Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans.
PF causes more than 600,000 deaths from malaria annually, mostly among children in Africa.
The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease’s most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases.
P. falciparum is therefore regarded as the deadliest parasite in humans.
Infection in humans begins with the bite of an female Anopheles mosquito.
Out of about 460 species of Anopheles mosquito, more than 70 species transmit falciparum malaria.
It is also associated with the development of Burkitt’s lymphoma and is classified as a Group 2A probable carcinogen.
The mosquito saliva contains antihaemostatic and anti-inflammatory enzymes that disrupt blood clotting and inhibit the pain reaction.
Typically, each infected bite contains 20–200 sporozoites.
The human-infective stage are sporozoites from the salivary gland of a mosquito, which grow and multiply in the liver to become merozoites.
Merozoites invade the erythrocytes to form trophozoites, schizonts and gametocytes, which initiate the symptoms of malaria.
In 2022, approximately 249 million cases of malaria worldwide resulted in an estimated 608000 deaths, with 80 percent being 5 years old or less.
Nearly all malarial deaths are caused by P. falciparum.
95% of cases of P. falciparum occur in Africa.
In Sub-Saharan Africa, almost 100% of cases were due to P. falciparum, whereas in most other malarial countries, other, less virulent plasmodial species predominate.
P. falciparum undergoes continuous change during the course of its life cycle.
A sporozoite is spindle-shaped and 10–15 μm long. In the liver it grows into an ovoid schizont of 30–70 μm in diameter.
Each schizont produces merozoites, each of which is roughly 1.5 μm in length and 1 μm in diameter.
In the erythrocyte the merozoite form a ring-like structure, becoming a trophozoite.
A trophozoite feeds on the haemoglobin and forms a granular pigment called haemozoin.
A mature gametocyte is 8–12 μm long and 3–6 μm wide.
Microscopic examination of a blood film reveals only early ring-formed trophozoites and gametocytes that are in the peripheral blood.
Mature trophozoites or schizonts are usually sequestered in the tissues.
Humans are the intermediate hosts for asexual reproduction of P. falciparum, and female anopheline mosquitos are the definitive hosts harbouring the sexual reproduction stage.
Anopheles gambiae is one of the best known and most prevalent vectors, particularly in Africa.
Some of sporozoites invade liver cells (hepatocytes).
The sporozoites move in the bloodstream by gliding via proteins actin and myosin beneath their plasma membrane.
Entering the hepatocytes, the parasite loses its apical complex and surface coat, and transform from a sporozoite into a trophozoite.
Within the hepatocyte, it undergoes 13–14 rounds of mitosis which produce a syncytial cell called a schizont.
From the schizont, tens of thousands of haploid daughter cells called merozoites emerge.
The liver stage can produce up to 90,000 merozoites, which are eventually released into the bloodstream in parasite-filled vesicles called merosomes.
Merozoites recognize and enter the host erythrocyte.
The merozoites first kbind to the erythrocyte in a random orientation, then in proximity to the erythrocyte membrane.
The malarial parasite forms a vacuole, to allow for its development inside the erythrocyte.
The infection cycle occurs in a highly synchronous fashion, with roughly all of the parasites throughout the blood in the same stage of development.
The parasite’s metabolism depends on the digestion of haemoglobin in the RBC>
The clinical symptoms of malaria such as fever, anemia, and neurological disorder are produced during this blood stage.
The parasite can also alter the morphology of the erythrocyte, and causes changes on the erythrocyte membrane, so that infected erythrocytes are often sequestered in various human tissues or organs, such as the heart, liver and brain.
Parasite-derived cell surface proteins on the erythrocyte membrane bind to receptors on human cells.
Sequestration in the brain causes cerebral malaria.
After invading the erythrocyte, the parasite loses its specific invasion organelles and de-differentiates into a round trophozoite located within a parasitophorous vacuole.
The trophozoite feeds on the haemoglobin of the erythrocyte.
The trophozoite digests its proteins and converts the remaining heme into insoluble and chemically inert β-hematin crystals called haemozoin.
The parasite replicates its DNA multiple times at this schizont stage and multiple mitotic divisions occur asynchronously.
Cell division and multiplication in the erythrocyte is referred to as erythrocytic schizogony.
Each schizont forms 16-18 merozoites, which rupture red blood cells.
Liberated merozoites then invade fresh erythrocytes in roughly 60 seconds.
The characteristic clinical manifestations of falciparum malaria, such as fever and chills, corresponding to the synchronous rupture of the infected erythrocytes.
Some merozoites differentiate into sexual forms, male and female gametocytes, taking roughly 7–15 days to reach full maturity.
These are then taken up by a female Anopheles mosquito during a blood meal.
The time of appearance of the symptoms from infection, the incubation period, is shortest for P. falciparum among Plasmodium species.
An average incubation period is 11 days, but may range from 9 to 30 days.
Prolonged incubation periods as long as 2, 3 or even 8 years have been recorded.
Pregnancy and co-infection with HIV are important conditions for delayed symptoms.
Parasites can be detected from blood samples by the 10th day after infection.
The sprozoites migrate to the mosquito salivary glands where they undergo further development and become infective to humans.
Sporozoites may migrate to the mosquito’s salivary glands and can enter a human host when the mosquito takes a blood meal.
The sporozoite then can move to the human host liver and infect hepatocytes.
A single anopheline mosquito can transmit hundreds of P. falciparum sporozoites in a single bite, but, in nature the number is generally less than 80.
The sporozoites remain in the skin for two to three hours.
About 15–20% of the sporozoites enter the lymphatic system, where they activate dendritic cells, which send them for destruction by T lymphocytes-(CD8+ T cells).
By 48 hours after infection, Plasmodium-specific CD8+ T cells can be detected in the lymph nodes connected to the skin cells, and most of the sporozoites in the skin tissue are subsequently killed by the innate immune system.
The sporozoite glycoprotein activates mast cells, which produce signaling molecules such as TNFα and MIP-2, which activate phagocytes) such as neutrophils and macrophages.
Only 0.5-5% of sporozoites enter the blood stream into the liver.
In the liver, activated CD8+ T cells bind the sporozoites.
Antigen presentation by dendritic cells in the skin tissue to T cells is important.
In the liver the parasites produce different proteins that help suppress communication of the immune cells:immune signals are not strong enough to activate macrophages or natural killer cells: it evades immunity by producing over 2,000 cell membrane antigens.
Thrombospondin-related anonymous protein (TRAP) and other secretory proteins (including sporozoite microneme protein essential for cell traversal allow the sporozoite to move through the blood, avoiding immune cells and penetrating hepatocytes.
During erythrocyte invasion, merozoites release proteins responsible for avoiding immune cells.
The virulence of P. falciparum is mediated by erythrocyte membrane proteins produced by the schizonts and trophozoites inside the erythrocytes and are displayed on the erythrocyte membrane.
The clinical symptoms of falciparum malaria are produced by the rupture and destruction of erythrocytes by the merozoites.
High fever is the most basic indication of the infection.
Each erythrocytic schizogony takes a cycle of 48 hours, i.e., two days, the febrile symptom appears every third day:tertian malignant fever.
The most common symptoms are fever (>92%), chills (79%), headaches (70%), and sweating (64%).
Generally associated symptoms include: dizziness, malaise, muscle pain, abdominal pain, nausea, vomiting, mild diarrhea, and dry cough, tachycardia, jaundice, pallor, orthostatic hypotension, enlarged liver, and enlarged spleen are also seen.
Haemozin, the insoluble β-hematin crystals produced from digestion of haemoglobin of the RBCs is the main agent that affects the body.
Haemozoin-containing RBCs cannot be attacked by phagocytes during immune response to malaria.
The phagocytes can ingest free haemozoins after being released from ruptured of RBCs by which they are induced to initiate chains of inflammatory reaction that results in increased fever.
Haemozoin deposited in body organs such as the spleen and liver, as well as in kidneys and lungs, that cause their enlargement and discolouration.
Haemozoin is known as malarial pigment.
Other malarias,have regular periodicity of fever.
Falciparum malaria exhibits a 48-hour cycle, and usually presents as irregular bouts of fever.
P. falciparum merozoites are able to invade a large number of RBCs sequentially without coordinated intervals, which is not seen in other malarial parasites.
P. falciparum is the cause for almost all severe human illnesses and deaths due to malaria.
Complicated malaria occurs more commonly in children under age 5, and sometimes in pregnant women.
Women become susceptible to severe malaria during their first pregnancy, and susceptibility to severe malaria is reduced in subsequent pregnancies due to increased antibody levels against variant surface antigens that appear on infected erythrocytes.
The increased immunity in the mother increases susceptibility to malaria in newborn babies.
P. falciparum works via sequestration of RBCs.
Mature schizonts change the surface properties of infected erythrocytes, causing them to stick to blood vessel walls, leading to obstruction of the microcirculation and results in dysfunction of multiple organs, such as the brain in cerebral malaria.
Cerebral malaria is the most dangerous malarial infection and the most severe form of neurological disorders.
Cerebral malaria’s clinical symptom is indicated by coma and diagnosis by high level of merozoites in the peripheral blood samples.
It is the deadliest form of malaria, and to it are attributed to 0.2 million to over a million annual deaths throughout the ages.
Most malaria deaths are of children of below 5 years of age.
It occurs when the merozoites invade the brain and causes brain damage.
Death is caused by hypoxia due to inflammatory cytokine production and vascular leakage induced by the merozoites.
Among survivors persistent medical conditions such as neurological impairment, intellectual disability, and behavioral problems exist.
Epilepsy is the most common persistent condition, and cerebral malaria is the leading cause of acquired epilepsy among African children.
The reappearance of falciparum symptom, a phenomenon called recrudescence, is often seen in survivors.
Recrudescence may take a few months or even several years.
Recrudescence is a common incident among pregnant women.
P. falciparum predominates in areas including Africa and the Caribbean.
P. falciparum is endemic in 84 countries, and is found in all continents except Europe.
Historically, it was present in most European countries, but improved health conditions led to the disappearance in the early 20th century.
The infection is most prevalent in Africa, where 94% of malaria deaths occur.
Children under five years of age are most affected, and 67% of malaria deaths occurred in this age group.
80% of the infection is found in Sub-Saharan Africa, 7% in the South-East Asia, and 2% in the Eastern Mediterranean.
Nigeria has the highest incidence, with 27% of the total global cases.
Outside Africa, India has the highest incidence, with 4.5% of the global burden.
Europe is regarded as a malaria-free region.
It is estimated that approximately 2.4 billion people are at constant risk of infection.
Treatment
Artemisinin-based combination therapies (ACTs) are the recommended first-line antimalarial treatments for uncomplicated malaria caused by P. falciparum.
WHO recommends combinations such as artemether/lumefantrine, artesunate/amodiaquine, artesunate/mefloquine, artesunate/sulfadoxine/pyrimethamine, and dihydroartemisinin/piperaquine
Artemisinin and its derivatives are not appropriate for monotherapy.
Second-line antimalarial treatment, when initial treatment does not work, an alternative ACT known to be effective in the region is recommended, such as artesunate plus tetracycline or doxycycline or clindamycin, and quinine plus tetracycline or doxycycline or clindamycin.
For pregnant women, the recommended first-line treatment during the first trimester is quinine plus clindamycin for 7 days.
Artesunate plus clindamycin for 7 days is indicated if this treatment fails.
For travellers returning to nonendemic countries, atovaquone/proguanil, artemether/lumefantrineany and quinine plus doxycycline or clindamycin are recommended.
For severe malaria
For adults, intravenous (IV) or intramuscular (IM) artesunate is recommended.
Quinine is an acceptable alternative if parenteral artesunate is not available.
For children, especially in the malaria-endemic areas of Africa, artesunate IV or IM, quinine and artemether IM are recommended.
Parenteral antimalarials should be administered for a minimum of 24 hours, irrespective of the patient’s ability to tolerate oral medication earlier.
Thereafter, complete treatment is recommended including complete course of ACT or quinine plus clindamycin or doxycycline. Vaccination
RTS,S is the only candidate as malaria vaccine to have gone through clinical trials.
The vaccine will not lead to full protection and eradication.
Malaria due to P. falciparum is a Group 2A carcinogen, meaning that the parasite is probably a cancer-causing agent in humans.
Its association with Burkitt’s lymphoma is established.
Epstein–Barr virus (EBV) is identified from the cancer cells, and virus was subsequently proved to be the direct cancer agent, and is now classified as Group 1 carcinogen.
EBV requires other infections such as with malaria to cause lymphocyte transformation. It was reported that the incidence of Burkitt’s lymphoma decreased with effective treatment of malaria over several years.
P. falciparum-infected erythrocytes directly bind to B lymphocytes an activates toll-like receptors (TLR7 and TLR10) causing continuous activation of lymphocytes to undergo proliferation and differentiation into plasma cells, thereby increasing the secretion of IgM and cytokines.
This binding activates an enzyme called activation-induced cytidine deaminase (AID), which tends to cause mutation in the DNA (by double-strand break) of an EBV-infected lymphocytes.
The damaged DNA undergoes uncontrolled replication, thus making the cell cancerous.
Several genetic factors provide some resistance to Plasmodium infection, including sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, and the absence of Duffy antigens on red blood cells.