The 4 Plasmodium species known to cause malaria include Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. A fifth species, Plasmodium knowlesi, has recently been identified as a clinically significant pathogen in humans. Timely identification of the infecting species is extremely important, as P falciparum infection can be fatal and is often resistant to standard chloroquine treatment. In some cases, individuals with malaria are infected with multiple Plasmodium species. P falciparum and P vivax are responsible for most new infections. Each Plasmodium species has a defined area of endemicity, although geographic overlap is common. Species can usually be distinguished by morphology on a blood smear. P falciparum is distinguished from the rest of plasmodia by its high level of parasitemia and the banana shape of its gametocytes.

Malaria in travelers typically manifests weeks after the individual leaves the endemic area. Presentation more than 4 weeks after returning from the endemic area is unusual. In some individuals, disease manifests months or years later, usually due to the presence of P vivax or P ovale hypnozoites, which can remain dormant in the liver and reactivate years after infection. Relapse with P vivax or P ovale infection is rare more than 5 years after initial infection. Because symptomatic delay is common, history of even a remote exposure to an endemic area should be elicited. Symptoms of malaria are nonspecific, and, because timely diagnosis and treatment are necessary, malaria should be considered in all patients from tropical areas who present with fever.
Pathophysiology
Individuals with malaria typically acquired the infection in an endemic area following a mosquito bite. Cases of airport malaria and infection secondary to transfusion of infected blood are extremely rare. The risk of infection depends on the intensity of malaria transmission and the use of precautions such as bed nets, diethyl-meta-toluamide (DEET), and malaria prophylaxis.

After a mosquito takes a blood meal, the malarial sporozoites enter hepatocytes (liver phase) within minutes and then emerge in the bloodstream after a few weeks. These merozoites rapidly enter erythrocytes and develop into trophozoites and then into schizonts over a period of days inside erythrocytes during the erythrocytic phase of the life cycle. Rupture of infected erythrocytes containing the schizont results in fever and merozoite release. The merozoites enter new red cells, and the process is repeated, resulting in a logarithmic increase in parasite burden.

The outcome of infection depends on host immunity. Individuals with immunity can spontaneously clear the parasites. In those without immunity, the parasites continue to expand the infection. P falciparum infection can result in death. A small percentage of parasites become gametocytes, which undergo sexual reproduction when taken up by the mosquito. These can develop into infective sporozoites, which continue the transmission cycle after a blood meal in a new host.

The mechanisms that underlie immunity remain poorly defined. Additionally, individuals who develop immunity to malaria who then leave the endemic area may lose protection. Travelers who return to an endemic area may request a test to demonstrate immunity; however, no reliable markers of immunity exist, and waning of immunity should be kept in mind when these patients are advised.

Each Plasmodium species has a specific incubation period. Reviews of travelers returning from endemic areas have reported that P falciparum infection typically develops within one month of exposure, thereby establishing the basis for continuing antimalarial prophylaxis for 4 weeks upon return from an endemic area. This should be emphasized to the patient to enhance posttravel compliance.

Rarely, P falciparum causes initial infection up to a year later. P vivax and P ovale may emerge weeks to months after the initial infection. In addition, P vivax and P ovale have a hypnozoite form during which the parasite can linger in the liver for months before emerging and inducing recurrence after the initial infection. In addition to treating the organism in infected blood, treating the hypnozoite form with a second agent (primaquine) is critical to prevent relapse from this latent liver stage.

P falciparum infection typically causes severe malaria. This species is more virulent because it may create high levels of parasitemia and sequestration that contribute to end-organ damage. Sequestration is a specific property of this species. As it develops through the 48-hour life cycle, it demonstrates adherence properties, which result in the sequestration of the parasite in small postcapillary vessels. For this reason, only early forms are observed in the peripheral blood, before the sequestration property develops; this is an important diagnostic clue that the patient is infected with P falciparum.

Sequestration of parasites may contribute to mental-status changes and coma, observed exclusively in P falciparum infection. In addition, cytokines and a high burden of parasites contribute to end-organ disease. End-organ disease may develop rapidly in patients with P falciparum infection, and it specifically involves the central nervous system (CNS), lungs, and kidneys. Other manifestations of P falciparum infection include hypoglycemia, lactic acidosis, severe anemia, and multiorgan dysfunction due to hypoxia. These severe manifestations may occur among travelers without immunity or young children who live in endemic areas.
Frequency
United States
Malaria was endemic in the southern United States until the 19th and early 20th centuries, but it has since been eradicated. Almost all US cases of malaria are imported from patients traveling from endemic areas. In some cases, infections in individuals who have not traveled occur near airports (so-called airport malaria). This is secondary to a local mosquito becoming infected through a blood meal from an infected traveler or a plane with an infected mosquito; this mosquito then takes a blood meal from a local nontraveling resident and transmits the infection.

Each year, 25-30 million people travel to tropical areas, and approximately 10,000-30,000 US and European travelers acquire malaria.
International
Approximately 40% of the world’s population live in endemic areas and are at risk for malaria. An estimated 350-500 million malaria cases occur each year, and more than one million people die of the infection.²
Mortality/Morbidity
Malaria is responsible for approximately 1-3 million deaths per year, typically in children in sub-Saharan Africa infected with P falciparum. Populations at an increased risk for mortality due to malaria include primigravida individuals, travelers without immunity, and young children aged 6 months to 3 years who live in endemic areas.
Age
Young children aged 6 months to 3 years who live in endemic areas are at an increased risk of death due to malaria. Travelers without immunity are at an increased mortality risk, regardless of age.
Clinical
History

• In patients with suspected malaria, obtaining a history of recent or remote travel to an endemic area is critical. Asking explicitly if they have traveled to a tropical area anytime in their life may enhance recall.
• Patients with malaria typically become symptomatic a few weeks after infection, although the host’s previous exposure or immunity to malaria affects the symptomatology and incubation period. In addition, each Plasmodium species has a typical incubation period. Importantly, virtually all patients with malaria present with headache.
• Notably, infection with P vivax, particularly in temperate areas of India, may cause symptoms up to 6-12 months after the host leaves the endemic area. In addition, patients infected with P vivax or P ovale may relapse after longer periods because of the hypnozoite stage in the liver. The hypnozoite form develops after initial infection and can remain dormant for months to years before entering the blood stream and producing symptoms.
• P malariae does not have a hypnozoite stage, but patients infected with P malariae may have a prolonged, asymptomatic, erythrocytic infection that becomes symptomatic years after leaving the endemic area.
• Tertian and quartan fevers are due to the cyclic lysis of red blood cells that occurs as trophozoites complete their cycle in erythrocytes every 2 or 3 days, respectively. P malariae causes quartan fever, while P vivax and P ovale cause the benign form and P falciparum the malignant form of tertian fever. The cyclic pattern of fever is very rare.

Physical

• The severity of illness is affected by previous exposure to malaria and the patient’s age. In addition, various genetic factors may enhance or limit disease severity. Protective factors include sickle cell disease, hemoglobinopathies, and polymorphisms in the host’s TNF (tumor necrosis factor) gene. New genetic polymorphisms that confer protection or susceptibility in the host continue to be defined. These protective mutations may lessen the likelihood of infection or disease severity; none is completely protective.
• The periodicity of fever associated with each species (ie, 48 h for P falciparum, P vivax, and P ovale; 72 h for P malariae) is not apparent during initial infection because of multiple broods emerging in the blood stream. In addition, the periodicity is often not observed in P falciparum infections. Patients with long-standing synchronous infections are more likely to present with classic fever patterns. In general, the occurrence of periodicity of fever is not a reliable clue to the diagnosis of malaria.
• Most patients with malaria have no physical findings, but splenomegaly may be present.
• Symptoms of malarial infection are nonspecific and may manifest as a flulike illness with fever, headache, malaise, fatigue, and muscle aches. Some patients with malaria present with diarrhea and other GI symptoms. Immune individuals may be completely asymptomatic or may present with mild anemia. Nonimmune patients may quickly become very ill. Severe malaria primarily involves P falciparum infection, although death due to splenic rupture has been reported in patients with non– P falciparum malaria.
• Severe malaria manifests as follows:
  • Cerebral malaria: This feature is almost always caused by P falciparum infection. Coma may occur. Coma can usually be distinguished from a postictal state secondary to generalized seizure if the patient does not regain consciousness after 30 minutes. When evaluating patients with coma-complicated malaria, hypoglycemia, and CNS infections should be excluded.
  • Severe anemia: The anemia associated with malaria is multifactorial and is usually associated with P falciparum infection. In nonimmune patients, anemia may be secondary to erythrocyte infection and a loss of infected RBCs. In addition, uninfected RBCs are inappropriately cleared, and bone marrow suppression may be involved.
  • Renal failure: This is a rare complication of malarial infection. Infected erythrocytes adhere to the microvasculature in the renal cortex, often resulting in oliguric renal failure. Renal failure is typically reversible, and supportive dialysis is often needed until kidney function recovers. In rare cases, chronic P malariae infection results in nephrotic syndrome.
  • Respiratory symptoms: Patients with malaria may develop metabolic acidosis and associated respiratory distress. In addition, pulmonary edema can occur. Signs of malarial hyperpneic syndrome include alar flaring, chest retraction (intercostals or subcostal), use of accessory muscles for respiration, or abnormally deep breathing.

Causes
The 4 Plasmodium species known to cause malaria include P falciparum (the most deadly), P vivax, P ovale, and P malariae. A fifth species, P knowlesi, has recently been identified in Southeast Asia as a clinically significant pathogen in humans.¹ Distinguishing among the various species, especially P falciparum, is imperative to ensure proper treatment and to improve the prognosis. Among patients with malaria, 5-7% are infected with more than a single Plasmodium species.

P falciparum and P vivax are responsible for most new infections. Each species has a defined area of endemicity, although geographic overlap is common. Species can be distinguished by morphology on a blood smear. The thick blood smear provides better sensitivity, while the thin blood smear is more specific and allows better identification of the Plasmodium species. In addition, rapid diagnostic tests are also available (eg, OptiMal, ParaSight, Kat-Quick).