observados no sangue periférico. Nesta fase o citoplasma é compacto e tem pigmento escuro.

—EsquizontesOs esquizontes são células-tronco que se reproduzem assexuadamente por merogonia e produzem merozoítos no seu interior. Eles raramente são observados no sangue periférico, eles têm 8-24 pequenos merozoitos. Eles têm pigmento escuro aglutinado em uma massa.

—Gametocito: tem a forma de uma cana com extremidades curvas, o macrogametócito apresenta cromatina em uma única massa, enquanto no microgametócito é difuso e o pigmento é escuro.

Disease burden

According to the latest World malaria report, released on 30 November 2020, there were 229 million cases of malaria in 2019 compared to 228 million cases in 2018. The estimated number of malaria deaths stood at 409 000 in 2019, compared with 411 000 deaths in 2018.

The WHO African Region continues to carry a disproportionately high share of the global malaria burden. In 2019, the region was home to 94% of all malaria cases and deaths.

In 2019, 6 countries accounted for approximately half of all malaria deaths worldwide: Nigeria (23%), the Democratic Republic of the Congo (11%), United Republic of Tanzania (5%), Burkina Faso (4%), Mozambique (4%) and Niger (4% each).

Children under 5 years of age are the most vulnerable group affected by malaria; in 2019 they accounted for 67% (274 000) of all malaria deaths worldwide.

Sintomas

Os primeiros sintomas da infecção pelo plasmodium falciparum podem não ser diferentes dos sintomas da gripe e normalmente começam cerca de sete a oito dias após a transmissão do parasita ter ocorrido. Porém, os sintomas podem ser potencialmente adiados se tiver usado tratamentos antimaláricos durante a sua viagem.

Estes sintomas podem piorar levando a um ataque de malária, que é quando o parasita plasmodium começa a causar a destruição dos glóbulos vermelhos. Este ataque pode ser identificado por uma febre superior a 38°C que pode variar durante as horas seguintes, dores de cabeça, influenza, diarreia, náusea e vómitos. No caso do plasmodium falciparum, este ataque pode levar a complicações futuras.

Blood parasites of the genus Plasmodium. There are approximately 156 named species of Plasmodium which infect various species of vertebrates. Four species are considered true parasites of humans, as they utilize humans almost exclusively as a natural intermediate host: P. falciparum, P. vivax, P. ovale and P. malariae. However, there are periodic reports of simian malaria parasites being found in humans, most reports implicating P. knowlesi. At the time of this writing, it has not been determined if P. knowlesi is being naturally transmitted from human to human via the mosquito, without the natural intermediate host (macaque monkeys, genus Macaca). Therefore, P. knowlesi is still considered a zoonotic malaria.

Life Cycle

The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites . (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage trophozoites mature into schizonts, which rupture releasing merozoites . Some parasites differentiate into sexual erythrocytic stages (gametocytes) . Blood stage parasites are responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal . The parasites’ multiplication in the mosquito is known as the sporogonic cycle . While in the mosquito’s stomach, the microgametes penetrate the macrogametes generating zygotes . The zygotes in turn become motile and elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into oocysts . The oocysts grow, rupture, and release sporozoites , which make their way to the mosquito’s salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle .

Geographic Distribution

Malaria generally occurs in areas where environmental conditions allow parasite multiplication in the vector. Malaria today is usually restricted to tropical and subtropical areas and altitudes below 1,500 m., although in the past malaria was endemic in much of North America, Europe and even parts of northern Asia, and today is still present on the Korean peninsula. However, this present distribution could be affected by climatic changes and population movements. Plasmodium falciparum is the predominant species in the world. P. vivax and P. ovale are traditionally thought to occupy complementary niches, with P. ovale predominating in Sub-Saharan Africa and P. vivax in the other areas; but their geographical ranges do overlap. These two species are not always distinguishable on the basis of morphologic characteristics alone, and the use of molecular tools will help clarify their diagnosis and exact distribution. P. malariae has wide global distribution, being found in South America, Asia, and Africa, but it is less frequent than P. falciparum in terms of association with cases of infection. P. knowlesi is found in southeast Asia.

Clinical Presentation

The symptoms of uncomplicated malaria can be rather non-specific and the diagnosis can be missed if health providers are not alert to the possibility of this disease. Since untreated malaria can progress to severe forms that may be rapidly (<24 hours) fatal, malaria should always be considered in patients who have a history of exposure (mostly: past travel or residence in disease-endemic areas). The most frequent symptoms include fever and chills, which can be accompanied by headache, myalgias, arthralgias, weakness, vomiting, and diarrhea. Other clinical features include splenomegaly, anemia, thrombocytopenia, hypoglycemia, pulmonary or renal dysfunction, and neurologic changes. The clinical presentation can vary substantially depending on the infecting species, the level of parasitemia, and the immune status of the patient. Infections caused by P. falciparum are the most likely to progress to severe, potentially fatal forms with central nervous system involvement (cerebral malaria), acute renal failure, severe anemia, or acute respiratory distress syndrome. Other species can also have severe manifestations. Complications of P. vivax malaria include splenomegaly (with, rarely, splenic rupture), and those of P. malariae include nephrotic syndrome.