Question

A 53-year-old newly married male had just returned from Mozambique where he spent his honeymoon. Two weeks later, he developed nausea and vomiting, abdominal pain, high fever and chills. He was admitted to hospital where thrombocytopenia and spleen enlargement were observed. When a diagnostic test was done, it revealed positive results indicating an infection with Plasmodium falciparum, and he was immediately treated with IV chloroquine.

a. Which disease can be caused by P. falciparum?

b. Discuss the plasmodium lifecycle in human host.

c. At which stage of the plasmodium life cycle does an infected person present with clinical manifestations of malaria?

d. Describe the mechanism of action of chloroquine.

e. Describe one chemoprophylactic drug that the patient could have taken prior to visiting Mozambique and the duration thereof.

Answer 1

(a)Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans.The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria.

(b) The malaria parasite is transmitted to the human host when an infected female Anopheles mosquito takes a blood meal and simultaneously injects a small number of sporozoites into the skin. After reaching the liver, the sporozoites invade hepatocytes in which they develop into a liver schizont and replicate asexually. After about seven days of liver stage development, each infected hepatocyte releases up to 40,000 merozoites that enter the peripheral blood stream. Once in the blood stream, merozoites quickly invade circulating red blood cells (RBCs), thereby initiating the repeated asexual replication cycle. Over the course of 48 hours, the parasite progresses through the ring and the trophozoite stages before finally replicating into 8–32 daughter merozoites at the schizont stage (schizogony). At this point, the parasitized RBC (pRBC) ruptures and releases merozoites into circulation, commencing another round of asexual replication. Mature asexual stages that display increased stiffness, trophozoites and schizonts, adhere to the vasculature in various organs, which allows them to avoid splenic clearance. During each cycle, a small subset of parasites divert from asexual replication and instead produce sexual progeny that differentiate the following cycle into male and female sexual forms, known as gametocytes. A subset of parasites leave the peripheral circulation and enter the extravascular space of the bone marrow, where gametocytes mature and progress through stages I–V over the course of eight to ten days (gametocytogenesis). Although evidence suggests that the bone marrow is the primary location of gametocyte maturation, some immature gametocytes have been observed elsewhere in the human body, such as in the spleen. By stage V, male and female gametocytes re-enter peripheral circulation, in which they become competent for infection to mosquitoes. Once ingested by a mosquito, male and female gametocytes rapidly mature into gametes (gametogenesis). Within the midgut, the male gametocyte divides into up to eight flagellated microgametes (exflagellation), whereas the female gametocyte develops into a single macrogamete. Fertilization of a macrogamete by a microgamete results in the formation of a zygote, which undergoes meiosis and develops into an invasive ookinete that penetrates the mosquito gut wall. The ookinete forms an oocyst within which the parasite asexually replicates, forming several thousand sporozoites (sporogony). Upon oocyst rupture, these sporozoites migrate to the salivary glands, where they can be transmitted back to the human host during a blood meal. Asexual parasites (in RBCs) are represented in pale yellow, sexual parasites in green.

(c)

Blood stage or erythrocytic schizogony

Merozoites use the apicomplexan invasion organelles (apical complex, pellicle and surface coat) to recognize and enter the host erythrocyte (red blood cell). The parasite first binds to the erythrocyte in a random orientation. It then reorients such that the apical complex is in proximity to the erythrocyte membrane. The parasite forms a parasitophorous vacuole, to allow for its development inside the erythrocyte.This infection cycle occurs in a highly synchronous fashion, with roughly all of the parasites throughout the blood in the same stage of development. This precise clocking mechanism has been shown to be dependent on the human host's own circadian rhythm.

Within the erythrocyte, the parasite metabolism depends on the digestion of hemoglobin. The clinical symptoms of malaria such as fever, anemia, and neurological disorder are produced during the blood stage.

The parasite can also alter the morphology of the erythrocyte, causing knobs on the erythrocyte membrane. Infected erythrocytes are often sequestered in various human tissues or organs, such as the heart, liver and brain. This is caused by parasite-derived cell surface proteins being present on the erythrocyte membrane, and it is these proteins that bind to receptors on human cells. Sequestration in the brain causes cerebral malaria, a very severe form of the disease, which increases the victim's likelihood of death.

(d)Chloroquine is an aminoquinolone derivative first developed in the 1940s for the treatment of malaria.It was the drug of choice to treat malaria until the development of newer antimalarials such as pyrimethamine, artemisinin, and mefloquine. Chloroquine and its derivative hydroxychloroquine have since been repurposed for the treatment of a number of other conditions including HIV, systemic lupus erythematosus, and rheumatoid arthritis.

Indication

Chloroquine is indicated to treat infections of P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum.It is also used to treat extraintestinal amebiasis.

Chloroquine is also used off label for the treatment of rheumatic diseases, as well as treatment and prophylaxis of Zika virus.Chloroquine is currently undergoing clinical trials for the treatment of COVID-19

Associated Conditions

Discoid Lupus Erythematosus (DLE)

Extraintestinal Amebiasis

Plasmodium Infections

Polymorphic Light Eruption (PLE)

Porphyria Cutanea Tarda

Rheumatoid Arthritis,

Malaria.

Pharmacodynamics

Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species.It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children.

Mechanism of action

Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin. Plasmodium species continue to accumulate toxic heme, killing the parasite.

Chloroquine passively diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the organelle and raising the surrounding pH.The raised pH in endosomes, prevent virus particles from utilizing their activity for fusion and entry into the cell.

Chloroquine does not affect the level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry.

(e)

General Information

Mozambique is a developing nation classified as low income. Located in southeastern Africa along the Indian Ocean (north of South Africa and south of Malawi), the climate classifications range from tropical dry winter to humid equatorial (long dry season).

Malaria risk due predominantly to P. falciparum exists throughout the year in the entire country.

Recommended prevention: – Risk of P. falciparum malaria, in combination with reported chloroquine and sulfadoxine–pyrimethamine resistance. Mosquito bite prevention plus atovaquone–proguanil or doxycycline or mefloquine chemoprophylaxis (select according to reported side effects and contraindications)
Alternatively, for travel to rural areas with low risk of malaria infection, mosquito bite prevention can be combined with stand–by emergency treatment (SBET).

Drug resistance3 : Chloroquine.

Malaria species: P. falciparum >90%, P. malariae, P. ovale, and P. vivax rare.

Recommended chemoprophylaxis: Atovaquone-proguanil, doxycycline, mefloquine, or tafenoquine.
Refers to P. falciparum malaria unless otherwise noted.
Primaquine and tafenoquine can cause hemolytic anemia in people with G6PD deficiency. Patients must be screened for G6PD deficiency before starting primaquine or tafenoquine.

How long does malaria medication last:-

DrugHalf life

Atovaquone2–3 days

Chloroquine6–60 days

Doxycycline12–24 hours

Mefloquine2–3 weeks