Caused by single-celled protozoan parasites of the genus Plasmodium.

Five Plasmodium spp. are known to infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.

 P. falciparum and P. vivax cause most of the malarial infections worldwide.

Of these, P. falciparum accounts for the majority of the burden of malaria in sub-Saharan Africa and is associated with the most severe disease. 

P. vivax accounts for half of the malaria burden in South and East Asia and >80% of the malarial infections in the America. Malaria due to P. ovale and P. malariae is relatively uncommon but requires identification both for treatment (P. ovale, like P. vivax, forms hypnozoites with the potential for relapse) and for epidemiological purposes (malarial infection, due mostly to P. malariae, can arise from blood transfusion). 

P. knowlesi,previously thought to infect only nonhuman primates, has emerged as a zoonotic malarial parasite and now is an important, sometimes lethal, cause of human malaria in parts of Southeast Asia (including Malaysia, Indonesia, Thailand, Singapore, and the Philippines; Cox-Singh et al., 2008). P. knowlesi should therefore be considered as a potential cause of malaria among travelers returning from this region. The vast majority of malaria cases occur via infection from Anopheles mosquitoes in endemic regions. Infections acquired congenitally or via transfusions or contaminated needles are known to occur but are rare.

Screening of blood donors has reduced the risk of transfusion-transmitted malaria to 1:4,000,000 in the U.S.

Incubation Period

Following the bite of an infected female Anopheles mosquito, the inoculated sporozoites go to the liver within one to two hours. Individuals are generally asymptomatic for 12 to 35 days but can commence symptoms as early as 7 days (depending on parasite species), until the erythrocytic stage of the parasite life cycle.

Plasmodium life cycle (Have Graphic)

 

(1) Plasmodium-infected Anopheles mosquito bites a human and transmits sporozoites into the bloodstream.

(2) Sporozoites migrate through the blood to the liver where they invade hepatocytes and divide to form multinucleated schizonts (preerythrocytic stage).

(3) Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P. ovale infection. This liver stage does not cause clinical symptoms, but with reactivation and release into the circulation, late onset or relapsed disease can occur up to many months after initial infection.

(4) The schizonts rupture and release merozoites into the circulation where they invade red blood cells. Within red cells, merozoites mature from ring forms to trophozoites to multinucleated schizonts (erythrocytic stage).

(5) Some merozoites differentiate into male or female gametocytes. These cells are ingested by the Anopheles mosquito and mature in the midgut, where sporozoites develop and migrate to the salivary glands of the mosquito. The mosquito completes the cycle of transmission by biting another host.

Release of merozoites from infected red cells when they rupture causes fever and the other manifestations of malaria.

 

In most cases, the incubation period for P. falciparum infection is about 12 to 14 days (range 7 to 30 days); most infections due to P. falciparum become clinically apparent within one month after exposure]. Longer incubation periods are more likely in semi-immune individuals and individuals taking ineffective malaria prophylaxis.

P. vivax and P. ovale

The incubation period for relapsing species P. vivax and P. ovale is also about two weeks but illness can occur months after the initial infection due to activation of residual hypnozoites in the liver. Relapses generally occur within two to three years of infection.

P. malariae

The incubation period for P. malariae is about 18 days; however, low-grade asymptomatic infections can very rarely persist for years).

Comparing the malaria species

	P. falciparum	P. vivax	P. ovale	P. malariae	P. knowlesi
Geography	Tropical, temperate zones	Tropical, temperate zones, absent from West Africa	Tropical, endemic in West Africa, present in Philippines, Indonesia, and Papua New Guinea	Tropical, isolated pockets	South and Southeast Asia
RBC preference	RBCs of all ages	Young RBCs (reticulocytes)	Young RBCs (reticulocytes)	Older RBCs	RBCs of all ages
Infected RBC diameter	Normal	Larger than normal	Larger than normal	Normal or smaller than normal	Normal
Ameboid trophozoites	No	Yes	Yes	No	No
Band forms	No	No	No	Yes	Yes
Schizont*	16 to 20 merozoites; very rare in peripheral circulation	20 to 24 merozoites	4 to 16 merozoites (8 typical)	6 to 12 merozoites (8 or 10 typical)	8 to 16 (10 typical)
Parasitemia	Can be very high	Usually <2 percent	Usually <2 percent	Usually very low	Can be high
Disease severity	End organ damage and death can occur	End organ damage and death less common than P. falciparum but can occur	Severe disease uncommon	Severe disease rare	Severe disease can occur
Chloroquine resistance	Yes	Yes	No	Rare	No
Relapses from liver	No	Yes	Yes	No	No
Incubation period	12 days (8 to 25)	14 days (10 to 30; occasionally months)	15 days (10 to 20)	18 days (15 to 35; occasionally months to years)	Uncertain in naturally infected humans
Prepatent period in liver	11 days	12 days¶	12 days	32 days	Uncertain in naturally infected humans
Cycle in red cell	48 hours	48 hours	48 hours	72 hours	Uncertain in naturally infected humans

RBC: red blood cell.
* Identification of a schizont with >12 merozoites in the peripheral circulation is an important diagnostic clue for P. vivax. In general, schizonts of P. falciparum are very rarely seen in blood films; they occur only in the setting of severe disease with hyperparasitemia.
¶ The latency period of vivax is typically longer than falciparum (refer to table summarizing time to symptoms for each species).

P. falciparum and P. malariae have no dormant (hypnozoite) phase, hence do not relapse.

Uncomplicated malaria — 

Symptoms

febrile illness if they have had exposure to a region where malaria is endemic..

Patients are considered to have uncomplicated malaria in the setting of symptoms of malaria and a positive parasitological test in the absence of signs of severe malaria [9].

Physical findings may include mild anemia and a palpable spleen. Anemia is common among young children in endemic areas and is often due to multiple causes in addition to malaria (including iron and other nutritional deficiencies as well as intestinal geohelminth infection) [10]. Mild jaundice may also develop in patients with otherwise uncomplicated falciparum malaria. Splenic enlargement is a frequent finding among otherwise healthy individuals in endemic areas; this condition may reflect repeated malaria infections or infection due to other causes. The spleen often shrinks due to infarctions after multiple malaria exposures, such that it is not palpable. In nonimmune individuals with acute malaria, the spleen may become palpable after several days. In such patients, lack of anemia early in clinical course is common and should not rule out the possibility of malaria.

Laboratory evaluation may demonstrate parasitemia (usually <5000 parasites/microL of blood, <0.1 percent parasitized red blood cells [RBCs]), anemia, thrombocytopenia, elevated transaminases, mild coagulopathy, and elevated blood urea nitrogen (BUN) and creatinine. (See "Diagnosis of malaria", section on 'Parasite density monitoring'.)

Uncomplicated malaria can occur with any Plasmodium species. Although falciparum malaria is the most virulent, it is often not possible to determine the species of malaria infection on clinical grounds alone; there are some unique characteristics associated with each species, and P. vivax, P. ovale, P. malariae, and P. knowlesi are discussed in detail separately. (See "Overview of non-falciparum malaria in nonpregnant adults and children".)

Plasmodium sporozoitesare inoculated into the dermis and enter the bloodstream following the bite of a Plasmodium-infected female anopheline mosquito.

Within minutes, sporozoites travel to the liver, where they infect hepatocytes via cell surface receptor-mediated events.

This process initiates the asymptomatic prepatent period, or exoerythrocytic stage of infection, which typically lasts ~1 week. During this period, the parasite undergoes asexual replication within hepatocytes, resulting in production of liver stage schizonts. Upon rupture of the infected hepatocytes, tens of thousands of merozoites are released into the bloodstream and infect red blood cells. After the initial exoerythrocytic stage, P. falciparum and P. malariae are no longer found in the liver. P. vivax and P. ovale, however, can maintain a quiescent hepatocyte infection as a dormant form of the parasite known as the hypnozoite. Consequently, P. vivax and P. ovalecan reinitiate symptomatic disease long after the initial symptoms of malaria are recognized and treated. Erythrocytic forms cannot reestablish infection of hepatocytes.

Transmission of human-infecting malarial parasites is maintained in human populations both by the extended persistence of hypnozoites (lasting from months to no more than a few years for P. vivax and P. ovale), by antigenic variation in P. falciparum (probably months), and presumably by antigen variation in P. malariae (for as long as several decades) (Vinetz et al., 1998).

The asexual erythrocytic stages of malarial parasites are responsible for the clinical manifestations of malaria. This part of the Plasmodium life cycle is initiated by merozoite recognition of red blood cells, mediated by cell surface receptors, followed by red blood cell invasion. Once inside a red blood cell, the merozoite develops into a ring form, which becomes a trophozoite that matures into an asexually dividing blood stage schizont. Upon rupture of the infected erythrocyte, these schizonts release 8-32 merozoites that can establish new infections in nearby red blood cells. The erythrocytic replication cycle lasts for 24 hours (for P. knowlesi), 48 hours (for P. falciparum, P. vivax, and P. ovale), and 72 hours (for P. malariae). As such, infections due to P. vivax and P. ovale can produce tertian fever patterns (48 hours), whereas those due to P. malariae can result in quartan fever (72 hours, as classically described in Hippocrates' Epidemics). Although most invading merozoites develop into schizonts, a small proportion become gametocytes, the form of the parasite that is infective to mosquitoes. Gametocytes are ingested into the mosquito midgut during an infectious blood meal and then transform into gametes that can fertilize to become zygotes. Zygotes mature into ookinetes, which penetrate the mosquito midgut wall and develop into oocysts. Numerous rounds of asexual replication occur in the oocyst to generate sporozoites over 10-14 days. Fully developed sporozoites rupture from oocysts and invade the mosquito salivary glands, from which they can initiate a new infection during subsequent mosquito blood meals.

Understanding the subtleties of the life cycles of Plasmodium parasites is important for tailoring drug therapies to the various species and geographic contexts.

Attention is increasingly being focused on measures to prevent parasite transmission from a human host to a mosquito vector. Bed nets and residual indoor insecticide treatment are the mainstay of malaria prevention in endemic areas. Drugs are being used to prevent transmission, but this strategy presents special problems related to toxicity. Whereas some antimalarials, such as 4-aminoquinolines and sulfadoxine-pyrimethamine, promote increased gametocytemia, others, including 8-aminoquinolines and artemisinins, can reduce gametocyte levels and thus reduce transmission. Although the gametocytocidal activity of primaquine and tafenoquine is potentially important, these agents cannot be used for mass treatment without first assessing glucose-6-phosphate dehydrogenase (G6PD) levels, because of the potential for hemolytic anemia in G6PD-deficient individuals.

Plasmodium falciparum

Widespread resistance of Plasmodium falciparum to chloroquine and other agents has complicated the treatment and prophylaxis of this type of malaria.

A combination of quinine and Fansidar is usually effective oral therapy for falciparum malaria; quinidine may be administered if intravenous therapy is needed. Mefloquine, which is currently recommended for prophylaxis against chloroquine-resistant P. falciparum, is also effective for single-dose oral treatment, although this regimen has not yet been approved by the Food and Drug Administration.

• swelling of the blood vessels of the brain, or cerebral malaria
• an accumulation of fluid in the lungs that causes breathing problems, or pulmonary edema
• organ failure of the kidneys, liver, or spleen
• anemia due to the destruction of red blood cells
• low blood sugar