Malaria I

Section Contents

Background
Epidemiology & Biology
Life cycle
Pathogenesis
Clinical Presentation
Other Media Resources (Optional)

Buckle up! Malaria will arguably be the longest lesson in our curricular series! It’s so long and so important that it deserves two parts. Part I includes all introductory aspects to the epidemiology, biology, and clinical presentation of malaria; and Part II includes the most high yield concepts in diagnosis, treatment and prevention. Let’s begin…

Background

Malaria is a mosquito-borne parasitic disease caused by protozoa of the genus Plasmodium. The word malaria comes from the italian term “mal aria” which translates to “bad air”, as it was believed to be transmitted through the air from swamps and marshes.

Malaria is arguably the most important parasitic infection worldwide, and it is common among tropical and subtropical areas of the world. According to the WHO (2024), there were close to 263 million cases worldwide, and approximately 597,000 malaria deaths in 2023. The majority of cases and deaths occur in sub-Saharan Africa, mostly in children under 5 years of age. There are five species known to infect the human host: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.

Epidemiology & Biology

Malaria is transmitted by the bite of the female Anopheles mosquito. The majority of species are predominantly night-biters, with most biting peaks occurring after dusk. Anopheles spp. (like other mosquitoes) breeds in water, thus rainfall and temperature are positively correlated with malaria incidence. An outline of the most medically-relevant features of Anopheles spp. in comparison to other arboviral vectors are summarized in the Table below.

	Anopheles	Aedes	Culex
Biting behavior	Night biters	Day biters	Night biters
Pathogens transmitted	Plasmodium spp.	Dengue virus, Chikungunya virus, Zika virus, Yellow fever virus, Rift Valley Fever virus	Japanese encephalitis virus, West Nile virus, Rift Valley Fever virus

Table 1. Comparison between common mosquitoes

Figure 1. Anopheles spp

Figure 2. Aedes aegypti

Note: Very rarely, malaria can be transmitted via intravenous drug use, needlestick injuries, transfusion of blood products, or transplantation.

Each Plasmodium species has very unique features, which will hopefully become more apparent as we describe more aspects of malaria. However, we want to highlight some basic concepts. Please click through each species to learn more:

P. falciparum

P. vivax

It’s the dominant species outside of Africa, because many individuals in Africa lack the Duffy antigen (receptor that mediates P. vivax invasion to the erythrocyte) and thus develop partial immunity to the infection. Clinical disease in P. vivax is classically milder than P. falciparum. Please know that P. vivax and P. ovale have dormant stages ("hypnozoites") that can reactivate after treatment. This important because it alters treatment choice.

P. malariae

P. ovale

P. knowlesi

P. knowlesi previously circulated exclusively among non-human primates, but the first natural infection of humans was described in 1965. More prevalent in Southeast Asia, and among humans with close contacts with macaques. The emergence of malaria as a zoonosis complicates the goal of malaria elimination in humans. FYI - it is the only species with a 24-hour life cycle, which is the shortest of all human and non-human primate malarias.

Life cycle

The life cycle of Plasmodium is complicated, but generally similar among species (except some key differences). It consists of two phases: asexual and sexual. The asexual phase occurs in mammals, and the sexual phase takes place in the mosquito.

Asexual phase (pre-erythrocytic stage): when the female Anopheles takes a blood meal, it injects salivary fluid into the wound. These fluids contain sporozoites, which travel to the hepatocytes in the liver. Inside the liver, they divide asexually several times - in a process called "liver schizogony ", which generates liver schizonts, each containing tens of merozoites. When schizonts rupture, they release merozoites into the bloodstream that go to invade the erythrocytes.

Note: ONLY in P. vivax and P. ovale infection - a subset of sporozoites differentiate into dormant stages in the liver, called hypnozoites. These stages (for unknown reasons) can remain quiescent in the liver for months to years, reactivate, and initiate a new infection.

Asexual phase (erythrocytic stage): once inside the erythrocytes, merozoites can differentiate asexually or sexually. The majority of merozoites undergo asexual reproduction, progressing from ring stages to early and late trophozoite stages, and then schizonts (composed of tens of merozoites). When schizonts rupture, merozoites are released into the blood stream and invade neighboring erythrocytes. This process (from invasion to release of merozoites in the erythrocytes) is called "blood schizogony". Further, some trophozoites will differentiate sexually into gametocytes. Gametocytes can be male (microgametocytes) or female (macrogametocytes), they accumulate in small skin capillaries where they can be taken up by the Anopheles mosquito in a blood meal, to continue the next part of the cycle. FYI - clinical symptoms are caused by the asexual stages (ring stages, trophozoites, schizonts, merozoites), but NOT by gametocytes.

Sexual phase: upon ingestion by the mosquito, the gametocytes shed their protective erythrocyte membrane in the gut of the mosquito. Male gametocytes fertilize their female counterparts, resulting in zygotes, and later into oocysts in the gut wall. Each oocyst produces thousands of sporozoites, which migrate and invade the salivary glands. When the female Anopheles bites another human host, sporozoites are introduced into the circulation, and a new cycle begins.

Figure 3. Life cycle of Plasmodium falciparum

Figure 4. Life cycle of Plasmodium vivax/ovale

Figure 5. Life cycle of Plasmodium spp in the mosquito (sporogony)

Pathogenesis

After the introduction of sporozoites, it generally takes about 1-3 weeks for the erythrocytic schizogony to cause symptoms in the human host. The initial liver stage (pre-erythrocytic schizogony) is not pathogenic. The pathogenesis we describe below primarily references P. falciparum - which is the most studied species! Exceptions for other species are noted.

The majority of the symptoms in malaria are centered around two pathogenic mechanisms: hemolysis and tissue ischemia. Pathogenesis of the most important clinical manifestations is described:

Malaria paroxysm (chills, fever, diaphoresis)

Infected erythrocytes rupture and release merozoites. Each schizogony releases “malarial toxins” (e.g., hemozoin, glycophosphatidylinositol) that induce the production of inflammatory cytokines (e.g., TNF-alpha, IL-1) by macrophages, monocytes, and natural killer cells. These cytokines stimulate the production of prostaglandins and initiate the febrile response. By altering the thermoregulatory center, it creates shivering (chills), and vasoconstriction for heat conservation purposes. This is followed by vasodilation, and heat loss through profuse sweating (diaphoresis).

Splenomegaly & thrombocytopenia

Infected erythrocytes are destroyed in the red pulp of the spleen, which can cause spleen congestion (splenomegaly) and hyperfunction (hypersplenism). The hyperplasia of the reticuloendothelial system also contributes to liver and splenic enlargement during malaria infection. Hypersplenism increases the consumption of platelets, which alongside immune-mediated destruction, suppression of thrombopoiesis and possible disseminated intravascular coagulation, collectively contribute to the presence of thrombocytopenia.

Anemia

Hypoglycemia

Malaria in pregnancy

Pregnant women exhibit particular susceptibility to severe malaria (more on this later). In pregnancy, infected erythrocytes express a membrane protein known as VAR2CSA (a pfEMP1 variant) - which sounds complicated but don't panic! We are here to explain it.

All you need to know for now is that this VAR2CSA protein facilitates the adhesion of the erythrocyte to chondroitin sulfate in the placenta and mediates placental sequestration, which leads to hypoxia and inflammation.

All of these phenomena decrease the metabolic supply between the mother and the fetus, leading to increased risk of death, miscarriage, preterm delivery, and increased risk of severe malaria. Increased susceptibility fundamentally seen in primigravids, as anti-adhesion antibodies to placental antigens have not been produced yet in the non-immune individuals.

Why is P. falciparum move severe?

Something that we have not told you is why P. falciparum is more than the others. Well, it is because of a few reasons. Click on each option below:

Polyparasitism

P. falciparum has two advantageous mechanisms over other species: 1) P. falciparum is able to invade erythrocytes of ALL AGES (young, old), 2) Many merozoites are able to invade the same erythrocyte ("polyparasitism"), To put it into perspective - in infections with P. vivax, P. ovale, and P. malariae, the destruction of infected erythrocytes is much more limited (rarely exceeds 2%), because it preferentially infects either very young (reticulocytes), or or very old erythrocytes. In addition, none of these species commonly produces polyparasitism.

Faster schizogony

Sequestration

P. falciparum induces the expression of a surface protein known as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) - we kind of talked about this before. The PfEMP1 allows the infected erythrocyte to bind to the endothelial vasculature, in a process known as cytoadherence, and can remain sequestered in the microvasculature. The PfEMP1 forms membrane protrusions in the erythrocyte called “knobs”, that function as anchoring sites to other cell surfaces (e.g., uninfected erythrocytes, or endothelial cells). A number of host molecules have been described as receptors for infected erythrocytes, including intercellular adhesion molecule 1(ICAM-1), thrombospondin, P selectin, chondroitin sulfate A, among others.

Rosette formation

Aside from attaching to the vasculature ("sequestration") - parasitized erythrocytes can bind to neighboring uninfected erythrocytes forming “rosette” structures in small capillaries and venules. The combination of cytoadherence, sequestration, and formation of rosettes leads to obstruction of the microcirculation, local inflammation, and tissue hypoxia, contributing to the appearance of severe malaria.

Antigenic variation

Now imagine all these phenomena happening in the same patient! This is why P. falciparum can cause such severe disease. In some cases, it affects the microvasculature of the central nervous system, leading to one of its most feared complications: cerebral malaria.

Clinical Presentation

The incubation period is ~1-3 weeks in human hosts, with a few exceptions:

P. vivax may take up to 6-12 months;
P. malariae takes closer to 30 days;

Clinical malaria presents in many different ways. To understand malaria you will need to recognize the symptoms, but also to acknowledge the severity of the disease. This is important because treatment is different! Based on the severity disease, malaria can be classified in uncomplicated or severe:

Uncomplicated malaria → individuals classically present as an acute febrile syndrome, ("malaria paroxysm"), and many other non-specific symptoms, such as: general malaise, headaches, anorexia, myalgias, arthralgias, jaundice, abdominal discomfort, nausea, or diarrhea. Patients may also have hepatosplenomegaly.
Note: Because symptoms of malaria can be non-specific, any fever or viral-like illness in an individual coming from a malaria endemic region, must make you think of malaria!
1. Malaria paroxysm → each paroxysm coincides with the rupture of infected erythrocytes. In the beginning, patients are more likely to be asynchronous, and fever can be daily before typical periodicity is achieved. Over time, schizogonies synchronize and can cause very distinct fever patterns (depends on each species):
  1. Quotidian fever: fever occurs at daily intervals, as schizogony takes ~24h to occur. Representative of P. knowlesi infections.
  2. Tertian fever: fever occurs on the 3rd day, as schizogony takes ~48h to occur. Representative of P. ovale/P. vivax (also called “tertian benign fever”), or P. falciparum (also called “tertian malignant fever”)
  3. Quartan fever: fever occurs on the 4th day, as schizogony takes ~72h to occur. Representative of P. malariae infections.
Note: Although this is frequently described in textbooks, asynchronous parasite’s cycles are not infrequent. These “classic” fever patterns are suggestive, but if the patient is having other fever patterns that does not exclude malaria.
What are the causes of massive splenomegaly in the tropics?
Answer

Hyperreactive Malarial Splenomegaly

Visceral Leishmaniasis

Brucellosis

Hepato-splenic schistosomiasis
Complicated (severe) malaria → occurs when (often P. falciparum) malaria leads to severe end-organ damage and/or metabolic derangements. Criteria for severe malaria per the WHO are listed below. The presence of one or more of the following criteria in the presence of asexual parasitemia with P. falciparum is diagnostic.

Criteria for severity	Definition
Impaired consciousness	Glasgow coma score <11 (adults) Blantyre coma score <3 (children)
Prostration	Generalized weakness so that the person is unable to sit, stand or walk w/o assistance
Convulsions	More than 2 episodes within 24h
Acidosis	A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as respiratory distress (rapid, deep, laboured)
Hypoglycemia	Blood/plasma glucose <2.2 mmol/L (<40 mg/dL)
Severe anemia	Hemoglobin concentration ≤ 5 g/dL or a haematocrit of ≤ 15% in children < 12 years of age (< 7 g/dL and 10 000/µL
Renal impairment	Plasma/serum creatinine > 265 µmol/L (3 mg/dL) or blood urea > 20 mmol/L
Jaundice	Plasma or serum bilirubin > 50 µmol/L (3 mg/ dL) with a parasite count > 100 000/ µL
Pulmonary edema	Radiologically confirmed or oxygen saturation 30/ min, often with chest indrawing and crepitations on auscultation
Significant bleeding	Including recurrent or prolonged bleeding from the nose, gums or venipuncture sites; haematemesis or melaena
Shock	Compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure < 70 mm Hg in children or < 80 mmHg in adults, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill).
Parasitemia	P. falciparum parasitaemia > 10%

Other clinical syndromes in malaria

We want you to know that in certain individuals (especially in those with non-severe malaria), there are distinct clinical syndromes that can happen:

Asymptomatic malaria

Relapse

Recrudescence

Hyperreactive Malarial Splenomegaly

Nephrotic syndrome

Okay. This was a lot. It's time to take a break. See you in Malaria part II.

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This lesson was last updated August 21 2025