INTRODUCTION

About 3.3 billion people - half the world's population - are at risk of malaria due to the main
causative parasite, Plasmodium falciparum. Over 200 million cases of malaria occur each year,
90% of which occur in Africa, and 655 000 people died from the disease in 2010, making it one
of the world's most important health problems. Increasing resistance of the parasite to currently
available drugs has created an urgent need to discover new treatments. However, this requires an
improved understanding of the pathogenesis of malaria.

Malarial infection begins when a person is bitten by an infected female Anopheles mosquito and
Plasmodium spp (species) parasites in the form of sporozoites are injected into the bloodstream.
The sporozoites travel to the liver, multiplying asexually over the next 7-10 days. During this
time there are no symptoms. The parasites, now in the form of merozoites, emerge from the liver
cells in vesicles and travel through the heart to the capillaries of the lungs. The vesicles eventually
disintegrate, releasing the merozoites to enter the bloodstream where they invade and multiply in
erythrocytes. When the cells burst, the parasites invade more erythrocytes. Clinical symptoms,
including fever, occur in synchrony with the rupture of infected erythrocytes and the release of
erythrocyte and parasite debris, including malarial pigment (hemozoin) and
glycophosphatidylinositol, the putative ‘malaria toxin'. In some infected blood cells, instead of
replicating asexually, the merozoites develop into sexual forms (gametocytes), which circulate in
the bloodstream and are ingested during mosquito bites. The ingested gametocytes develop in the
mosquito into mature sex cells (gametes) which develop into ookinetes that actively burrow
through the mid-gut wall of the mosquito and form oocysts, in which develop thousands of active
sporozoites. The oocyst eventually bursts, releasing sporozoites that travel to the salivary glands
of the mosquito. The cycle of human infection begins again when the mosquito bites another
person.

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 BACKGROUND
Malaria is a potentially life-threatening disease caused by the Plasmodium parasites transmitted to
humans through the bites of infected female Anopheles mosquitoes. There are several species of
Plasmodium that can infect humans, with Plasmodium falciparum being the deadliest.
The severity of malaria varies based on the species of plasmodium:

• Plasmodium falciparum (or P. falciparum)

• Plasmodium malariae (or P. malariae)
• Plasmodium vivax (or P. vivax)
• Plasmodium ovale (or P. ovale)
• Plasmodium knowlesi (or P. knowlesi)

Key facts about malaria include:

Transmission: Malaria is primarily transmitted through the bites of infected female Anopheles
mosquitoes. It can also be transmitted through blood transfusion, organ transplantation, and from mother
to fetus during childbirth.
Symptoms: Malaria symptoms typically include fever, chills, headache, and muscle aches. Other
symptoms can include fatigue, nausea, and vomiting. In severe cases, malaria can lead to organ failure
and death.
Geographical Distribution: Malaria is most prevalent in tropical and subtropical regions, including sub-
Saharan Africa, Southeast Asia, the Indian subcontinent, and parts of Central and South America.
Preventive Measures: Preventive measures include the use of insecticide-treated bed nets, indoor
residual spraying, and antimalarial medications for individuals living in or traveling to malaria-endemic
areas.
Diagnosis and Treatment: Malaria can be diagnosed through blood tests. Prompt and effective treatment
is essential to prevent the progression of the disease. Artemisinin-based combination therapies (ACTs)
are commonly used to treat uncomplicated malaria, while severe cases may require hospitalization and
intravenous medications.
Preventive Medications for Travelers: Travelers to malaria-endemic areas may be prescribed
antimalarial medications for prevention. The choice of medication depends on the specific region and the
risk of drug resistance.
Efforts to control and eliminate malaria involve a combination of vector control measures, prompt and
effective treatment, and research into new interventions such as vaccines. Organizations like the World
Health Organization (WHO) and various governments collaborate on global malaria control initiatives.
Despite progress, malaria remains a significant public health challenge in many parts of the world.
Malaria is the infection caused by inoculation with the mostly obligate

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intraerythrocytic protozoa of the genus Plasmodium. Severe malaria manifests as multiple organ
dysfunction with high parasitemia counts characterized by coma, stupor, and severe metabolic acidosis.
Physicians in the United States do not frequently encounter patients with malaria, and the drugs are only
available through the Centers for Disease Control and Prevention, which makes the management of this
disease somewhat complicated. In 2019, the marketing of quinine for malaria was discontinued. In May
2020, the US Food and Drug Administration approved the use of intravenous artesunate for the treatment
of adults and children with severe malaria.

PATHOPHYSIOLOGY
All the manifestations of malarial illness are caused by the infection of the red blood cells by the
asexual forms of the malaria parasite and the involvement of the red cells makes malaria a
potentially multisystem disease, as every organ of the body is reached by the blood. All types of
malaria manifest with common symptoms such as fever, some patients may progress into severe
malaria. Although severe malaria is more often seen in cases of P. falciparum infection,
complications and even deaths have been reported in non-falciparum malaria as well.

Malaria
Plasmodium-derived
Hemozoin
Hemozoin
“presents" or
internalizes
plasmodial DNA

Plasmodium DNA

TLR9 recognizes
plasmodial DNA
TLR-9 and initiates the
Host cell innate immune
response
Signaling

nucleus ( NF-kappaB NF-kappaB-

activated
Protein proinflammatory
synthesis cytokines induce I COX-
2

Pro-inflammatory Cytokines COX-2 upregulates

prostaglandins leading
to a change in the set-
COX-2 point of I the
thermoregulatory^
center (fever)
Fever

Fig: Pathophysiology of Malaria

At the completion of the schizogony within the red cells, each cycle lasting 24-72 hours depending on the
species of the infecting parasite, newly developed merozoites are released by the lysis of infected
erythrocytes and along with them, numerous known and unknown waste substances, such as red cell
membrane products, hemozoin pigment, and other toxic factors such as

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glycosylphosphatidylinositol (GPI) are also released into the blood. These products, particularly the GPI,
activate macrophages and endothelial cells to secrete cytokines and inflammatory mediators such as
tumor necrosis factor, interferon-y, interleukin-1, IL-6, IL-8, macrophage colony-stimulating factor, and
lymphotoxin, as well as superoxide and nitric oxide(NO).Many studies have implicated the GPI tail,
common to several merozoite surface proteins such as MSP-1, MSP-2, and MSP-4, as a key parasite
toxin. The systemic manifestations of malaria such as headache, fever and rigors, nausea and vomiting,
diarrhea, anorexia, tiredness, aching joints and muscles, thrombocytopenia, immunosuppression,
coagulopathy, and central nervous system manifestations have been largely attributed to the various
cytokines released in response to these parasite and red cell membrane products In addition to these
factors, the plasmodial DNA is also highly proinflammatory and can induce cytokinemia and fever. The
plasmodial DNA is presented by hemozoin (produced during the parasite development within the red cell)
to interact intracellularly with the Toll-like receptor-9, leading to the release of proinflammatory
cytokines that in turn induce COX-2-upregulating prostaglandins leading to the induction of fever.
Hemozoin has also been linked to the induction of apoptosis in developing erythroid cells in the bone
marrow, thereby causing anemia.

PATHOGENESIS
Pathogenesis, the manner of development of a disease, for a human malasria clinical illness is a complex
story that has many players, settings, and potential outcomes. As with any truly successful parasite, the
observed outcome of evolution in malaria is the undisturbed transition from mosquito to human to
mosquito with little impact on the vector and host. Although impact of malaria can be seen at the
individual, community, country, and global level, from the parasite's perspective, a healthy host serving
as two blood meals with a bit of fever in between is the norm. In fact, human clinical disease is quite rare
relative to the global interaction network of mosquitoes and humans.

Fig: Schematic representation of pathogenesis of severe malaria

 TREATMENT AND PREVENTION

It’s important to start treating malaria as soon as possible. Some parasites are resistant to malaria drugs.
Some drugs are given in combination with other drugs. The type of parasite will determine what type of
medication you take and how long you take it.
Antimalarial drugs include:

•Artemisinin drugs (artemether and artesunate). The best treatment for Plasmodium falciparum malaria, if
available, is artemisinin combination therapy

•Atovaquone (Mepron®)

•Chloroquine (There are parasites that are resistant to this medication)

•Doxycycline (Doxy-100®, Monodox®, Oracea®)

•Mefloquine

•Quinine

•Primaquine

PREVENTION

If you plan on living temporarily in or traveling to an area where malaria is common, talk to your provider about
taking medications to prevent malaria. You will need to take the drugs before, during and after your stay.
Medications can greatly reduce the chances of getting malaria. These drugs can’t be used for treatment if you do
develop malaria despite taking them.
You should also take precautions to avoid mosquito bites. To lower your chances of getting malaria, you should:
•Apply mosquito repellent with DEET (diethyltoluamide) to exposed skin.
•Drape mosquito netting over beds.
•Put screens on windows and doors.
•Treat clothing, mosquito nets, tents, sleeping bags and other fabrics with an insect repellent called permethrin.
•Wear long pants and long sleeves to cover your skin.

VACCINATION
There’s a vaccine for children which was developed and tested in Ghana, Kenya and Malawi in a pilot program.
The RTS, S/AS01 vaccine is effective against Plasmodium falciparum malaria, which causes severe disease in
children.

This case report describes a case of Plasmodium falciparum malaria in a 55-year-old woman who returned home to Florida
from a visit to Ghana.

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 CASE PRESENTATION ON MALARIA
(Plasmodium falciparum)

OVERVIEW
• Malaria is a disease caused by a plasmodium parasite, transmitted by the bite of infected mosquitoes.
In 2020, nearly half of the world's population was at risk of malaria. Most cases and deaths occur in sub-
Saharan Africa. However, the WHO regions of South-East Asia, Eastern Mediterranean, Western Pacific,
and the Americas also report significant numbers of cases and deaths.
• There were an estimated 247 million cases of malaria in 2021, and the estimated number of malaria
deaths stood at 619 000. The WHO African Region carries a disproportionately high share of the global
malaria burden. In 2020, the region was home to 95% and 96% of malaria cases and deaths, respectively.
• Children under 5 years of age are the most vulnerable group affected by malaria; in 2021, they
accounted for nearly 80% of all malaria deaths in the WHO African Religion.

SYMPTOMS

•Shaking chills
•Headache
•Muscle aches
•Tiredness
•Nausea
•Vomiting
•Diarrhea
•Abdominal pain
•Rapid breathing
•Rapid heartrate
•Cough

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 ETIOLOGY

Malaria is caused by a single-celled parasite of the genus

plasmodium. The parasite is transmitted to humans most
commonly through mosquito bites.

Malaria transmission cycle

Malaria spreads when a mosquito becomes infected with the
disease after biting an infected person, and the infected mosquito
then bites a noninfected person. The malaria parasites enter that
person's bloodstream and travel to the liver. When the parasites
mature, they leave the liver and infect red blood cells.
•Uninfected mosquito. A mosquito becomes infected by feeding on a
person who has malaria.

•Transmission of parasite. If this mosquito bites you in the future, it

can transmit malaria parasites to you.

•In the liver. Once the parasites enter your body, they travel to your
liver — where some types can lie dormant for as long as a year.

•Into the bloodstream. When the parasites mature, they leave the liver
and infect your red blood cells. This is when people typically develop
malaria symptoms.

•On to the next person. If an uninfected mosquito bites you at this

point in the cycle, it will become infected with your malaria parasites
and can spread them to the other people it bites.

Other modes of transmission

Because the parasites that cause malaria affect red blood cells, people
can also catch malaria from exposure to infected blood, including:
•From mother to unborn child
•Through blood transfusions
•By sharing needles used to inject drugs
Fig: Blood smear stained with Giemsa, showing a white blood cell (on left
side) and several red blood cells, two of which are infected with Plasmodium
falciparum (on right side).

PATIENT DEMOGRAPHIC DETAILS

• NAME- XYZ
• AGE- 55 yrs
• SEX- Female
• ADDRESS- FLORIDA

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Recent findings
Cerebral malaria and AKI are serious and well recognized complications of severe malaria. Common
pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized
erythrocytes, systemic inflammatory responses, and endothelial activation. Recent MRI studies show
significant brain swelling in both adults and children with evidence of posterior reversible
encephalopathy syndrome-like syndrome although targeted interventions including mannitol and
dexamethasone are not beneficial. Recent work shows association of cell-free hemoglobin oxidation
stress involved in the pathophysiology of AKI in both adults and children. Paracetamol protected renal
function likely by inhibiting cell-free-mediated oxidative stress. It is unclear if heme-mediated
endothelial activation or oxidative stress is involved in cerebral malaria.