1. Malaria is a major global health problem caused by Plasmodium parasites and transmitted via mosquito bites. P. falciparum causes the most severe and potentially fatal form of the disease. 2. Accurate diagnosis of malaria species and parasite load is important for guiding treatment. Standard diagnosis methods include microscopy of blood smears and rapid diagnostic tests detecting malaria antigens. 3. Severe malaria is a medical emergency defined by danger signs such as cerebral malaria, jaundice, severe anemia, respiratory distress, or low blood sugar, and requires prompt parenteral treatment with artemisinin derivatives like artesunate or quinine.

1. MALARIA
MD III

2. Malaria - introduction
• Malaria is a major global health problem
– 40% of the world’s population (> 3.3 billion people)
are at risk for malaria to varying degrees in countries
• Malaria transmission still occurs in 99 countries
– malaria caused an estimated 655 000 deaths in 2010

4. The Human malaria species
• P. falciparum
• P. vivax
• P. ovale
• P. malariae
• P. knowlesi

5. Malaria - introduction
• P. falciparum is common in the tropics and causes
the most serious form of the disease.
– Infections with P. falciparum can be fatal in the
absence of prompt recognition of the disease and its
complications.
• Resistance of parasites to anti malaria agents
continues to be a threat to malaria control and
elimination efforts globally

6. The life cycle
• The malaria parasite has a complex, multistage
life cycle occurring within the vector mosquitoes
and the vertebrate hosts
• The parasite passes through several stages of
development such as the sporozoites = seeds;
the infectious form injected by the mosquito),
merozoites (the stage invading the erythrocytes),
trophozoites (nourishment; the form multiplying
in erythrocytes), and gametocytes (sexual
stages).

7. The life cycle
• Plasmodium sporozoites injected by an
infected mosquito migrate to the liver and
initiate the hepatic stage by invading
hepatocytes within which they multiply and
differentiate into schizonts containing
thousands of hepatic merozoites.
• Merozoites are subsequently released into the
blood where they initiate the erythrocytic
stage by invading and replicating within RBCs.

8. The life cycle
• Some of these asexual blood parasites
differentiate into gametocytes that will ensure
parasite transmission to the mosquito vector.
• P. vivax and P. ovale show a slightly different
life cycle within the mammalian host, as some
sporozoites once in the liver do not develop
immediately into schizonts, but remain at an
uninucleate stage, in a quiescent form named
hypnozoite, causing relapses weeks, months or
even years after the primary infection.

9. Life cycle of plasmodium

10. Diagnosis of Malaria
• Accurate diagnosis of malaria is critical for
implementation of appropriate treatment to
reduce associated morbidity and mortality.
• Epidemiological screening and surveillance to
inform malaria control strategies
• Research purposes in testing efficacy of
antimalarial drugs and vaccines, and for blood
bank screening.

11. Importance of parasitological diagnosis
– Improved pt care in parasite +ve pts owing to
greater certainty that the patient has malaria.
– Identification of parasite-negative patients in
whom another dx must be sought.
– Prevention of unnecessary exposure to anti-
malarial, thereby reducing side-effects, drug
interactions and selection pressure.
– Improved health information.
– Confirmation of treatment failures.

12. PARASITE-BASED DIAGNOSIS
• Confirmation of parasitemia should be pursued
whenever malaria is suspected clinically
LIGHT MICROSCOPY
• Giemsa-stained blood smears is the std tool for
dx of malaria and remains the most common
onsite diagnostic method
• Identification of the Plasmodium spp as well as
quantification of parasitemia.
• It also enables diagnosis of hematologic
abnormalities and other infectious diseases such
as filariasis, trypanosomiasis,

13. PARASITE-BASED DIAGNOSIS
• There might be a discrepancy between
peripheral parasitemia and severity
• Parasite density and prognosis varies with
background level of immunity

14. ANTIGEN BASED DIAGNOSIS
• Rapid diagnostic tests
– important diagnostic tools in RLS due to their
accuracy and ease of use.
– They require no electricity or laboratory
infrastructure
– give results within 15 to 20 minutes
• RDTs provide a qualitative result but cannot
provide quantitative information regarding
parasite density

15. Antigen based diagnosis - mRDTs
• mRDTs detect one or more of the following
antigens:
– Histidine-rich protein 2 (HRP2)
– Plasmodium lactate dehydrogenase (pLDH)
– Aldolase.

16. Why is falciparum malaria so malignant?
• Each cycle releases 20 times more merozoites
than other spp
• Multiple infestation of RBC
• Invade RBCs of all ages (young and old)
• Early hemolysis and endotoxin release, cerebral
toxicity
• Bilirubin load affects kidneys and liver
• Hypovolemia and shock may occur

17. Treatment of uncomplicated
falciparum malaria
• Acute falciparum malaria presents as a
continuum from mild to severe disease.
• The severity of disease dictates the approach
to therapy.
• Uncomplicated malaria consists of
symptomatic malaria parasitemia < 5 %
without evidence of vital organ dysfunction,
with the ability to take oral therapy.

18. Treatment of uncomplicated
falciparum malaria
• Treatment of uncomplicated malaria consists
of oral therapy with a combination of two
agents.
• The goal of this strategy is to forestall the
development of further antimalarial resistance
and protect the agents that are presently
effective.

19. Artemisinin-based Combination
Therapy (ACT)
• ACT is an antimalarial combination therapy
with an artemisinin derivative as one
component of the combination given for at
least 3 days
• Artemisinin derivatives (artesunate,
artemether, artemotil, dihydroartemisinin)
• Artemisinin and its derivatives are rapidly
eliminated from the body

20. Rationale For Anti-malarial
Combination Therapy
• In the event that a mutant parasite that is
resistant to one of the drugs the parasite will
be killed by the other drug.
• This mutual protection is thought to prevent
or delay the emergence of resistance.
• To realize the two advantages, the partner
drugs in a combination must be independently
effective.

21. Why Artemisinins
• Short half-life; hence good for combination
• Rapid substantial reduction of the parasite
biomass
• Rapid resolution of clinical symptoms
• Effective action against multi-drug resistant P.
falciparum
• Reduction of gametocyte carriage
• No documented parasite resistance yet
• Few reported adverse effects.

22. ACTs
• Artemisinin and its derivatives are eliminated
rapidly from the body.
• ACTs reduce gametocyte carriage markedly,
and therefore reduce transmission.
• ACTs currently in use:
– Artemether + lumefantrine
– artesunate + amodiaquine
– artesunate + mefloquine
– artesunate + sulfadoxine–pyrimethamine.

23. Artemether/Lumefantrine
• Effective schizonticidal and gametocidal drug
• Short half life 2 - 6 hours
• Interferes with the conversion of Haem to non
toxic hemozoin in the parasite
Lumefantrine
• Schizonticidal
• Half life 3-6 days
• Acts on the food vacuole of parasite
• Inhibition of Nucleic acid and protein
synthesis in the parasite

25. Severe malaria
Convulsions
Impaired level of consciousness
Prostration: Inability to sit, stand or walk without support
Acidosis Base deficit of > 8 mEq/L OR
Plasma bicarbonate levels < 15 mmol/L OR
Venous plasma lactate ≥ 5 mmol/L
Clinically - severe acidosis manifests as respiratory distress (rapid, deep,
labored breathing)
Hypoglycemia Blood or plasma glucose < 2.5 mmol/L (45mg/dl)
Renal impairment Serum Creatinine > 265 µmol/L or BUN > 20 mmol/L
Jaundice serum bilirubin > 50 µmol/L (3mg/dl) with a parasite count of > 100,000µL
Pulmonary edema Radiological confirmed or SaO2 < 92% on room air with RR > 30/min, often
with chest in drawing and crepitations on auscultation.
Severe malarial anemia Hb ≤ 7 g/dl with parasite count > 100,000µL
Significant bleeding Including recurrent or prolonged bleeding
Shock Decompensated shock SBP < 80 with evidence of impaired perfusion (cool
peripheries, or prolonged capillary refill > 3 seconds)
Hyper-parasitemia P. falciparum malaria of > 10%
It is a medical emergency defn as one or more of the following, occurring in the
presence of P. falciparum asexual parasitemia and in the absence of an identified
alternative cause.

26. Pathogenesis of cerebral malaria
- Mechanical -
• Sequestration of RBCs in cerebral
capillaries/venules
– Parasite growth is promoted in the relatively
hypoxic environment
– Parasite evades destruction by the reticular
endothelial system
• This results in critical reduction in supply of
metabolic substrates to the brain
– Aggravated by anemia, hypoglycemia, seizures,
increased metabolism

27. Mechanisms of sequestration of RBCs
- mechanical -
• Cytoadherence
– Adhesion of infected erythrocytes to endothelium
of capillaries/venules
– Mediated by proteins encoded by the highly
variable,var, genes of the parasite
• Parasite ligand, P falciparum erythrocyte membrane
protein-1, PfEMP-1
• Endothelial receptors, CD36, E-selectin,Chondrotin
sulphate

28. Mechanisms of sequestration of RBCs
- mechanical -
• Rosetting
– Binding of infected erythrocytes to non infected
erythrocytes
• Blood group O protects against severe malaria through
reduced rosetting
• Platelet mediated clumping
– Platelet micro particles attaching to infected
erythrocytes

29. Pathogenesis of severe malaria

30. Antimalarial agents
• There are two major classes of drugs available
for parenteral treatment of severe malaria:
– Cinchona alkaloids (quinine and quinidine)
– Artemisinin derivatives (artesunate, artemether)

31. Artesunate
• Artesunate is the most rapidly acting of the
artemisinin compounds because of its water
solubility.
• The standard dosing regimen
– The powder for injection should be reconstituted
with 5% NaHCO₃ and diluted in an equal volume
of physiological saline or 5% (w/v) glucose.
– It should be administered immediately by either iv
or im injection.

32. Artesunate dosage
• The recommended dose of artesunate for severe
malaria is 2.4 mg/kg at time 0, 12, and 24 h then
daily once a day.
• One vial contains artesunate 60 mg
– For easy practice, number of vials for injection
artesunate for severe malaria can be used, eg. 2 vials
for 26-50 kg, 3 vials for 51-75 kg and 76-100 kg body
weight respectively

33. Artesunate dilution
• Before injection, artesunate dissolved with
sodium bicarbonate should be diluted in 0.9%
NaCl or 5% Dextrose sol.
• For IV route
– artesunate solution should be made to concentration
10 mg/ml and rounded up to the next whole number,
e.g. dose in ml needed for 60 kg patient is
2.4×60/10=14.4 ml which can be rounded up to 15 ml.

34. Artesunate dilution
• For IM route
• artesunate solution should be made to
concentration 20 mg/ml and rounded up to the
next whole number, e.g. dose in ml needed for
60 kg patient is 2.4 ×60/20=7.2 ml which can be
rounded up to 8 ml

35. Quinine
• Quinine can act as pancreatic secretagogues,
leading to hyperinsulinemic hypoglycemia.
– Other toxic effects include tinnitus, reversible
hearing loss, nausea, vomiting, dizziness, and
visual disturbances.

36. Treatment: Severe Malaria
1st line: Artesunate 2.4mg/kg IV or IM given on admission, then at 12 hours, then at 24 hours.
After 24hrs change to ACT if the patient can take oral, if not parenteral Artesunate should
continue OD for a maximum of 7 days.
(Given in 5% dextrose IV/IM concentration 10 mg/ml and 20mg/ml rounded up to the next whole
number respectively, IV at a rate of 3-4ml/min)
If Artesunate is not available, use Artemether in preference to quinine:
3.2 mg/kg as a loading dose by intramuscular injection, followed by 1.6 mg/kg daily until the
patient is able to tolerate oral medication or for a maximum of 7 days.
IV Quinine 10mg/kg up to 600mg IV every 8 hours, given in 500mls of 5% dextrose. Must infuse
very slowly (over 4 hours), can cause hypotension
May cause hyper-Insulinemic hypoglycemia, especially during pregnancy, QT prolongation,
arrhythmias, and ototoxicity
Reduce dose by 1/3 after 48 hours in cases of renal or hepatic impairment
Quinine is safe to use in pregnancy, during all trimesters
Increased risk of hypoglycemia during pregnancy; monitor the RBG
Once PO administration is appropriate, continue Quinine TDS dosing for 7-10 days
Control Microscopy: Should be done at 24, 48 and 72hrs