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 — 


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.


Image not available.

Life cycle of malaria parasites.

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

Mechanisms of erythrocyte invasion include initial binding by merozoites to specific red blood cell surface ligands. P. falciparum has a family of binding proteins that can recognize a variety of host cell molecules. P. falciparum invades all stages of erythrocytes and therefore can achieve high parasitemias. P. vivax selectively binds to the Duffy chemokine receptor protein as well as reticulocyte-specific proteins. Thus, P. vivax does not establish infection in Duffy-negative individuals and only invades reticulocytes. (However, P. vivax has reportedly mutated in Madagascar to enable infection of Duffy-negative individuals [Ménard et al., 2010].) Because of this restricted subpopulation of suitable erythrocytes, P. vivax rarely exceeds 1% parasitemia in the bloodstream. P. ovale is similar to P. vivax in its predilection for young red blood cells, but the mechanism of its erythrocyte recognition is unknown. P. malariae parasitizes senescent red blood cells, maintains a very low parasitemia, and typically causes an indolent infection.

P. falciparum assembles cytoadherence proteins (PfEMP1s, encoded by a highly variable family of var genes) into structures called knobs that are presented on the erythrocyte surface. Knobs allow the P. falciparum-parasitized erythrocyte to bind to postcapillary vascular endothelium, so as to avoid spleen-mediated clearance and allow the parasite to grow in a low oxygen, high carbon dioxide microenvironment. For the patient, the consequences are microvascular blockage in the brain and organ beds, and local release of cytokines and direct vascular intermediates such as nitric oxide. These lead to severe complications such as cerebral malaria, pulmonary edema, acute renal failure, and placental malaria. These can result in low birthweight and translocation of bacteria from the gastrointestinal (GI) tract to the blood (septic complications, so-called algid malaria).

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.

Clinical Manifestations of Malaria.

The cardinal signs and symptoms of malaria are high, spiking fevers (with or without periodicity), chills, headaches, myalgias, malaise, and GI symptoms. Severe headache, a characteristic early symptom in malaria caused by all Plasmodium spp., often heralds the onset of infection, before fever and chills. P. falciparum causes the most severe disease and may lead to organ failure and death. Placental malaria, of particular danger for primigravidae, is due to P. falciparum adherence to chondroitin sulfate A (CSA) in the placenta. This often leads to severe complications, including miscarriage. When treated early, symptoms of malarial infection usually improve within 24-48 hours.

Acute illness due to P. vivax infection may appear severe due to high fever and prostration. Indeed, the pyrogenic threshold of this parasite (i.e., parasite burden associated with fever) is lower than that of P. falciparum. Nonetheless, P. vivax malaria generally has a low mortality rate. P. vivax malaria is characterized by relapses caused by the reactivation of latent tissue forms. Clinical manifestations of relapse are the same as those of primary infection. In recent years, severe P. vivax malaria from Oceania (Papua New Guinea, Indonesia) and India possess important similarities to severe malaria caused by P. falciparum. These include neurological symptoms (diminished consciousness, seizure) and pulmonary edema. Rare but life-threatening complications can occur, including splenic rupture, acute lung injury, and profound anemia.

Povale causes a clinical syndrome similar to that of P. vivax but may be milder with lower levels of parasitemia. It shares with P. vivax the ability to form the hypnozoite (dormant liver stage) that may relapse after months to 2 years later. P. ovale is more common in sub-Saharan Africa and some islands in Oceania.

P. malariae causes a generally indolent infection with very low levels of parasitemia and often does not produce clinical symptoms. This parasite can be found in all malaria-endemic areas but is most common in sub-Saharan Africa and the southwest Pacific. Interestingly, P. malariae prevalence increases during the dry season and can be found as a co-infection with P. falciparum. Although uncommon, a potentially fatal complication of P. malariae is a glomerulonephritis syndrome that does not respond to antimalarial treatment.

P. knowlesi infection is often misdiagnosed as P. malariae by light microscopy. This infection is distinguished by a shorter erythrocytic cycle (24 hours compared with 72 hours for P. malariae) and higher levels of parasitemia. Like P. malariae, P. knowlesi is generally sensitive to chloroquine, but patients presenting with advanced disease nonetheless may progress to death despite adequate drug dosing.

Asymptomatic P. falciparum and P. vivax infections are common in endemic regions, and they represent important potential reservoirs for malaria transmission. Although different studies are not entirely consistent in the definition of "asymptomatic," generally this state implies a lack of fever, headache, and other systemic complaints, within a defined time period prior to a positive test for malaria parasitemia. Migration of asymptomatic individuals, to areas where malaria is not present but vector mosquitoes are (i.e., anophelism without malaria), is an important mechanism for the introduction or reintroduction of malaria, in addition to facilitating the spread of drug-resistant isolates. Novel approaches to preventing transmission from asymptomatic reservoirs—whether through new drugs or vaccines—will be essential for future malaria control, elimination, and eradication strategies.



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.


In areas where malaria is transmitted throughout the year, older children and adults develop partial immunity after repeated infections and are at relatively low risk for severe disease.

Travelers to malarious areas generally have had no previous exposure to malaria parasites or have lost their immunity if they left the endemic area; they are at very high risk for severe disease if infected with Plasmodium falciparum




  • 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 kidneysliver, or spleen
  • anemia due to the destruction of red blood cells
  • low blood sugar



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A 50-year-old woman presents to your office with the complaints of fever, chills, nausea, and vomiting for the past 5 days. She is especially concerned because she just returned from a 3-week long church mission trip to central Africa during which she did not take the recommended malaria prophylaxis. She was careful about using insect repellent and wearing long-sleeved clothing, but she did not take the recommended weekly dose of mefloquine because it made her nauseous. Starting a few days after her return, she has had episodes of shaking chills followed by fever spikes as high as 103.5°F (39.7°C) and then profuse sweating. After these episodes she would feel so exhausted that she would sleep for hours. These severe episodes have been occurring every other day. In between these episodes, she has had low-grade fever, myalgias, nausea, vomiting, and diarrhea. On examination, she appears very fatigued and pale. Her temperature is 99.9°F (37.7°C), pulse is 100 beats/minute, blood pressure is 110/80 mm Hg, and respiratory rate is 18 breaths/minute. Other than signs of dehydration, her examination is unremarkable. A complete blood count shows her to be anemic. She has elevated blood urea nitrogen, creatinine, and lactate dehydrogenase levels. A thin-blood smear is sent to the laboratory, which shows erythrocytes with ring forms at the periphery of the cell and multiple erythrocytes with 3 or 4 ring forms present.

What is the most likely etiology of her infection?

All of the following can be used for malaria prophylaxis EXCEPT:

The correct answer is C.

Azithromycin is not indicated in the treatment or prevention of malaria. All the others are indicated for malaria prophylaxis and each has its pros and cons. Azithromycin can be used to treat traveler's diarrhea.


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