DDx
Diagnostic Considerations
Malaria Differential Diagnosis
Malaria is the most common life-threatening cause of fever in a returning traveler from malaria-endemic countries. [35] Given the potential for relapse or delayed primary infection from P vivax or ovale, malaria always should be ruled out if the patient has an epidemiologic travel link over the prior several months. Remeber that a consideration for malaria should occur for any fever in a traveler from an endemic area, as the disease may present with other ailments concomitantly, or the patient may experience unique malaria-related protean manifestations of their own.
Travel Timeline & Incubation Period
Etiologies of travel-related fever may be classified in a clinically useful fashion through the understanding of specific infectious diseases’ incubation periods. Once a proper timeframe of expected disease presentation is established, the list of differential diagnoses may be narrowed further by the geography of the patient’s itinerary and likely transmission risks. Below are lists of diseases associated with their usual incubation periods:
Incubation period < 14 days
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Influenza 1-3 days
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Chikungunya 2-4 days
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Crimean Congo Hemorrhagic Fever 3-7 days
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Zika 3-14 days
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Arboviral encephalitis 3-14 days
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Dengue 4-8 days
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Legionellosis 5-6 days
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Meningococcemia < 10 days
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Rickettsia (spotted fever group) < 10 days
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Malaria ( P vivax) 8-365 days (~1/2 present after 30 days)
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Malaria ( P falciparum) 6-30 days
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Leptospirosis 7-12 days
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Typhoid & paratyphoid 7-18 days
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Ebola & Lassa 7-21 days
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Acute HIV 10-28 days
Incubation period 14-42 days
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Typhoid & paratyphoid 7-18 days
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Ebola & Lassa 7-21 days
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Acute HIV 10-28 days
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Malaria ( P falciparum) 6-30 days
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Malaria ( P vivax) 8-365 days (~1/2 present after 30 days)
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Amebic liver abscess weeks-months
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Hepatitis A 28-30 days
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Hepatitis E 26-42 days
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Acute schistosomiasis 29-56 days
Incubation period >42 days
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Malaria ( P vivax) 8-365 days (~1/2 present after 30 days)
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Hepatitis E 26-42 days
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Amebic liver abscess weeks-months
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Acute schistosomiasis 29-56 days
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Hepatitis B 90 days
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Visceral leishmaniasis 2-10 months
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Tuberculosis weeks (primary infection), years (reactivation)
Media Gallery
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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].
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Tables
Table 1. Histologic Variations Among Plasmodium Species
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. |
