DEFINITION, ETIOLOGY, TRANSMISSION, INCUBATION PERIOD, CLINICAL PRESENTATION, LIFECYCLE OF MALARIAL PARASITE, PATHOGENESIS, DIAGNOSIS, TREATMENT, PREVENTION AND PRECAUTIONS

1. MALARIA Dr. Niranjana ES, Pharm D.,
Assistant Professor
Department of Pharmacy Practice,
SSM College of Pharmacy, Erode, Tamil Nadu

2. MALARIA – (“mala”- bad/foul “aria”- air )
• Malaria is a common and life-threatening disease in many tropical and subtropical areas.
• As per WHO, There are currently over 100 countries and territories where there is a risk of
malaria transmission, and these are visited by more than 125 million international travellers
every year.
• Mainly occurs in travellers to and residents of malaria-endemic regions
• It is a protozoal febrile blood infection caused by a mosquito-borne
apicomplexan parasite, which is transmitted to humans during the bite of an
infected female Anopheles mosquito species

3. EPIDEMIOLOGY
 The exact geographic distribution of the
various species is not well documented; it
is reported that
• Plasmodium vivax is more prevalent in India,
Pakistan, Bangladesh, Sri Lanka, and Central
America
• Plasmodium falciparum is predominant in
Africa, Haiti, Dominican Republic, the Amazon
region of South America, and New Guinea.
• Plasmodium ovale occur in Africa, and the
distribution of Plasmodium malariae is
considered worldwide
Epidemiological trends of Malaria in India
 The World Malaria Report (WMR) 2020
released by WHO, which gives the estimated
cases for malaria across the world.
 India achieved a reduction of 83.34% in
malaria morbidity and 92% in malaria
mortality between the year 2000
(20,31,790 cases, 932 deaths) and 2019
(3,38,494 cases, 77 deaths)

4. ETIOLOGY
TRANSMISSION
The malaria parasite is transmitted by female
Anopheles mosquitoes, which bite mainly between dusk and
dawn
Malaria is caused by the
protozoan parasite Plasmodium.
Human malaria is caused by four
different species of Plasmodium:
 P. Falciparum
 P. Malariae
 P. ovale
 P. vivax.
Humans occasionally become infected
with Plasmodium species that normally
infect animals, such as P. knowlesi. As
yet, there are no reports of human–
mosquito–human transmission of such
“zoonotic” forms of malaria
INCUBATION PERIOD
As per CDC; the incubation period in most cases varies
from 7 to 30 days.
 The shorter periods are observed most frequently with P.
falciparum and the longer ones with P. malariae.

5. CLINICAL PRESENTATIONS
Malaria is an acute febrile illness with an incubation period of 7 days or longer. Thus, a febrile illness developing less than 1 week after
the first possible exposure is not malaria
The most severe form is caused by P. falciparum;
INITIAL PRESENTATIONS
Variable clinical features include; (Flu like symptoms)
 Fever
Chills
Headache
Muscular aching and weakness
Vomiting
Cough
Diarrhoea
Abdominal pain.
**The initial symptoms, which may be mild, may not be easy to recognize as being due to malaria**

6. CLINICAL PRESENTATIONS
Uncomplicated Malaria
The classical (but rarely observed) malaria attack
lasts 6–10 hours. It consists of;
 A cold stage (sensation of cold, shivering)
 A hot stage (fever, headaches, vomiting; seizures in young
children)
 Finally a sweating stage (sweats, return to normal
temperature, tiredness).
 combination of other flu like symptoms
Physical findings may include the following:
 Elevated temperatures
 Perspiration
 Weakness
 Enlarged spleen
 Mild jaundice
 Enlargement of the liver
 Increased respiratory rate
Severe Malaria (Mainly associated with P. falciparum)
Occurs when infections are complicated by serious organ
failures or abnormalities in the patient’s blood or metabolism. The
manifestations include the following:
 Cerebral malaria, with abnormal behavior, impairment of
consciousness, seizures, coma, or other neurologic abnormalities
 Severe anemia due to hemolysis
 Hemoglobinuria (hemoglobin in the urine) due to hemolysis
 Acute respiratory distress syndrome (ARDS), (an inflammatory
reaction in the lungs that inhibits oxygen exchange,)
 Abnormalities in blood coagulation
 Low blood pressure caused by cardiovascular collapse
 Acute kidney injury
 Hyperparasitemia, where more than 5% of the red blood cells are
infected by malaria parasites
 Metabolic acidosis
 Hypoglycemia (low blood glucose).

7. The Life Cycle of Malaria

8. The Life Cycle of Malaria
To start the cycle, an infected female
Anopheles mosquito injects sporozoites into
the skin while feeding.
Sporozoites enter the blood stream and are
carried to the liver, where they infect liver
cells.
Within liver cells, the parasites develop
into schizonts. In some malaria species,
parasites remain in the liver, causing
relapses. (Asxeual Cycle )
The schizonts rupture, releasing thousands
of individual merozoites into the bloodstream
MOSQUITO STAGES (7-10 days) - sporogonic cycle/Sexual Cycle
When the mosquito feeds, gametocytes are ingested into its
stomach initiate gametogenesis. The flagellated forms of microgametes (Male),
formed by exflagellation, penetrate or fertilize the macrogametes (Female)
generating zygotes.
The zygotes elongate into ookinete which move through the
stomach walls; the ookinetes then develop into oocysts. Inside the oocyst,the nucleus
divides repeatedly, with the formation of a large number of sporozoites and
enlargement of the oocyst. When the sporozoites are fully formed, the oocyst bursts,
releasing the sporozoites into the haemocoel (the mosquito’s body cavity).
After 10-18 days the sporozoites migrate to the salivary
glands, thus completing the life cycle. Entrance of the sporozoites from the
mosquito’s salivary glands into a new human host perpetuates the malaria life cycle.
Merozoites infect red blood cells; they invade RBC to grow
by consuming hemoglobin. Within the host RBC,the parasite undergoes
development from the early ring stage to late trophozoite and then after
mitotic divisions to the schizont stage, which contains 6 to 32 merozoites,
depending on the parasite species
When the erythrocytic schizont ruptures,it releases
merozoites and continue the life cycle by invading other RBCs. (Cyclical
fevers occurs shortly before or at the time of RBC lysis as schizonts rupture
to release new infectious merozoites)
During this repeated cycle some merozoites differentiate
into male and female sexual forms known as erythrocytic gametocytes
with one nucleus and then awaiting the arrival of a blood seeking female
Anopheles mosquito

9. NOTES
P. vivax is one of two forms of relapsing malaria to infect humans It has the ability to
become dormant in the liver (“hypnozoite”) and can be reactivated after months or even
years leading to an attack of blood stage malaria despite the absence of a mosquito bite.
The majority of available antimalarials target the blood stage in the parasite lifecycle,
since this leads to the clinical symptoms of malaria
All the manifestations of malarial illness are caused by the infection of the RBCs 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

10. PATHOGENESIS
Schizonts rupture
About 4 to 36 daughter merozoites, (depending on the
plasmodium species,) released into the circulation
Invade fresh RBC to perpetuate the asexual life cycle
Release of large amount of toxins and parasite
products like hemozoin pigment, and other toxic
factors such as glycosylphosphatidylinositol (GPI)
Activation of macrophages and endothelial cells to
secrete cytokines and inflammatory mediators such
as TNF, Interferon-γ, interleukin-1, IL-6, IL-8,
macrophage colony-stimulating factor, and
lymphotoxin, as well as superoxide and nitric
oxide(NO).
Occurence of systemic manifestations such as headache, fever
and rigors, nausea and vomiting, diarrhea, anorexia, tiredness,
aching joints and muscles, thrombocytopenia, immunosuppression,
coagulopathy, and central nervous system manifestations
Hemozoin Induce apoptosis in developing erythroid
cells in the bone marrow, thereby causing anemia
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
Induce cox-2-upregulating prostaglandins leading to
the induction of fever

11. PATHOGENESIS – Severe Malaria
In P. falciparum Infection
The red cells infected with late stages of P. Falciparum (during the second half of the 48 hour life cycle)
adhere to the capillary and post capillary venular endothelium in the deep microvasculature (cytoadherence)
Cytoadherence leads to the adherence of infected RBCs (IRBC) to endothelial cells in the microcirculation of
various organs such as the heart, lung, brain, liver, kidney, intestines, adipose tissue, subcutaneous tissues,
and placenta. (Sequestration; which allows them to escape clearance by the spleen and to hide from the
immune system).
The IRBCs then o adhere to the uninfected red cells, resulting in the formation of red cell rosettes (Rosetting)
Unbridled multiplication increases the parasite load.
Uninhibited cytoadherence-rosetting-sequestration of infected and uninfected erythrocytes in the vital organs
results in blockage of blood flow, limits the local oxygen supply, hampers mitochondrial ATP synthesis, and
stimulates cytokine production – all these factors contributing to the development of severe disease.
The released toxins causes
stimulation of innate response
and uncontrolled production of
inflammatory mediators
Tissue damage
IRBC and RBC become more
rigid
Rupture of late stage infected
erythrocytes
Multifactorial Anemia; Reduced
Gluconeogenesis And Hypoglycemia;
Myocardial Depression And Cardiac
Insufficiency; Loss Of Endothelial
Integrity And Vascular Damage In
The Lungs And Brain; Cerebral
Malaria

12. DIAGNOSIS
LABORATORY DIAGNOSIS
 Conventional microscopic diagnosis by staining thin and thick
peripheral blood smears
 Quantitative Buffy Coat (QBC) Method
 Rapid diagnostic tests (RDTs)
 Serological tests
 Immunofluorescence antibody testing (IFA)
 Molecular Techniques
 PCR technique
CLINICAL DIAGNOSIS
Based on the patient’s symptoms
and on physical findings at examination.
The initial symptoms (most often fever, chills,
sweats, headaches, muscle pains, nausea and
vomiting) and physical findings (elevated
temperature, perspiration, tiredness) of malaria
are often non specific and are also found in other
diseases
In severe malaria (primarily caused
by Plasmodium falciparum), clinical findings
(confusion, coma, neurologic focal signs, severe
anemia, respiratory difficulties) may increase the
index of suspicion for malaria.
**Clinical findings should always be
confirmed by a laboratory test for
malaria**

13. Microscopic diagnosis using stained thin and thick peripheral blood smears (PBS)
NOTES “
To prepare a thick blood film - a blood spot is stirred in a circular motion with
the corner of the slide and allowed to dry without fixative. After drying, the spot is
stained with diluted Giemsa (1 : 20, vol/vol) for 20 min, and washed by placing the
film in buffered water for 3 min. The slide is allowed to airdry in a vertical position
and examination using a light microscope
A thin blood film - Prepared by immediately placing the smooth edge of a spreader
slide in a drop of blood. The film is then allowed to air-dry and is fixed with absolute
methanol. After drying, the sample is stained with diluted Giemsa (1 : 20, vol/vol)
for 20 min and washed by briefly dipping the slide in and out of a jar of buffered
water (excessive washing will decolorize the film). The slide is then allowed to air-
dry in a vertical position and examined under a light microscope
Enable visualization of malaria
parasites.
The patient’s finger is cleaned with
70% ethyl alcohol, allowed to dry and
then the side of fingertip is picked
with a sharp sterile lancet and two
drops of blood are placed on a glass
slide.

14. QBC Technique
• The QBC technique was designed to enhance
microscopic detection of parasites and simplify
malaria diagnosis
• Rapid and sensitive test
• It involves staining parasite deoxyribonucleic acid
(DNA) in micro-hematocrit tubes with fluorescent
dyes, e.g. acridine orange, and its subsequent
detection by epi-fluorescent microscopy.
• Procedure - finger-prick blood is collected in a
hematocrit tube containing acridine orange and
anticoagulant. The tube is centrifuged at 12,000 g
for 5 min and immediately examined using an epi-
fluorescent microscope. Parasite nuclei fluoresces
bright green, while cytoplasm appears yellow-
orange.
Rapid diagnostic tests (RDTs
• Developed by WHO
• New, simple, quick, accurate, and cost-
effective diagnostic tests for determining
the presence of malaria parasites, to
overcome the deficiencies of light
microscopy, and other malaria-diagnostic
techniques
• Detect malaria antigen in blood flowing
along a membrane containing specific anti-
malaria antibodies

15. Serological tests
• Usually based on the detection of antibodies
against asexual blood stage malaria parasites
• Used method - Immunofluorescence antibody
testing (IFA)
o Simple and sensitive, but time-consuming
o Infection with Plasmodium species, can result
production of specific antibodies within 2 wk of
initial infection, and persist for 36 months after
parasite clearance. IFA uses specific antigen or
crude antigen prepared on a slide, coated and kept
at -30℃until used, and quantifies both IgG and IgM
antibodies in patient serum samples.
Titers > 1 : 20 are usually deemed positive,
Titers < 1 : 20 unconfirmed.
Titers >1 : 200 can be classified as recent
infections
PCR technique
• Used extensively to confirm malaria
infection, follow-up therapeutic response,
and identify drug resistance
• More sensitive than QBC

16. TREATMENT
TREATMENT OF UNCOMPLICATED PLASMODIUM
FALCIPARUM MALARIA
• Artemisinin combination therapy (ACT)-
drug of choice for all confirmed cases of
uncomplicated PF cases.
• The ACT recommended in the National
Program in India is artesunate (AS) +
sulfadoxine and pyrimethamine (SP).
• Other ACTs can also be used. Oral AS
monotherapy is banned in India.
Artemisinin combination therapy for adults

17. TREATMENT OF UNCOMPLICATED PLASMODIUM
VIVAX MALARIA
 Chloroquine (drug of choice) - 10 mg/kg (600
mg) on day-1 and day-2 and 300 mg on day-3.
 Primaquine at a dose of 0.25 mg/kg (15
mg/day) for 14 days is to be added to prevent
relapse.
Treatment of uncomplicated PF cases in
pregnancy:
Quinine is the drug of choice in the first
trimester, in a dose of 10 mg/kg for 8 hourly
orally for 7 days. But, in the second and third
trimester ACT is recommended

18. TREATMENT OF SEVERE PLASMODIUM FALCIPARUM
MALARIA
 Parenteral artemisinin derivative or quinine should
be promptly given to prevent death
Artesunate (drug of choice):
 It should be given in a dose of 2.4 mg/kg IV on
admission (0 hour), then at 12 hours and 24 hours
and then once daily till the patient takes orally or
for 7 days. Then, they should get full course of ACT
for 3 days.
Quinine
Alternative to AS.
Given at a dose of 20 mg quinine salt/kg of body weight in 5%
dextrose/ dextrose saline, over 4 hours, on admission.
It is followed by 10 mg/kg of body weight, 8 hourly infusions which
should be started 8 hours after the 1st loading dose. The infusion rate
should not exceed 5 mg/kg of body weight/hour. Initial loading dose
should not be given if patient has already taken quinine.
If quinine therapy is used beyond 48 hours, the dose should be reduced
to 7 mg/kg of body weight 8 hourly till patient takes orally. Then, he
should be given oral quinine in a dose of 10 mg/kg of body weight 8
hourly to complete 7 days of therapy.
Doxycycline in a dose of 3 mg/kg of body weight per day for 7 days is
to be added when the patient starts taking orally.
Doxycycline is contraindicated in pregnancy and children below 8 years
of age. In those cases, instead of doxycycline, clindamycin is to be given
in a dose of 10 mg/kg of body weight 12 hourly for 7 days

19. MALARIA TREATMET ALGORITHM

20. CHEMOPROPHYLAXIS
Long-term Prophylaxis (> 6 Weeks)
Mefloquine: 250 mg weekly (5 mg/kg of body weight/week)
to be started 2 weeks before going to the affected area and
continued for 4 weeks after leaving the affected area.
It is contraindicated in cases with history of convulsions,
neuropsychiatric problems and cardiac conditions
Short-term Prophylaxis (< 6 Weeks)
Doxycycline: 100 mg/day (1.5 mg/kg of body weight
per day) to be started 2 days before and continued 4
weeks after leaving a malarias area.
It is not recommended for pregnant and lactating
women and children below 8 years of age.

21. Travellers and their advisers should note the four principles – the ABCD – of malaria protection:
PRECAUTIONS

22. PREVENTION

23. Malaria Vaccine
So far, three types of vaccine candidates have been intensively investigated:
Pre-erythrocytic vaccines to prevent blood-stage infection;
Blood-stage vaccines to clear parasitaemia and prevent clinical disease
Transmission-blocking vaccines to prevent infection of mosquitoes and interrupt malaria
transmission in populations
The only approved vaccine as of 2021 is RTS,S, known by the brand name Mosquirix. It
requires four injections, and has a relatively low efficacy
Vaccines under trial are - RTS,S/AS01, falciparum sporozoite vaccine(PfSPZ), vivax
malaria protein 1 (VMP001/AS01B), cell-traversal protein for ookinetes and
sporozoites (CelTOS) [FMP012/ GLA-SE or AS01]

24. REFERENCES
1. Global Health, Division of Parasitic Diseases and Malaria
2. Centre for Disease Control and Prevention – Malaria
3. Guidelines for the treatment of malaria, second edition. Geneva, World Health Organization, 2010.
4. Malaria vector control and personal protection: report of a WHO Study Group. Geneva, World
Health Organization, 2006 (WHO Technical Report Series, No. 936).
5. Joseph T. DiPiro et al.,Pharmacotherapy- A Pathophysiological Approach;7 th edition.
6. Dejen Nurey et al., Old and Recent Advances in Life Cycle, Pathogenesis, Diagnosis, Prevention,
and Treatment of Malaria Including Perspectives in Ethiopia. Scientific World Journal;Volume
2020