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Malaria

[Plasmodium falciparum] [Plasmodium knowlesi] [Plasmodium malariae] [Plasmodium ovale] [Plasmodium vivax]

Causal Agent

Blood parasites of the genus Plasmodium. There are approximately 156 named species of Plasmodium which infect various species of vertebrates. Four species are considered true parasites of humans, as they utilize humans almost exclusively as a natural intermediate host: P. falciparum, P. vivax, P. ovale and P. malariae. However, there are periodic reports of simian malaria parasites being found in humans, most reports implicating P. knowlesi. At the time of this writing, it has not been determined if P. knowlesi is being naturally transmitted from human to human via the mosquito, without the natural intermediate host (macaque monkeys, genus Macaca). Therefore, P. knowlesi is still considered a zoonotic malaria.

Life Cycle

lifecycle

The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host The number 1. Sporozoites infect liver cells The number 2 and mature into schizonts The number 3, which rupture and release merozoites The number 4. (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony The letter A), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony The letter B). Merozoites infect red blood cells The number 5. The ring stage trophozoites mature into schizonts, which rupture releasing merozoites The number 6. Some parasites differentiate into sexual erythrocytic stages (gametocytes) The number 7. Blood stage parasites are responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal The number 8. The parasites' multiplication in the mosquito is known as the sporogonic cycle The letter C. While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes The number 9. The zygotes in turn become motile and elongated (ookinetes) The number 10 which invade the midgut wall of the mosquito where they develop into oocysts The number 11. The oocysts grow, rupture, and release sporozoites The number 12, which make their way to the mosquito's salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle The number 1.

Geographic Distribution

Malaria generally occurs in areas where environmental conditions allow parasite multiplication in the vector.  Malaria today is usually restricted to tropical and subtropical areas and altitudes below 1,500 m., although in the past malaria was endemic in much of North America, Europe and even parts of northern Asia, and today is still present on the Korean peninsula. However, this present distribution could be affected by climatic changes and population movements. Plasmodium falciparum is the predominant species in the world. P. vivax and P. ovale are traditionally thought to occupy complementary niches, with P. ovale predominating in Sub-Saharan Africa and P. vivax in the other areas; but their geographical ranges do overlap. These two species are not always distinguishable on the basis of morphologic characteristics alone, and the use of molecular tools will help clarify their diagnosis and exact distribution. P. malariae has wide global distribution, being found in South America, Asia, and Africa, but it is less frequent than P. falciparum in terms of association with cases of infection. P. knowlesi is found in southeast Asia.

More on: Malaria Risk Information and Prophylaxis by Country

Clinical Presentation

The symptoms of uncomplicated malaria can be rather non-specific and the diagnosis can be missed if health providers are not alert to the possibility of this disease. Since untreated malaria can progress to severe forms that may be rapidly (<24 hours) fatal, malaria should always be considered in patients who have a history of exposure (mostly: past travel or residence in disease-endemic areas). The most frequent symptoms include fever and chills, which can be accompanied by headache, myalgias, arthralgias, weakness, vomiting, and diarrhea. Other clinical features include splenomegaly, anemia, thrombocytopenia, hypoglycemia, pulmonary or renal dysfunction, and neurologic changes. The clinical presentation can vary substantially depending on the infecting species, the level of parasitemia, and the immune status of the patient. Infections caused by P. falciparum are the most likely to progress to severe, potentially fatal forms with central nervous system involvement (cerebral malaria), acute renal failure, severe anemia, or acute respiratory distress syndrome. Other species can also have severe manifestations. Complications of P. vivax malaria include splenomegaly (with, rarely, splenic rupture), and those of P. malariae include nephrotic syndrome.

Plasmodium falciparum

Ring-form trophozoites of P. falciparum in thick and a thin blood smear.

 

Ring-form trophozoites (rings) of Plasmodium falciparum are often thin and delicate, measuring on average 1/5 the diameter of the red blood cell. Rings may possess one or two chromatin dots. They may be found on the periphery of the RBC (accolé, appliqué) and multiply-infected RBCs are not uncommon. Ring forms may become compact or pleomorphic depending on the quality of the blood or if there is a delay in making smears. There is usually no enlargement of infected RBCs.
	Figure A

Figure A: Rings of P. falciparum in a thick blood smear.

	Figure B

Figure B: Rings of P. falciparum in a thick blood smear.

	Figure C

Figure C: Rings of P. falciparum in a thick blood smear.

	Figure D

Figure D: Rings of P. falciparum in a thick blood smear.

	Figure E

Figure E: Rings of P. falciparum in a thick blood smear.

	Figure F

Figure F: Rings of P. falciparum in a thick blood smear.

	Figure G

Figure G: Rings of P. falciparum in a thin blood smear.

	Figure H

Figure H: Rings of P. falciparum in a thin blood smear.

	Figure I

Figure I: Rings of P. falciparum in a thin blood smear.

	Figure J

Figure J: Rings of P. falciparum in a thin blood smear.

	Figure K

Figure K: Rings of P. falciparum in a thin blood smear.

	Figure L

Figure L: Rings of P. falciparum in a thin blood smear. Image courtesy of the Arizona State Public Health Laboratory.

Ring-form trophozoites of P. falciparum in thin blood smears exhibiting Maurer's clefts.

 

Maurer's clefts can be seen in P. falciparum infections containing older ring-form trophozoites and asexual stages. Maurer's clefts resemble the Schüffner's dots seen in P. vivax and P. ovale, but are usually larger and more coarse. Visualization of these structures is dependent on the quality of the smear preparation and the pH of the Giemsa stain. Like Schüffner's dots, Maurer's clefts appear to play a role in the metabolic pathways of the infected RBCs.
	Figure A

Figure A: Ring-form trophozoites of P. falciparum in a thin blood smear, exhibiting Maurer's clefts.

	Figure B

Figure B: Ring-form trophozoites of P. falciparum in a thin blood smear, exhibiting Maurer's clefts.

	Figure C

Figure C: Ring-form trophozoites of P. falciparum in a thin blood smear, exhibiting Maurer's clefts.

	Figure D

Figure D: Ring-form trophozoites of P. falciparum in a thin blood smear, exhibiting Maurer's clefts.

	Figure E

Figure E: Ring-form trophozoites of P. falciparum in a thin blood smear, exhibiting Maurer's clefts.

	Figure F

Figure F: Ring-form trophozoites of P. falciparum in a thin blood smear, exhibiting Maurer's clefts.

Developing and older trophozoites of P. falciparum in thick and a thin blood smear.

 

Developing trophozoites of P. falciparum tend to remain in ring form, but may become thicker and more compact. The amount of pigment and chromatin may also increase. Compact or amoeboid forms may be seen in smears where there was a delay in processing the blood.
	Figure A

Figure A: Trophozoites of P. falciparum in a thick blood smear.

	Figure B

Figure B: Trophozoite of P. falciparum in a thin blood smear.

	Figure C

Figure C: Trophozoite of P. falciparum in a thin blood smear.

	Figure D

Figure D: Trophozoite of P. falciparum in a thin blood smear. In this figure, a gametocyte can also be seen in the upper half of the image.

	Figure E

Figure E: Trophozoites of P. falciparum in a thin blood smear.

	Figure F

Figure F: Trophozoites of P. falciparum in a thin blood smear.

Gametocytes of P. falciparum in thick and a thin blood smear.

 

Gametocytes of Plasmodium falciparum are crescent- or sausage-shaped, and are usually about 1.5 times the diameter of an RBC in length. The cytoplasm of the macrogametocytes (female) are usually a darker, deeper blue; the cytoplasm of the microgametocytes (male) is usually more pale. The red chromatin and pigment is more coarse and concentrated in the macrogametocytes than the microgametocytes. Sometimes in thin blood smears, the remnants of the host RBC can be seen; this is often referred to as Laveran's bib.
	Figure A

Figure A: Gametocyte of P. falciparum in a thick blood smear. Note also the presence of many ring-form trophozoites.

	Figure B

Figure B: Gametocytes of P. falciparum in a thick blood smear. Note also the presence of many ring-form trophozoites.

	Figure C

Figure C: Gametocytes of P. falciparum in a thick blood smear.

	Figure D

Figure D: Gametocyte of P. falciparum in a thin blood smear. Also seen in this image are ring-form trophozoites and an RBC exhibiting basophilic stippling (upper left).

	Figure E

Figure E: Gametocyte of P. falciparum in a thin blood smear. Also seen in this image are ring-form trophozoites exhibiting Maurer's clefts.

	Figure F

Figure F: Gametocyte of P. falciparum in a thin blood smear. In these specimens, Laveran's bibs can be seen.

	Figure G

Figure G: Gametocytes of P. falciparum in a thin blood smear. In these specimens, Laveran's bibs can be seen.

	Figure H

Figure H: Gametocyte of P. falciparum in a thin blood smear, showing Laveran's bib. Also seen in this image are ring-form trophozoites exhibiting Maurer's clefts.

	Figure I

Figure I: Gametocytes of P. falciparum in a thin blood smear. The gametocyte in the upper right is undergoing exflagellation, a process that normally occurs in the mid-gut of the mosquito host. However, it may be observed in human blood specimens when there is a delay in processing the blood.

Schizonts of P. falciparum in a thin blood smear.

 

Schizonts are rarely seen in peripheral blood of Plasmodium falciparum infections, except in severe cases. When seen, schizonts contain anywhere from 8-24 merozoites. A mature schizont usually fills about 2/3 of the infected RBC.
	Figure A

Figure A: Schizont of P. falciparum in a thin blood smear.

	Figure B

Figure B: Schizont of P. falciparum in a thin blood smear.

	Figure C

Figure C: Schizont of P. falciparum in a thin blood smear. Trophozoites are also seen in this image.

Plasmodium knowlesi

Ring-form trophozoites of P. knowlesi in a thin blood smear.

 

Early ring-form trophozoites (rings) of P. knowlesi are similar to P. falciparum, as rings may show double chromatin dots. Appliqué forms may appear, as well as rectangular rings harboring one or more accessory chromatin dots. Red blood cells may also be multiply-infected. When full-grown, non-amoeboid rings may occupy half or more of the host RBC.
	Figure A

Figure A: Ring-form trophozoites of P. knowlesi in a Giemsa-stained thin blood smear from a human patient that traveled to the Philippines. Note a multiply-infected RBC in this image. Image courtesy of the Wadsworth Center, New York State Department of Health.

	Figure B

Figure B: Ring-form trophozoite of P. knowlesi in a Giemsa-stained thin blood smear from a human patient that traveled to the Philippines. Image courtesy of the Wadsworth Center, New York State Department of Health.

	Figure C

Figure C: Ring-form trophozoites of P. knowlesi in a Giemsa-stained thin blood smear from a human patient that traveled to the Philippines. Note a multiply-infected RBC in this image. Image courtesy of the Wadsworth Center, New York State Department of Health.

	Figure D

Figure D: Ring-form trophozoites of P. knowlesi in a Giemsa-stained thin blood smear from a human patient that traveled to the Philippines. Image courtesy of the Wadsworth Center, New York State Department of Health.

	Figure E

Figure E: Ring-form trophozoites of P. knowlesi in a Giemsa-stained thin blood smear from a human patient that traveled to the Philippines. Image courtesy of the Wadsworth Center, New York State Department of Health.

	Figure F

Figure F: Ring-form trophozoites of P. knowlesi in a Giemsa-stained thin blood smear from a human patient that traveled to the Philippines. Note a multiply-infected RBC in this image. Image courtesy of the Wadsworth Center, New York State Department of Health.

Older, developing trophozoites of P. knowlesi in a thin blood smear.

 

In developing trophozoites of P. knowlesi, band forms may appear that are similar in appearance to P. malariae. As the vacuole is lost during maturation of the trophozoite stage, the parasite becomes smaller and more compact. The pigment appears as dark grains and the red nucleus increases in size. Stippling appears, often referred to as 'Sinton and Mulligan's' stippling, as it is not of the Schüffner type.
	Figure A

Figure A: Band-form trophozoite of P. knowlesi in a Giemsa-stained thin blood smear from a human patient that traveled to the Philippines. Image courtesy of the Wadsworth Center, New York State Department of Health.

	Figure B

Figure B: Band-form (upper) and ring-form (lower) trophozoites of P. knowlesi, from the same specimen as Figure A.

Gametocytes of P. knowlesi in thin blood smears.

 

Mature macrogametocytes of P. knowlesi are usually spherical and fill the host RBC. The cytoplasm stains blue and the eccentric nucleus stains red. Pigment is coarse and black, and is scattered irregularly in the cytoplasm. The microgametocyte is often, but not always, smaller than the macrogametocyte.  The cytoplasm usually stains a pale pink, while the nucleus stains a darker red. The nucleus may make up half the parasite. The coarse, black pigment is scattered irregularly thought the cytoplasm.
	Figure A

Figure A: Gametocyte of P. knowlesi in a Giemsa-stained thin blood smear from a patient that traveled to the Philippines. Image courtesy of the Wadsworth Center, New York State Department of Health.

	Figure B

Figure B: Gametocyte of P. knowlesi in a Giemsa-stained thin blood smear from a patient that traveled to the Philippines. Note also a ring-form trophozoite in the lower left of this image. Image courtesy of the Wadsworth Center, New York State Department of Health.

Schizonts of P. knowlesi in a thin blood smear.

 

In developing schizonts, Sinton and Mulligan's stippling may be observed. The nucleus continues to divide until there are up to 16 (average 10) merozoites. As the schizont matures, it fills the host RBC and the pigment collects into one or a few masses. In the mature schizont, the merozoites may appear 'segmented' and the pigment has collected into a single mass.
	Figure A

Figure A: Mature schizont in a Giemsa-stained thin blood smear from a patient that traveled to the Philippines.Images courtesy of the Wadsworth Center, New York State Department of Health.

	Figure B

Figure B: Mature schizont in a Giemsa-stained thin blood smear from a patient that traveled to the Philippines. Note also a ring-form trophozoite to the right of the schizont in this figure. Images courtesy of the Wadsworth Center, New York State Department of Health.

	Figure C

Figure C: Developing schizont in a Giemsa-stained thin blood smear from the same patient seen in Figures A and B.

	Figure D

Figure D: Mature schizont in a Giemsa-stained thin blood smear from the same patient seen in Figures A-C.

	Figure E

Figure E: Developing schizont in a Giemsa-stained thin blood smear from the same patient as Figures A-D.

Plasmodium malariae

Ring-form trophozoites of P. malariae in thick and think blood smears.

 

Ring-form trophozoites have one (rarely two) chromatin dots and a cytoplasm ring that tends to be thicker than P. falciparum. 'Bird's-eye' forms may appear. There is no enlargement of infected RBCs.
	Figure A

Figure A: Ring-form (lower right) and developing (upper left) trophozoites of P. malariae in a thick blood smear.

	Figure B

Figure B: "Birds-eye" trophozoite of P. malariae in a thin blood smear.

	Figure C

Figure C: Ring-form trophozoite of P. malariae in a thin blood smear.

	Figure D

Figure D: Ring-form trophozoite of P. malariae in a thin blood smear.

Trophozoites of P. malariae in a thick blood smear.

 

In developing trophozoites of P. malariae, chromatin is rounded or streaky and the cytoplasm is usually compact with no vacuole. Pigment may be coarse and peripheral. As the trophozoites mature, the cytoplasm may elongate across the host RBC, forming a 'band-form', or may be oval with a vacuole forming a 'basket-form'. Chromatin is usually in a single mass, less definite in outline. Pigment granules become larger and tend to have a more peripheral arrangement.
	Figure A

Figure A: Trophozoite of P. malariae in a thick blood smear.

	Figure B

Figure B: Trophozoite of P. malariae in a thick blood smear.

Band-form trophozoites of P. malariae in a thin blood smear.

 

In developing trophozoites of P. malariae, chromatin is rounded or streaky and the cytoplasm is usually compact with no vacuole. Pigment may be coarse and peripheral. As the trophozoites mature, the cytoplasm may elongate across the host RBC, forming a 'band-form', or may be oval with a vacuole forming a 'basket-form'. Chromatin is usually in a single mass, less definite in outline. Pigment granules become larger and tend to have a more peripheral arrangement.
	Figure A

Figure A: Band-form trophozoite of P. malariae in a thin blood smear.

	Figure B

Figure B: Band-form trophozoite of P. malariae in a thin blood smear.

	Figure C

Figure C: Band-form trophozoite of P. malariae in a thin blood smear.

	Figure D

Figure D: Band-form trophozoite of P. malariae in a thin blood smear.

	Figure E

Figure E: Band-form trophozoite of P. malariae in a thin blood smear.

Basket-form trophozoites of P. malariae in a thin blood smear.

 

In developing trophozoites of P. malariae, chromatin is rounded or streaky and the cytoplasm is usually compact with no vacuole. Pigment may be coarse and peripheral. As the trophozoites mature, the cytoplasm may elongate across the host RBC, forming a 'band-form', or may be oval with a vacuole forming a 'basket-form'. Chromatin is usually in a single mass, less definite in outline. Pigment granules become larger and tend to have a more peripheral arrangement.
	Figure A

Figure A: Basket-form trophozoite of P. malariae in a thin blood smear.

	Figure B

Figure B: Basket-form trophozoite of P. malariae in a thin blood smear.

	Figure C

Figure C: Basket-form trophozoite of P. malariae in a thin blood smear.

Gametocytes of P. malariae in thick and a thin blood smear.

 

Gametocytes of P. malariae are compact and tend to fill the host RBC. There is no enlargement of the infected RBC and sometimes there is a reduction in size. The cytoplasm stains blue and the chromatin pink to red. Abundant dark pigment may be scattered throughout the cytoplasm.
	Figure A

Figure A: Gametocyte of P. malariae in a thick blood smear.

	Figure B

Figure B: Gametocyte of P. malariae in a thick blood smear.

	Friends C

Figure C: Gametocyte of P. malariae in a thin blood smear.

	Figure D

Figure D: Gametocyte of P. malariae in a thin blood smear.

	Figure E

Figure E: Developing gametocyte of P. malariae in a thin blood smear.

	Figure F

Figure F: Developing gametocyte of P. malariae in a thin blood smear.

Schizonts of P. malariae in thick and a thin blood smear.

 

Schizonts of P. malariae have 6-12 (usually 8-10) merozoites, often arranged in a rosette or irregular cluster. Mature schizonts nearly fill the normal-sized host RBC. Pigment is course and often peripheral. Schizonts can be common in peripheral blood circulation.
	Figure A

Figure A: Schizont of P. malariae in a thick blood smear.

	Figure B

Figure B: Schizont of P. malariae in a thick blood smear.

	Figure C

Figure C: Schizonts of P. malariae in a thick blood smear.

	Figure D

Figure D: Schizont of P. malariae in a thick blood smear.

	Figure E

Figure E: Schizonts of P. malariae in a thin blood smear.

	Figure F

Figure F: Schizont of P. malariae in a thin blood smear.

	Figure G

Figure G: Schizont of P. malariae in a thin blood smear.

	Figure H

Figure H: Schizont of P. malariae in a thin blood smear.

	Figure I

Figure I: Schizont of P. malariae in a thin blood smear.

	Figure J

Figure J: Schizont of P. malariae in a thin blood smear.

Plasmodium ovale

Ring-form trophozoites of P. ovale in thick and a thin blood smear.

 

Ring-form trophozoites usually contain a single chromatin dot, but may contain double-chromatin dots. Multiply-infected RBCs may be seen, making the rings difficult to differentiate from P. falciparum. The sing rings may be difficult to differentiate from P. vivax, as the cytoplasm is usually thick with a large chromatin dot. As the trophozoites mature, they are less amoeboid than P. vivax and may exhibit fimbriation and Schüffner's dots. Infected RBCs are not usually enlarged as in P. vivax infections.
	Figure A

Figure A: Ring-form trophozoite of P. ovale in a thick blood smear.

	Figure B

Figure B: Ring-form trophozoite of P. ovale in a thick blood smear.

	Figure C

Figure C: Ring-form trophozoites of P. ovale in a thin blood smear. Note the multiply-infected RBC in this image.

	Figure D

Figure D: Ring-form trophozoites of P. ovale in a thin blood smear.

	Figure E

Figure E: Ring-form trophozoites of P. ovale in a thin blood smear. Note the multiply-infected RBC in this image.

Trophozoites of P. ovale in thick and thin blood smears.

 

Developing trophozoites of P. ovale are compact with little vacuolation. Infected RBCs are often slightly enlarged and may exhibit fimbriation and Schüffner's dots. Pigment is less-coarse and diffuse.
	Figure A

Figure A: Trophozoite of P. ovale in a thick blood smear.

	Figure B

Figure B: Trophozoite of P. ovale in a thin blood smear. Note the fimbriation.

	Figure C

Figure C: Trophozoite of P. ovale in a thin blood smear. Note the fimbriation and Schüffner's dots.

	Figure D

Figure D: Trophozoite of P. ovale in a thin blood smear. Note the fimbriation and Schüffner's dots.

	Figure E

Figure E: Trophozoites of P. ovale in a thin blood smear.

	Figure F

Figure F: Infected RBCs showing developing (lower) and ring-form (upper two) trophozoites of <em.P. ovale in a thin blood smear.

	Figure G

Figure G: Trophozoites of P. ovale in a thin blood smear.

Gametocytes of P. ovale in thick and thin blood smears.

 

Gametocytes of P. ovale can be difficult to distinguish from those of P. vivax, although there is generally less enlargement of the infected RBC. The mature macrogametocyte fills the host RBC; the microgametocyte is smaller. Schüffner's dots may be seen with proper staining and fimbriation may occur.
	Figure A

Figure A: Gametocyte of P. ovale in a thick blood smear.

	Figure B

Figure B: Gametocyte of P. ovale (red arrow) nestled between two white blood cells in a thick blood smear.

	Figure C

Figure C: Microgametocyte of P. ovale in a thin blood smear. Note the elongated, oval shape and the Schüffner's dots.

	Figure D

Figure D: Macrogametocyte of P. ovale in a thin blood smear. Note the fimbriation.

	Figure E

Figure E: Macrogametocyte of P. ovale in a thin blood smear. Note the fimbriation.

	Figure F

Figure F: Macrogametocyte of P. ovale in a thin blood smear, showing Schüffner's dots.

	Figure G

Figure G: Macrogametocyte of P. ovale in a thin blood smear.

	Figure H

Figure H: Macrogametocyte of P. ovale in a thin blood smear.

Schizonts of P. ovale in thick and thin blood smears.

 

Schizonts of P. ovale can be similar to P. vivax, although tend to be smaller and contain fewer merozoites (4-16, on average 8). Elongation to an oval shape and fimbriation are common. Schüffner's dots can be observed with proper staining. Pigment is lighter and less coarse, similar to P. vivax.
	Figure A

Figure A: Schizont of P. ovale in a thick blood smear.

	Figure B

Figure B: Schizonts of P. ovale in a thick blood smear.

	Figure C

Figure C: Schizont of P. ovale in a thick blood smear.

	Figure D

Figure D: Schizont of P. ovale in a thin blood smear. Notice the fimbriation.

	Figure E

Figure E: Schizont of P. ovale in a thin blood smear. Notice the fimbriation.

	Figure F

Figure F: Schizont of P. ovale in a thin blood smear.

	Figure G

Figure G: Schizont (upper right) and ring-form trophozoite (lower left) of P. ovale in a thin blood smear.

Plasmodium vivax

Ring-form trophozoites of P. vivax in thick and thin blood smears.

 

Ring-form trophozoites of P. vivax usually have a thick cytoplasm with a single, large chromatin dot. Rings may be difficult to distinguish from those of P. ovale. The cytoplasm becomes amoeboid and Schüffner's dots may appear as the trophozoites mature. Infected RBCs are often larger than uninfected RBCs. Multiply-infected RBCs are not uncommon.
	Figure A

Figure A: Ring-form trophozoites of P. vivax in a thick blood smear.

	Figure B

Figure B: Ring-form trophozoites of P. vivax in a thick blood smear.

	Figure C

Figure C: Ring-form trophozoite of P. vivax in a thin blood smear.

	Figure D

Figure D: Ring-form trophozoites of P. vivax in a thin blood smear.

	Figure E

Figure E: Ring-form trophozoites of P. vivax in a thin blood smear.

	Figure F

Figure F: Ring-form trophozoites of P. vivax in a thin blood smear.

	Figure G

Figure G: Ring-form trophozoites of P. vivax in a thin blood smear.

Trophozoites of P. vivax in thick and thin blood smears.

 

Developing trophozoites of P. vivax become increasingly amoeboid, with tenuous pseudopodial processes and large vacuoles.  Schüffner's dots are visible with proper staining. Pigment tends to be fine and brown. Infected RBCs are usually noticeably larger than uninfected RBCs.
	Figure A

Figure A: Trophozoite of P. vivax in a thick blood smear.

	Figure B

Figure B: Trophozoite of P. vivax in a thin blood smear. Note the amoeboid appearance, Schüffner's dots and enlarged infected RBCs.

	Figure C

Figure C: Trophozoites of P. vivax in a thin blood smear. Note the amoeboid appearance, Schüffner's dots and enlarged infected RBCs.

	Figure D

Figure D: Trophozoite of P. vivax in a thin blood smear. Note the amoeboid appearance, Schüffner's dots and enlarged infected RBCs.

	Figure E

Figure E: Trophozoite of P. vivax in a thin blood smear. Note the amoeboid appearance, Schüffner's dots and enlarged infected RBCs.

	Figure F

Figure F: Trophozoite of P. vivax in a thin blood smear. The infected RBCs are also noticeably larger than the uninfected RBCs.

	Figure G

Figure G: Trophozoite of P. vivax in a thin blood smear. Note the band-like appearance of the trophozoite in this figure that may be mistaken for a band-form trophozoite of P. malariae. Note, however, the fine, light brown pigment that is distributed throughout the cytoplasm (pigment in P. malariae is usually darker and coarser and distributed on the periphery of the cytoplasm). The infected RBCs are also noticeably larger than the uninfected RBCs.

Gametocytes of P. vivax in thick and thin blood smears.

 

Macrogametocytes of P. vivax are round to oval and usually fill the host cell. The infected RBC is usually noticeably larger than uninfected RBCs. The cytoplasm is usually a darker blue and contains fine brown pigment throughout. Schüffner's dots may be seen with proper staining. Microgametocytes are usually the size of an uninfected RBC and have a paler blue, pink or gray cytoplasm.
	Figure A

Figure A: Gametocyte (upper) and trophozoite (lower) of P. vivax in a thick blood smear.

	Figure B

Figure B: Gametocyte of P. vivax in a thick blood smear.

	Figure C

Figure C: Macrogametocytes of P. vivax in a thin blood smear. Note the enlargement of the gametocytes compared to uninfected RBCs.

	Figure D

Figure D: Macrogametocyte of P. vivax in a thin blood smear. Note the enlargement of the gametocytes compared to uninfected RBCs.

	Figure E

Figure E: Macrogametocyte of P. vivax in a thin blood smear. Note the enlargement of the gametocytes compared to uninfected RBCs.

	Figure F

Figure F: Macrogametocyte of P. vivax in a thin blood smear. Note the enlargement of the gametocytes compared to uninfected RBCs.

	Figure G

Figure G: Macrogametocytes of P. vivax in a thin blood smear.

	Figure H

Figure H: Macrogametocyte of P. vivax in a thin blood smear.

Ookinetes of P. vivax in thick and thin blood smears.

 

Ookinetes are motile zygotes formed by the combination of macrogametocytes and exflagellated microgametocytes in the mid-gut of the mosquito host. Ookinetes invade epithelial cells of the mosquito's mid-gut where an oocyst is formed. Ookinetes are not found in peripheral blood in the human host and are very rarely found on blood smears. Their presence on smears usually indicates a substantial delay occurred between the time the blood was collected and the time the slide was prepared. The following ookinetes were observed on a specimen courtesy of the Florida State Department of Health. The patient had traveled to India.
	Figure A

Figure A: Ookinete of P. vivax in a thick blood smear.

	Figure B

Figure B: Ookinete of P. vivax in a thick blood smear.

	Figure C

Figure C: Ookinete of P. vivax in a thick blood smear.

	Figure D

Figure D: Ookinete of P. vivax in a thin blood smear.

	Figure E

Figure E: Ookinete of P. vivax in a thin blood smear.

Schizonts of P. vivax in thick and thin blood smears.

 

Developing schizonts of P. vivax are large and amoeboid. Chromatin is arranged in two or more masses; pigment is also usually arranged in more than one mass. Mature schizonts contain 12-24 merozoites, each of which contains a dot of chromatin and a mass of cytoplasm. Pigment is usually organized in one or two clumps. Like other stages, infected RBCs are usually larger than uninfected RBCs.
	Figure A

Figure A: Schizont of P. vivax in a thick blood smear.

	Figure B

Figure B: Schizont of P. vivax in a thick blood smear.

	Figure C

Figure C: Schizont of P. vivax in a thick blood smear.

	Figure D

Figure D: Schizont of P. vivax in a thick blood smear.

	Figure E

Figure E: Schizont of P. vivax in a thick blood smear.

	Figure F

Figure F: Schizont of P. vivax in a thin blood smear.

	Figure G

Figure G: Schizont of P. vivax in a thin blood smear.

	Figure H

Figure H: Schizont of P. vivax in a thin blood smear.

	Figure I

Figure I: Ruptured schizont of P. vivax in a thin blood smear, showing free merozoites and pigment.

Diagnostic Findings

Microscopy

Microscopy (morphologic analysis) continues to be the "gold standard" for malaria diagnosis. Parasites may be visualized on both thick and thin blood smears stained with Giemsa, Wright, or Wright-Giemsa stains. Giemsa is the preferred stain, as it allows for detection of certain morphologic features (e.g. Schüffner’s dots, Maurer’s clefts, etc.) that may not be seen with the other two. Ideally, the thick smears are used to detect the presence of parasites while the thin smears are used for species-level identification. Quantification may be done on both thick and thin smears.

Comparison of Plasmodium Species Which Cause Malaria in Humans
Plasmodium species Stages found in blood Appearance of Erythrocyte (RBC) Appearance of Parasite
P. falciparum Ring normal; multiple infection of RBC more common than in other species; Maurer's clefts (under certain staining conditions) delicate cytoplasm; 1 to 2 small chromatin dots; occasional appliqué (accolé) forms
Trophozoite normal; rarely, Maurer's clefts (under certain staining conditions) seldom seen in peripheral blood; compact cytoplasm; dark pigment
Schizont normal; rarely, Maurer's clefts (under certain staining conditions) seldom seen in peripheral blood; mature = 8 to 24 small merozoites; dark pigment, clumped in one mass
Gametocyte distorted by parasite crescent or sausage shape; chromatin in a single mass (macrogametocyte) or diffuse (microgametocyte); dark pigment mass
P. vivax Ring normal to 1.25x, round; occasionally fine Schüffner's dots; multiple infection of RBC not uncommon large cytoplasm with occasional pseudopods; large chromatin dot
Trophozoite enlarged 1.5 to 2x; may be distorted; fine Schüffner's dots large amoeboid cytoplasm; large chromatin; fine, yellowish-brown pigment
Schizont enlarged 1.5 to
2x; may be distorted; fine Schüffner's dots
large, may almost fill RBC; mature = 12 to 24 merozoites; yellowish-brown, coalesced pigment
Gametocyte enlarged 1.5 to 2x; may be distorted; fine Schüffner's dots round to oval; compact; may almost fill RBC; chromatin compact, eccentric (macrogametocyte) or diffuse (microgametocyte); scattered brown pigment
P. ovale Ring normal to 1.25x, round to oval; occasionally Schüffner's dots; occasionally fimbriated; multiple infection of RBC not uncommon sturdy cytoplasm; large chromatin
Trophozoite normal to 1.25x; round to oval; some fimbriated; Schüffner's dots compact with large chromatin; dark-brown pigment
Schizont normal to 1.25x, round to oval, some fimbriated, Schüffner's dots mature = 6 to 14 merozoites with large nuclei, clustered around mass of dark-brown pigment
Gametocyte normal to 1.25x; round to oval, some fimbriated; Schüffner's dots round to oval; compact; may almost fill RBC; chromatin compact, eccentric (macrogametocyte) or more diffuse (microgametocyte); scattered brown pigment
P. malariae Ring normal to 0.75x sturdy cytoplasm; large chromatin
Trophozoite normal to 0.75x; rarely, Ziemann's stippling (under certain staining conditions) compact cytoplasm; large chromatin; occasional band forms; coarse, dark-brown pigment
Schizont normal to 0.75x; rarely, Ziemann's stippling (under certain staining conditions) mature = 6 to 12 merozoites with large nuclei, clustered around mass of coarse, dark-brown pigment; occasional rosettes
Gametocyte normal to 0.75x; rarely, Ziemann's stippling (under certain staining conditions) round to oval; compact; may almost fill RBC; chromatin compact, eccentric (macrogametocyte) or more diffuse (microgametocyte); scattered brown pigment
P. knowlesi Ring normal to 0.75x; multiple infection not uncommon. delicate cytoplasm; 1 to 2 prominent chromatin dots; occasional appliqué (accolé) forms
Trophozoite normal to 0.75x; rarely, Sinton and Mulligan's stippling (under certain staining conditions) compact cytoplasm; large chromatin; occasional band forms; coarse, dark-brown pigment
Schizont normal to 0.75x; rarely, Sinton and Mulligan's stippling (under certain staining conditions) mature = up to 16 merozoites with large nuclei, clustered around mass of coarse, dark-brown pigment; occasional rosettes; mature merozoites appear segmented
Gametocyte normal to 0.75x; rarely, Sinton and Mulligan's stippling (under certain staining conditions) round to oval; compact; may almost fill RBC; chromatin compact, eccentric (macrogametocyte) or more diffuse (microgametocyte); scattered brown pigment

Molecular Diagnosis

Agarose gel (2%) analysis of a PCR diagnostic test for species-specific detection of Plasmodium DNA.

Agarose gel (2%) analysis of a PCR diagnostic test for species-specific detection of Plasmodium DNA.

Morphologic characteristics of malaria parasites can determine a parasite species, however, microscopists may occasionally fail to differentiate between species in cases where morphologic characteristics overlap (especially Plasmodium vivax and P. ovale), as well as in cases where parasite morphology has been altered by drug treatment or improper storage of the sample. In such cases, the Plasmodium species can be determined by using confirmatory molecular diagnostic tests. In addition, molecular tests such as PCR can detect parasites in specimens where the parasitemia may be below the detectable level of blood film examination. The methods currently used at CDC are described below.

Species-specific PCR diagnosis of malaria

Plasmodium genomic DNA is extracted from 200 µl whole blood using the QIAamp Blood Kit (Cat. No. 29106; Qiagen Inc., Chatsworth, CA.) or a similar product that can yield the comparable concentration of genomic DNA from the same volume of blood.

Detection and identification of Plasmodium to the species level is done with a  real-time PCR assay as described by Rougemont et al 2004. This is a dual duplex assay that detects P. falciparum and P. vivax in one reaction, and P. malariae and P. ovale in a parallel reaction, using species-specific TaqMan probes.  In cases where infection by more than one Plasmodium species  is suspected, there is an option to use a conventional nested PCR assay (Snounou el al, 1993) that has an improved resolution of mixed infection compared to the real-time PCR assay.

Agarose gel (2%) analysis of a PCR diagnostic test for species-specific detection of Plasmodium DNA. PCR was performed using nested primers of Snounou et al.1

  • Lane S: Molecular base pair standard (50-bp ladder). Black arrows show the size of standard bands.
  • Lane 1: The red arrow shows the diagnostic band for P. vivax (size: 120 bp).
  • Lane 2: The red arrow shows the diagnostic band for P. malariae (size: 144 bp).
  • Lane 3: The red arrow shows the diagnostic band for P. falciparum (size: 205 bp).
  • Lane 4: The red arrow shows the diagnostic band for P. ovale (size: 800 bp).
Reference:

Mathieu Rougemont, Madeleine Van Saanen, Roland Sahli, Hans Peter Hinrikson, Jacques Bille and Katia Jaton. Detection of Four Plasmodium Species in Blood from Humans by 18S rRNA Gene Subunit-Based and Species-Specific Real-Time PCR Assays. J. Clin. Microbiol. 2004, 42(12):5636.

Snounou G, Viriyakosol S, Zhu XP, et al. High sensitivity detection of human malaria parasites by the use of nested polymerase chain reaction. Mol Biochem Parasitol 1993;61:315-320.

Antibody Detection

Agarose gel (2%) analysis of a PCR diagnostic test for species-specific detection of Plasmodium DNA.

Positive IFA result with P. malariae schizont antigen.

Malaria antibody detection for clinical diagnosis is performed using the indirect fluorescent antibody (IFA) test. The IFA procedure can be used as a diagnostic tool to determine if a patient has been infected with Plasmodium. Because of the time required for development of antibody and also the persistence of antibodies, serologic testing is not practical for routine diagnosis of acute malaria. However, antibody detection may be useful for:

  • screening blood donors involved in cases of transfusion-induced malaria when the donor's parasitemia may be below the detectable level of blood film examination
  • testing a patient who has been recently treated for malaria but in whom the diagnosis is questioned

Species-specific testing is available for the four human species: P. falciparum, P. vivax, P. malariae, and P. ovale. Cross reactions often occur between Plasmodium species and Babesia species. Blood stage Plasmodium species schizonts (meronts) are used as antigen. The patient's serum is exposed to the organisms; homologous antibody, if present, attaches to the antigen, forming an antigen-antibody (Ag-Ab) complex. Fluorescein-labeled antihuman antibody is then added, which attaches to the patient's malaria-specific antibodies. When examined with a fluorescence microscope, a positive reaction is when the parasites fluoresce an apple green color.

Reference:

Sulzer AJ, and Wilson M. The fluorescent antibody test for malaria. Crit Rev Clin Lab Sci 1971;2:601-609.

Antigen Detection

In addition to microscopy and molecular methods, there are methods for detecting malaria parasites on the basis of antigens or enzymatic activities associated with the parasites. These methods are often packaged as individual test kits called rapid diagnostic tests or RDTs.

These methods include, among others:

  • detection of an antigen (histidine rich protein-2, HRP-2) associated with malaria parasites (P. falciparum)
  • detection of a Plasmodium specific aldolase
  • detection of a Plasmodium associated lactate dehydrogenase (pLDH) either through its enzymatic activity or by immunoassay

There is currently only one RDT licensed for use in the United States. For additional information visit http://www.cdc.gov/malaria/diagnosis_treatment/rdt.html

Bench Aids

Treatment Information

Guidelines for Treatment of Malaria in the United States Adobe PDF file (Based on drugs currently available for use in the United States – updated July 1, 2013)

Malaria can be a severe, potentially fatal disease (especially when caused by Plasmodium falciparum) and treatment should be initiated as soon as possible.

Patients who have severe P. falciparum malaria or who cannot take oral medications should be given the treatment by continuous intravenous infusion.

Most drugs used in treatment are active against the parasite forms in the blood (the form that causes disease) and include:

  • chloroquine
  • atovaquone-proguanil (Malarone®)
  • artemether-lumefantrine (Coartem®)
  • mefloquine (Lariam®)
  • quinine
  • quinidine
  • doxycycline (used in combination with quinine)
  • clindamycin (used in combination with quinine)
  • artesunate (not licensed for use in the United States, but available through the CDC malaria hotline)

In addition, primaquine is active against the dormant parasite liver forms (hypnozoites) and prevents relapses. Primaquine should not be taken by pregnant women or by people who are deficient in G6PD (glucose-6-phosphate dehydrogenase). Patients should not take primaquine until a screening test has excluded G6PD deficiency.

How to treat a patient with malaria depends on:

  • The type (species) of the infecting parasite
  • The area where the infection was acquired and its drug-resistance status
  • The clinical status of the patient
  • Any accompanying illness or condition
  • Pregnancy
  • Drug allergies, or other medications taken by the patient

Report a serious drug side effect

If you have had a serious side effect while taking a drug, you or your health care provider can report that side effect to the federal Food and Drug Administration (FDA). MedWatch is the FDA Safety Information and Adverse Event Reporting Program. You are encouraged to take the reporting form www.fda.gov/medwatch/SAFETY/3500.pdf Adobe PDF fileExternal Web Site Icon to your health care provider.

Alternatively, health care providers can report to the FDA.

The advantage to having your health care provider file the report is that he/she can provide clinical information based on your medical record that can help the FDA evaluate the report.

However, for a variety of reasons, you may not wish to have the form completed by your provider, or the provider may not wish to complete the form. Your health care provider is not required to report to the FDA. In this case, you may complete the online reporting form at www.fda.gov/medwatch/report/consumer/consumer.htmExternal Web Site Icon yourself via the Internet.

Related Links

The CDC malaria diagnosis and treatment guidelines have also been published in an article in JAMA May 23, 2007 and can be accessed for free online: view JAMA articleExternal Web Site Icon.

DPDx is an education resource designed for health professionals and laboratory scientists. For an overview including prevention and control visit www.cdc.gov/parasites/.

  • Page last reviewed: May 3, 2016
  • Page last updated: May 3, 2016
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