History
In patients with suspected malaria, obtaining a history of recent or remote travel to an endemic area is critical. Asking explicitly if they traveled to a tropical area at any time in their life may enhance recall. Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.
Also determine the patient's immune status, age, and pregnancy status; allergies or other medical conditions that they may have; and medications that they may be using.
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. Clinical symptoms include the following:
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Cough
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Fatigue
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Malaise
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Shaking chills
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Arthralgia
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Myalgia
Patients experience a paroxysm of fever, shaking chills, and sweats (every 48 or 72 h, depending on species). The classic paroxysm begins with a period of shivering and chills, which lasts for approximately 1-2 hours and is followed by a high fever. Finally, the patient experiences excessive diaphoresis, and the body temperature of the patient drops to normal or below normal.
Many patients, particularly early in infection, do not present the classic paroxysm but may have several small fever spikes a day. Indeed, the periodicity of fever associated with each species (ie, 48 h for P falciparum, P vivax, and P ovale [or tertian fever]; 72 h for P malariae [or quartan fever]) is not apparent during initial infection because of multiple broods emerging in the bloodstream. In addition, the periodicity often is not observed in P falciparum infections. Patients with long-standing, synchronous infections are more likely to present with classic fever patterns. In general, however, the occurrence of periodicity of fever is not a reliable clue to the diagnosis of malaria.
Less common malarial symptoms include the following:
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Anorexia and lethargy
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Nausea and vomiting
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Diarrhea
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Jaundice
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. Patients infected with P vivax or P ovale may relapse after longer periods, because of the hypnozoite stage in the liver.
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; P vivax and P ovale cause the benign form of tertian fever; and P falciparum causes the malignant form. The cyclic pattern of fever is very rare.
Travelers to forested areas of Southeast Asia and South America have become infected by Plasmodium knowlesi, a dangerous species normally found only in long-tailed and pigtail macaque monkeys (Macaca fascicularis and M nemestrina, respectively). This species can cause severe illness and death in humans, but, under the microscope, the parasite looks similar to the more benign P malariae and sometimes has been misdiagnosed.
Because P malariae infection typically is relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographic areas who are severely ill and have microscopic evidence of P malariae infection. Diagnosis may be confirmed via polymerase chain reaction (PCR) assay test methods.
Physical Examination
Most patients with malaria have no specific 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 gastrointestinal (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 cerebral malaria, severe anemia, respiratory symptoms, and renal failure.
In children, malaria has a shorter course, often rapidly progressing to severe malaria. Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice.
Cerebral malaria
This feature almost always is caused by P falciparum infection. Coma may occur; coma usually can be distinguished from a postictal state secondary to generalized seizure if the patient does not regain consciousness after 30 minutes. When evaluating comatose patients with malaria, hypoglycemia and CNS infections should be excluded.
Severe anemia
The anemia associated with malaria is multifactorial and usually is 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
Renal failure 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 typically is reversible, although supportive dialysis often is 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, and 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.
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Malarial merozoites in the peripheral blood. Note that several of the merozoites have penetrated the erythrocyte membrane and entered the cell.
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This micrograph illustrates the trophozoite form, or immature-ring form, of the malarial parasite within peripheral erythrocytes. Red blood cells infected with trophozoites do not produce sequestrins and, therefore, are able to pass through the spleen.
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An erythrocyte filled with merozoites, which soon will rupture the cell and attempt to infect other red blood cells. Notice the darkened central portion of the cell; this is hemozoin, or malaria pigment, which is a paracrystalline precipitate formed when heme polymerase reacts with the potentially toxic heme stored within the erythrocyte. When treated with chloroquine, the enzyme heme polymerase is inhibited, leading to the heme-induced demise of non–chloroquine-resistant merozoites.
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A mature schizont within an erythrocyte. These red blood cells (RBCs) are sequestered in the spleen when malaria proteins, called sequestrins, on the RBC surface bind to endothelial cells within that organ. Sequestrins are only on the surfaces of erythrocytes that contain the schizont form of the parasite.
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Malaria life cycle. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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Proportion of 2021 Global Malaria Burden. Gray area accounts for the remaining estimated 4.4% of worldwide malaria burden. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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Confirmed P falciparum or P vivax Cases Per Country 2021. The map accounts for the total of the cases per country where either species were confirmed as the primary infection. The map does not include confirmed “mixed infections.” Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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North American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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South American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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African Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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Asian and Oceanic Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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South Pacific Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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Global P falciparum to P vivax Case Ratios 2021. Gray indicates that there were either no data available or there were zero endemic cases. Red indicates higher proportion of P vivax cases, whereas blue indicates higher proportion of P falciparum cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].
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Thin blood smear showing the ring forms of P falciparum that look like headphones with double chromatin dots. Note how P falciparum is seen infecting erythrocytes of all ages – a trait that can be utilized by the microscopist by noting the similar size of infected erythrocytes to other surrounding uninfected erythrocytes. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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Thick blood smear depicting the banana shaped gametocyte of P falciparum. Multiple ring-form trophozoite precursors are also visible in the background. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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Thin blood smear of the ring forms of P vivax. Note that P vivax typically has a single chromatin dot vs the two chromatin dots in P falciparum. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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The diagnostic form of P vivax is the amoeboid trophozoite form where the cytoplasm has finger-like projections (pseudopods) without a typical round/oval structure. These pseudopods are unique to P vivax. Numerous small pink-red dots are also seen in both P vivax and P ovale; these are known as caveola-vesicle complexes (CVCs or Schüffner’s dots) and are composed of numerous flask-like indentations on infected reticulocytes membrane skeleton associated with tube-like vesicles. CVCs are thought to play a role in nutrient uptake or release of metabolites from parasite-infected erythrocytes. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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Thin smear of P ovale in ring stage. Note that typically there is a single chromatin dot, larger cells are infected indicative of reticulocytes, and multiple ring forms may be present intracellularly. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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Thin smear of P ovale trophozoite. Note that this species is difficult to differentiate from P vivax as it contains CVCs (Schüffner’s dots) and infects reticulocytes; a notable unique characteristic of P ovale is the presence of fimbriae on the reticulocyte membrane, which are even more likely to be seen in gametocyte infected red blood cells. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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Thin blood smear of “band form” trophozoite of P malariae. Note that the infected erythrocyte is smaller than surrounding cells, indicating that P malariae infects older erythrocytes. As the trophozoite matures, the cytoplasm elongates and dark pigment granules of hemozoin are visualized toward the periphery. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
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Thin blood smear of P knowlesi trophozoites. An immature ring form is seen on the right next to the mature band form trophozoite on the left. Note the small size of the infected red blood cells and how the band form is similar in appearance to P malariae. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].
Tables
Findings |
P falciparum |
P vivax |
P ovale |
P malariae |
Only early forms present in peripheral blood |
Yes |
No |
No |
No |
Poly-infected RBCs |
Often |
Occasionally |
Rare |
Rare |
Age of infected RBCs |
RBCs of all ages |
Young RBCs |
Young RBCs |
Old RBCs |
Schüffner dots |
No |
Yes |
Yes |
No |
Other features |
Cells have thin cytoplasm, 1 or 2 chromatin dots, and applique forms. |
Late trophozoites develop pleomorphic cytoplasm. |
Infected RBCs become oval, with tufted edges. |
Bandlike trophozoites are distinctive. |
