The vector for malaria is the female anopheline mosquito. When the vector takes a blood meal, sporozoites contained in the salivary glands of the mosquito are discharged into the puncture wound (Figure 49-1). Within an hour, these infective sporozoites are carried via the blood to the liver, where they penetrate hepatocytes and begin to grow, initiating the preerythrocytic or primary exoerythrocytic cycle. The sporozoites become round or oval and begin dividing repeatedly. Schizogony results in large numbers of exoerythrocytic merozoites. Once these merozoites leave the liver, they invade the red blood cells (RBCs), initiating the erythrocytic cycle. A dormant schizogony may occur in P. vivax and P. ovale organisms, which remain quiescent in the liver. These resting stages have been termed hypnozoites and lead to a true relapse, often within 1 year or up to more than 5 years later. Delayed schizogony does not occur in P. falciparum, P. malariae, or P. knowlesi.

Figure 49-1 Life cycle of *Plasmodium*. (Modified from Wilcox A: *Manual for the microscopical diagnosis of malaria in man,* Washington, DC, 1960, U.S. Public Health Service. Illustration by Nobuko Kitamura.)

Once the RBCs and reticulocytes have been invaded, the parasites grow and feed on hemoglobin. Within the RBC, the merozoite (or young trophozoite) is vacuolated, ring shaped, more or less ameboid, and uninucleate. The excess protein and hematin present from the metabolism of hemoglobin combine to form malarial pigment. Once the nucleus begins to divide, the trophozoite is called a developing schizont. The mature schizont contains merozoites (whose number depends on the species), which are released into the bloodstream. Many of the merozoites are destroyed by the immune system, but others invade RBCs and initiate a new cycle of erythrocytic schizogony. After several erythrocytic generations, some of the merozoites begin to undergo development into the male and female gametocytes.

Although malaria is often associated with travelers to endemic areas, other situations resulting in infection include blood transfusions, use of contaminated hypodermic needles, bone marrow transplantation, congenital infection, and transmission within the United States by indigenous mosquitoes that acquired the parasites from imported infections.

Plasmodium Vivax (Benign Tertian Malaria)

General Characteristics

P. vivax infects only the reticulocytes; thus, the parasitemia is limited to approximately 2% to 5% of the available RBCs (Tables 49-1 to 49-3, Figures 49-2 and 49-3). Splenomegaly occurs during the first few weeks of infection, and the spleen will progress from being soft and palpable to hard, with continued enlargement during a chronic infection. If the infection is treated during the early phases, the spleen will return to its normal size. A secondary or dormant schizogony occurs in P. vivax and P. ovale, which remain quiescent in the liver. These resting stages have been termed hypnozoites.

TABLE 49-1

Plasmodium spp.: Clinical Characteristics of the Five Human Infections

Infection	P. vivax	P. ovale	P. malariae	P. falciparum	P. knowlesi	Comments
Incubation period	8-17 days	10-17 days	18-40 days	8-11 days	9-12 days	All may be extended for months to years
Prodromal symptoms Severity Initial fever pattern	Mild to moderate Irregular (48 hr)	Mild Irregular (48 hr)	Mild to moderate Regular (72 hr)	Mild Continuous remittent	Mild to moderate Regular (24 hr)	All may mimic influenza symptoms Early symptoms may reflect lack of regular periodicity
Symptom periodicity	48 hr	48 hr	72 hr	36-48 hr	24-27 hr
Initial paroxysm Severity Mean duration	Moderate to severe 10 h	Mild 10 h	Moderate to severe 11 h	Severe 16-36 h	Moderate to severe Not available	P. knowlesi might increase/lose virulence on passage in humans
Duration of untreated primary attack	3-8+ wk	2-3 wk	3-24 wk	2-3 wk	Not available
Duration of untreated infection	5-7 yr	12 mo	20+ yr	6-17 mo	Not available
Parasitemia limitations	Young RBCs	Young RBCs	Old RBCs	All RBCs	All RBCs
Anemia	Mild to moderate	Mild	Mild to moderate	Severe	Moderate to severe	P. knowlesi can be as dangerous as P. falciparum
CNS involvement	Rare	Possible	Rare	Very common	Possible
Nephrotic syndrome	Possible	Rare	Very common	Rare	Probably common

TABLE 49-2

Plasmodia in Giemsa-Stained Thin Blood Smears

	Plasmodium vivax	Plasmodium malariae	Plasmodium falciparum	Plasmodium ovale	Plasmodium knowlesi
Persistence of exoerythrocytic cycle	Yes	No	No	Yes	No
Relapses	Yes	No, but long-term recrudescence is recognized	No long-term relapses	Possible, but usually spontaneous recovery	No
Time of cycle	44-48 hr	72 hr	36-48 hr	48 hr	24 hr
Appearance of parasitized RBCs; size and shape	1.5-2 times larger than normal; oval to normal; may be normal size until ring fills half of cell	Normal shape; size may be normal or slightly smaller	Both normal	60% of cells larger than normal and oval; 20% have irregular, frayed edges	Normal shape, size
Schüffner’s dots (eosinophilic stippling)	Usually present in all cells except early ring forms	None	None; occasionally comma-like red dots are present (Maurer’s dots)	Present in all stages including early ring forms; dots may be larger and darker than in P. vivax	No true stippling; occasional faint dots
Color of cytoplasm	Decolorized, pale	Normal	Normal, bluish tinge at times	Decolorized, pale	Normal
Multiple rings/cell	Occasional	Rare	Common	Occasional	Common
All developmental stages present in peripheral blood	All stages present	Ring forms few, since ring stage brief; mostly growing and mature trophozoites and schizonts	Young ring forms and no older stages; few gametocytes	All stages present	All stages present
Appearance of parasite; young trophozoite (early ring form)	Ring is diameter of cell, cytoplasmic circle around vacuole; heavy chromatin dot	Ring often smaller than in P. vivax, occupying of cell; heavy chromatin dot; vacuole at times “filled in”; pigment forms early	Delicate, small ring with small chromatin dot (frequently 2); scanty cytoplasm around small vacuoles; sometimes at edge of red cell (appliqué form) or filamentous slender form; may have multiple rings per cell	Ring is larger and more ameboid than in P. vivax; otherwise similar to P. vivax	Rings to diameter of RBC; double chromatin dots; appliqué forms rare; multiple rings per RBC
Growing trophozoite	Multishaped irregular ameboid parasite; streamers of cytoplasm close to large chromatin dot; vacuole retained until close to maturity; increasing amounts of brown pigment	Non-ameboid rounded or band-shaped solid forms; chromatin may be hidden by coarse dark brown pigment	Heavy ring forms; fine pigment grains	Ring shape maintained until late in development; non-ameboid compared to P. vivax	Slightly ameboid and irregular; band forms seen; very little pigment
Mature trophozoite	Irregular ameboid mass; 1 or more small vacuoles retained until schizont stage; fills almost entire cell; fine brown pigment	Vacuoles disappear early; cytoplasm compact, oval, band shaped, or nearly round and almost filling cell; chromatin may be hidden by peripheral coarse dark brown pigment	Not seen in peripheral blood (except in severe infections); development of all phases following ring form occurs in capillaries of viscera	Compact; vacuoles disappear; pigment dark brown, less than in P. malariae	Denser cytoplasm (slightly ameboid) band forms seen; little to no malaria pigment (scattered, fine brown grains)
Schizont (pre-segmenter)	Progressive chromatin division; cytoplasmic bands containing clumps of brown pigment	Similar to P. vivax except smaller; darker, larger pigment granules peripheral or central	Not seen in peripheral blood (see above)	Smaller and more compact than P. vivax	Between 2 and 5 divided nuclear chromatin masses; abundant pigment granules occupy of RBC
Mature schizont	16 (12-24) merozoites, each with chromatin and cytoplasm, filling entire red cell, which can hardly be seen	8 (6-12) merozoites in rosettes or irregular clusters filling normal-sized cells, which can hardly be seen; central arrangement of brown-green pigment	Not seen in peripheral blood	of cells occupied by 8 (8-12) merozoites in rosettes or irregular clusters	RBCs normal size; distorted/fimbriated RBCs very rare; occupy whole RBC; maximum of 16 merozoites; no rosettes; grapelike clusters
Macrogametocyte	Rounded or oval homogeneous cytoplasm; diffuse delicate light brown pigment throughout parasite; eccentric compact chromatin	Similar to P. vivax, but fewer in number; pigment darker and more coarse	Gender differentiation difficult; “crescent” or “sausage” shapes characteristic; may appear in “showers” with black pigment near chromatin dot, which is often central	Smaller than P. vivax	Occupy most of RBC; bluish cytoplasm; dense pink chromatin at periphery of parasite
Microgametocyte	Large pink to purple chromatin mass surrounded by pale or colorless halo; evenly distributed pigment	Similar to P. vivax, but fewer in number; pigment darker and more coarse	Same as macrogametocyte (described above)	Smaller than P. vivax	Occupy most of RBC; cytoplasm pinkish purple; early forms similar to mature trophozoite
Main criteria	Large pale red cell; trophozoite irregular; pigment usually present; Schüffner’s dots not always present; several phases of growth seen in one smear; gametocytes appear as early as third day	Red cell normal in size and color; trophozoites compact, stain usually intense, band forms not always seen; coarse pigment; no stippling of red cells; gametocytes appear after a few weeks	Development following ring stage takes place in blood vessels of internal organs; delicate ring forms and crescent-shaped gametocytes are only forms normally seen in peripheral blood; gametocytes appear after 7-10 days	Red cell enlarged, oval, with fimbriated edges; Schüffner’s dots seen in all stages; gametocytes appear after 4 days or as late as 18 days	Ring forms compact; single/double chromatin dots, appliqué forms, multiple rings/RBC (mimic P. falciparum); overall RBCs not enlarged; developing stages mimic P. malariae (band forms, 16 merozoites in mature schizont, but no rosettes)

TABLE 49-3

Malaria Characteristics with Fresh Blood or Blood Collected Using EDTA with No Extended Lag Time *

Type of Malaria	Characteristics
Plasmodium vivax (benign tertian malaria)	1. 48-hour cycle 2. Tends to infect young cells 3. Enlarged RBCs 4. Schüffner’s dots (true stippling) after 8-10 hours 5. Delicate ring 6. Very ameboid trophozoite 7. Mature schizont contains 12-24 merozoites
Plasmodium malariae (quartan malaria)	1. 72-hour cycle (long incubation period) 2. Tends to infect old cells 3. Normal size RBCs 4. No stippling 5. Thick ring, large nucleus 6. Trophozoite tends to form “bands” across the cell 7. Mature schizont contains 6-12 merozoites
*Plasmodium ovale*	1. 48-hour cycle 2. Tends to infect young cells 3. Enlarged RBCs with fimbriated edges (oval) 4. Schüffner’s dots appear in the beginning (in RBCs with very young ring forms, in contrast to P. vivax) 5. Smaller ring than P. vivax 6. Trophozoite less ameboid than that of P. vivax 7. Mature schizont contains an average of 8 merozoites
Plasmodium falciparum (malignant tertian malaria)	1. 36-48-hour cycle 2. Tends to infect any cell regardless of age, thus very heavy infection may result 3. All sizes of RBCs 4. No Schüffner’s dots (Maurer’s dots: may be larger, single dots, bluish) 5. Multiple rings/cell (only young rings, gametocytes, and occasional mature schizonts are seen in peripheral blood) 6. Delicate rings, may have two dots of chromatin/ring, appliqué or accolé forms 7. Crescent-shaped gametocytes
Plasmodium knowlesi (simian malaria)*	1. 24-hour cycle 2. Tends to infect any cell regardless of age, thus very heavy infection may result 3. All sizes of RBCs, but most tend to be normal size 4. No Schüffner’s dots (faint, clumpy dots later in cycle) 5. Multiple rings/cell (may have 2-3) 6. Delicate rings, may have two or three dots of chromatin/ring, appliqué forms 7. Band form trophozoites commonly seen 8. Mature schizont contains 16 merozoites, no rosettes 9. Gametocytes round, tend to fill the cell Early stages mimic P. falciparum; later stages mimic P. malariae

^*Preparation of thick and thin blood films within <60 min of collection.

After a few days of irregular periodicity, a regular 48-hour cycle is established. An untreated primary attack may last from 3 weeks to 2 months or longer. Over time, the paroxysms (symptomatic period) become less severe and more irregular in frequency and then cease altogether. In approximately 50% of patients infected with P. vivax, relapses occur after weeks, months, or even after 5 years or more. The RBCs tend to be enlarged (young RBCs), there may be Schüffner’s dots (exclusively found in P. vivax and P. ovale) after 8 to 10 hours, the developing rings are ameboid, and the mature schizont contains 12 to 24 merozoites (Figure 49-3 [3]).

Pathogenesis and Spectrum of Disease

In patients who have never been exposed to malaria, symptoms such as headache, photophobia, muscle aches, anorexia, nausea, and sometimes vomiting may occur before organisms can be detected in the bloodstream. In other patients with prior exposure to the malaria, the parasites can be found in the bloodstream several days before symptoms appear.

Severe complications are uncommon in P. vivax infections, although coma and sudden death or other symptoms of cerebral involvement have been reported, particularly in patients with varying degrees of primaquine resistance. These patients can exhibit cerebral malaria, renal failure, circulatory collapse, severe anemia, hemoglobinuria, abnormal bleeding, acute respiratory distress syndrome, and jaundice. Acute cerebral malaria involves changes in mental status and if untreated may result in fatality within 3 days.

Plasmodium Ovale

General Characteristics

Although P. ovale and P. vivax infections are clinically similar, P. ovale malaria is usually less severe, tends to relapse less frequently, and usually ends with spontaneous recovery, often after no more than 6 to 10 paroxysms (see Tables 49-1 to 49-3, Figures 49-2 and 49-3). Like P. vivax, P. ovale infects only the reticulocytes, so that the parasitemia is limited to approximately 2% to 5% of the available RBCs. For many years the literature has stated that as with P. vivax, a secondary or dormant schizogony occurs in P. ovale, which remain quiescent in the liver. However, newer findings indicate that hypnozoites have never been demonstrated by biologic experiments.