Malaria is a vector borne disease and a leading cause of mortality throughout the world mainly in third world countries.

1. Malaria
Dr. Kamala Sanjel
Internal medicine Resident
NAMS

2. Contents
• Introduction
• Epidemiology
• Pathogenesis
• Clinical Features
• Diagnosis
• Treatment
• Prevention

3. Introduction
• Malaria: Italian: Mala aria, literally "bad air,
• A protozoal disease transmitted by the bite of infected
female Anopheles mosquitoes.
• Overwhelming problem in tropical developing countries
• Nearly 40% of the world’s population is at risk for acquiring malaria
• However Mortality rates have decreased dramatically over the past
15 years as a result of highly effective control programs in several
countries after introduction of chloroquine.

4. Epidemiology
• Malaria is endemic throughout most of the tropics, ongoing
transmission occurs in 85 countries and territories .
• The World Health Organization (WHO) reported 241 million cases
and 627 thousand deaths from malaria in 2020.
• Over 95 percent of the burden occurs in the African region of the
World Health Organization, followed by 2 percent each in the South
East Asian and Eastern Mediterranean regions.

5. In Nepal
• Malaria remains a public health priority in Nepal and the country is set for
malaria elimination by 2025
• The malaria disease distribution has decreased significantly, 1,187 total malaria
cases recorded in 2017/18, and distribution is more towards the far-west region
of the country as seen in the recent malaria microstratification 2018.
• Plasmodium vivax is the predominant species in Nepal and P. falciparum is the
other important species.
• P. vivax: increasing from 71 % in 2010 to 95 % in 2018
• P. falciparum: on the decline from around 29 % in 2010 to 5 % in 2018
• P. malariae has not been detected for long time (more than20 years)
• P. ovale has been reported from the private sector among patients returning from
Africa

6. Pathogen
• Plasmodium parasites belong to the Apicomplexa group of protozoa,
which includes other pathogens, such as Babesia, Toxoplasma, and
Cryptosporidium species.
• Four Plasmodium species are classified as human malaria parasites:
P. falciparum, P. vivax, P. ovale, and P. Malaria
• Some malaria parasites of other primates (e.g., P. knowlesi, P.
cynomolgi, and P. simium) can also infect humans under natural
conditions.

7. Pathogen
• P. knowlesi,a natural pathogen of macaque monkeys, has been
proposed to be a “fifth human malaria parasite” responsible for
significant morbidity and mortality in Malaysia
• Two morphologically identical sympatric species of P. ovale (curtisi
and wallikeri)
• While almost all deaths are caused by falciparum malaria,
P. knowlesi and occasionally P. vivax can also cause severe illness.

8. Pathogen
• P. falciparum and P. vivax infections account for most cases of human
malaria.
• P. falciparum and P. malariae are found worldwide.
• P. vivax is infrequent in most of sub-Saharan Africa but is common
elsewhere.
• P. ovale occurs in Africa and in foci within Asia and Oceania and is
often present with other Plasmodium species as a mixed infection.

9. Vector
• Anopheles gambiae and Anopheles funestus transmit malaria with
notoriously high efficiency and are the predominant vectors in sub-
Saharan Africa.
• Bite occurs mainly between dusk and dawn.
• Highest levels of transmission typically occur during the wet season in
endemic areas.
• Malaria may also be acquired from needles shared among drug users,
blood transfusion,or solid-organ transplantation and as congenital
infection.

10. Host
• Groups at highest risk include young children (6 to 59 month) and
pregnant women.
• Older children and adults develop partial immunity after repeated
infections and are at relatively low risk for severe disease.
• Travelers to malarious areas who generally have had no previous
exposure to malaria parasites or have lost their immunity if they left
the endemic area are at very high risk for severe disease if infected
with Plasmodium falciparum.

11. CHARACTERISTIC
FINDING FOR INDICATED
SPECIES
P. FALCIPARUM P. VIVAX P. OVALE P. MALARIAE P. KNOWLESI
Duration of
intrahepatic
phase (days)
5.5 8 9 15 5.5
Erythrocytic
cycle (hours)
48 48 50 72 24
Red cell
preference
Younger cells (but can
invade cells of all ages)
Reticulocytes and
cells up to 2 weeks
old
Reticulocytes Older cells Younger cells
Morphology
Usually only ring
forms; banana-shaped
gametocytes
Irregularly shaped
large rings and
trophozoites;
enlarged
erythrocytes
Schüffner’s dots
Infected
erythrocytes,
enlarged and oval
with tufted ends;
Schüffner’s dots
Band or rectangular
forms of trophozoites
common
Resembles P.
falciparum
(early trophozoites)
or P. malariae (later
trophozoites,
including
band forms)
Ability to cause
relapses
No Yes Yes No No

13. Life cycle

14. Life cycle
• Sporozoites are the infective form,are injected by infective mosquito
• The injected sporozoites typically take several hours to travel through
dermal tissues and migrate across host cell barriers before they enter blood
and lymphatic systems and are carried to the liver.
• Sporozoites must first invade and replicate in hepatocytes before they can
differentiate into merozoites capable of entering the intra-erythrocytic
cycle.
• All P. falciparum and P. malariae parasites complete their liver-stage
development in about 1 to 2 weeks.
• P. vivax and P.ovale liver stages also can develop promptly or can remain
latent as hypnozoites in the liver for months to years before emerging to
produce relapses of malaria.

15. Life cycle
• Once a merozoite egresses by protease activity from its host
hepatocyte (or from its host erythrocyte in the bloodstream cycle),it
engages loosely with an uninfected erythrocyte and then reorients so
that its apical end faces the cell surface.
• An envelope of invaginated membrane surrounds the merozoite as it
enters, forming the parasitophorous vacuole once invasion is
complete.
• A number of studies have also established a dependence of P. vivax
merozoites on interaction with erythrocyte Duffy antigen receptor for
chemokines (DARC).

16. Life cycle
• Within erythrocytes, merozoites develop from ring forms into
trophozoites and then schizonts over 24 hours (P. knowlesi), 48 hours
(P. falciparum, P. vivax, and P. ovale), or 72 hours (P. malariae).
• After breaking down their host cell membrane by enzymatic
digestion, 24 to 32 merozoites enter the bloodstream and are each
capable of infecting a new erythrocyte.
• Parasites in the bloodstream reproduce asexually in the haploid state.
During erythrocytic development, a small minority of parasites
undergo a switch to sexual-stage development.

17. Life cycle
• The resulting male and female gametocytes are the forms that are taken up
by and infect female anopheline mosquito.
• Gametocytes emerge from erythrocytes in the mosquito midgut as male
and female gametes that cross-fertilize to form diploid zygotes, which in
turn differentiate into ookinetes that burrow through the midgut wall.
• Each ookinete develops into an oocyst containing up to 1000 sporozoites,
which emerge and are then carried by the insect hemolymph to invade the
salivary glands.
• These processes in the mosquito require an incubation period of about 1 to
2 weeks.
• Female mosquitoes inject sporozoites into humans while taking a blood
meal.

18. Pathogenesis
• Cycles of invasion and growth in erythrocytes produce a parasite
biomass that enlarges rapidly, causing fever and leading to pathologic
processes, such as erythrocyte loss (anemia), sequestration of
infected erythrocytes in microvascular beds (cerebral malaria), and
adverse sequelae of inflammatory cascades and cytokine release.
• Although P. vivax can cause serious and fatal illness, by far the largest
fraction of deaths directly attributable to malaria are caused by
severe complications of P. falciparum infection, including cerebral
malaria, severe anemia, respiratory distress, renal failure, and severe
malaria of pregnancy.

19. Pathogenesis
• Erythrocytic Changes:malarial parasite consumes and degrades
intracellular proteins ie hemoglobin
• Toxic heme is detoxified by lipid-mediated crystallization to
biologically inert hemozoin (malaria pigment).
• Alters the RBC membrane by changing its transport properties,
exposing cryptic surface antigens, and inserting new parasite-derived
proteins and RBC becomes more irregular in shape, more antigenic,
and less deformable.
• Membrane protuberances(knob) appear on the erythrocyte’s surface
12–15h after the cell’s invasion.

20. Pathogenesis
• Membrane adhesive protein (PfEMP1) mediates attachment to
receptors on venular and capillary endothelium (cytoadherence).
• Erythrocytes containing more mature parasites stick inside and
eventually block capillaries and venules.
• These infected RBCs may also adhere to uninfected RBCs (to form
rosettes) and to other parasitized erythrocytes (agglutination).
• Processes of cytoadherence, rosetting, and agglutination are central
to the pathogenesis of falciparum malaria.

21. Pathogenesis
• A (CSA )and endothelial protein C receptor, which is involved in the
deadly sequestration of parasitized erythrocytes leads to cerebral
Malaria
• Infected erythrocytes that bind CSA expressed by
syncytiotrophoblasts sequester selectively in placental tissue and are
responsible for malaria of pregnancy.
• P. falciparum can infect erythrocytes of all ages, promoting heavy
parasite burdens, high parasite densities, increased parasite
multiplication rates and evidence of high parasite.

22. Pathogenesis
• Systemic sequestration of metabolically active parasites, blood cells
and platelets likely contributes to the metabolic acidosis and
thrombocytopenia commonly seen in severe malaria.
• Metabolic acidosis,hypoglycemia, hyperpyrexia, and nonconvulsive
status epilepticus can contribute significantly to the cerebral malaria
presentation, as suggested by the rapid clinical improvement of some
patients after fluid resuscitation,blood transfusion, dextrose infusion,
fever reduction, and anticonvulsant therapy in addition to
antimalarial treatment.

23. Pathogenesis

24. Pathogenesis
Host Response:
• Splenic immunologic and filtrative clearance functions are augmented, and
the removal of both parasitized and uninfected erythrocytes is accelerated.
• Removes damaged ring-form parasites (a process known as “pitting”) and
returns the once-infected erythrocytes to the circulation, where their
survival is shortened.
• The parasitized cells escaping splenic removal are destroyed when the
schizont ruptures and the release of proinflammatory cytokines, which
cause fever with Temperatures of ≥40°C(≥104°F) damage mature parasites.
• In untreated infections, the effect of such temperatures is to further
synchronize the parasitic cycle, with eventual production of the regular
fever spikes and rigors that originally characterized the different malarias.

25. Pathogenesis
• These regular fever patterns (quotidian, daily; tertian, every 2 days;
quartan, every 3 days) are seldom seen today as patients receive
prompt and effective antimalarial treatment.
• Hypoglycemia: In children:hypoglycemia is associated with impaired
hepatic gluconeogenesis and increased consumption of glucose by
hypermetabolic peripheral tissues.
• In adults, hypoglycemia is often associated with hyperinsulinemia
which may result from pancreatic islet cell stimulation by parasite-
derived factors or parenteral quinine or quinidine therapy, or both.

26. Pathogenesis
Anemia:
• multifactorial
• Intravascular lysis and phagocytic removal of infected erythrocytes.
• Excess removal of uninfected erythrocytes be mediated by processes
(e.g., oxidative stress) that accelerate the senescence and reduce the
deformability of erythrocytes.
• Release of inflammatory cytokines (e.g., TNF) is associated with
impaired production of erythropoietin leads to normochromic
normocytic anemia seen in malaria and explain the notable absence
of a robust reticulocyte response.

27. Pathogenesis
• Metabolic (Lactic) Acidosis: reduced delivery of oxygen to tissues
due to combined effects of anemia (decreased oxygen-carrying
capacity), sequestration (microvascular obstruction), and
hypovolemia (reduced perfusion) resulting from fluid losses caused by
fever, decreased oral intake, vomiting, and diarrhea.
• Renal Impairment: erythrocyte sequestration and agglutination
interfering with renal microcirculatory flow and metabolism,
manifests as acute tubular necrosis.
• Liver Dysfunction: Severe jaundice results from hemolysis,
hepatocyte injury, and cholestasis.

28. Pathogenesis
Pulmonary Edema and Respiratory Distress:
• Sequestration of infected erythrocytes in the lungs is thought to
initiate regional production of inflammatory cytokines that increase
capillary permeability, leading sequentially to pulmonary edema,
dyspnea, hypoxia, acute lung injury, and acute respiratory distress
syndrome.
Malaria of Pregnancy:
• Placental malaria results in maternal morbidity and mortality,
intrauterine growth retardation, premature delivery, low birth weight,
and increased newborn mortality infection.
• Placental malaria in subsequent pregnancies is typically less severe
than in the first pregnancy , presumably because of a woman’s
previous exposure to CSA-binding parasites.

29. Genetic Resistance to Malaria
• Hemoglobins S, C, and E:mechanisms of protection, freshly drawn
and infected HbAS and HbAC erythrocytes were found to be impaired
in their adherence to microvascular endothelial cells and monocytes
• Thalassemias: infected thalassemic erythrocytes bind increased
amounts of antibody from both nonimmune and immune sera, which
suggests the possibility of enhanced opsonization
• Glucose-6-PhosphateDehydrogenase Deficiency: Enhanced
phagocytosis of infected G6PD-deficient erythrocytes
• Blood group O,DARC negativity, G6PD Deficiency, Southeast Asian
Ovalocytosis and Hereditary Xerocytosis

30. Clinical Presentation
Uncomplicated malaria
• Uncomplicated malaria typically presents as an undifferentiated febrile
illness.
• Fever (100%); headache (100%); weakness (94%); profuse night sweats
(91%); insomnia (69%); arthralgias (59%); myalgias (56%); diarrhea (13%);
and abdominal cramps (8%).
• Individuals are generally asymptomatic for 12 to 35 days after infection,
but symptoms can commence as early as 7 days (depending on parasite
species).
• Longer incubation periods are more likely in semi-immune individuals and
individuals taking incompletely effective malaria prophylaxis.

31. Clinical Presentation
• Symptoms begin during the erythrocytic stage of the parasite life
cycle, when infected red cells rupture and release merozoites, leading
to fever and other symptoms.
• Malaria presents as an acute febrile illness that is often but not
always characterized by the classic malaria paroxysm.
• Cyclic paroxysms of chills and rigors, followed by fever spikes up to
40°C (104°F), and then profuse sweating that can ultimately give way
to extreme fatigue and sleep is characteristic.
• Febrile paroxysms may occur every other day for P. vivax, P. ovale,
and P. falciparum and every third day for P. malariae

32. Clinical Presentation
• Malaria is not associated with a rash, lymphadenopathy
• A travel history that reveals risk of exposure months to years before in
an endemic region is an alert for malaria and should always be sought
in presentation of fever.
Physical findings
• Pallor-Removal of infected erythrocytes by the stimulated spleen ,
may contribute to anemia
• Mild Jaundice
• Splenomegaly often accompanies malaria and is thought to indicate
an important role of the spleen in parasite clearance.

33. P. vivax and P. ovale
• Infections with P. vivax and P. ovale can be considered similar
• P. vivax infections can be tremendously debilitating and are
sometimes associated with serious complications, including acute
lung injury and splenic pathology.
• Splenic rupture has been associated with acute and chronic infections
and can occur spontaneously or with minor trauma, including manual
examination of the spleen.
• P. vivax merozoites selectively invade reticulocytes.
• Because these cells account for only a small proportion of the total
erythrocyte mass, parasitemias in P. vivax infections are usually less
than 1% even when the pathology of vivax malaria is severe.

34. Plasmodium malariae
• The quartan malaria of P. malariae usually presents with fever and
paroxysms similar to those of P. vivax but with a 3-day rather than 2-
day periodicity.
• P. malariae often establishes parasitemias that are below the level of
detection by microscopy.
• Patients can remain infected and asymptomatic for many years before
presenting with fevers, malaise, and splenomegaly decades after they
have left an endemic area.
• Chronic P. malariae infection can lead to nephrotic syndrome in
young children living in endemic areas.

35. P. knowlesi
• A large focus of human malaria caused by P. knowlesi occurs in
Malaysia, where high case-fatality rates have been reported.
• P. knowlesi is indistinguishable from P. malariae on blood smear
examination, showing both immature and mature forms in the
circulation.
• Unlike P. malariae, however, P. knowlesi replicates every 24 hours and
can cause daily fever spikes and hyperparasitemias that are life
threatening.
• In addition to hyperparasitemia, severe P. knowlesi malaria cases have
been associated with metabolic acidosis, hepatorenal dysfunction,
respiratory distress, severe anemia, and refractory hypotension.

36. Sever Falciparum Malaria
• WHO has established clinical and laboratory criteria for severe P.
falciparum malaria, which must be treated as an emergency requiring
intensive medical care.
• Severe malaria is defined as presence of P. falciparum parasitemia
and one or more of the manifestations of severe malaria and with
reasonable exclusion of an alternative diagnosis.
• Severe complications of P. falciparum infection, including cerebral
malaria, severe anemia, respiratory distress, renal failure, and severe
malaria of pregnancy occurs.

37. Diagnostic features of Severe malaria

38. Severe falciparum malaria
Unarousable
coma/cerebral malaria
Failure to localize or respond appropriately to noxious stimuli; coma persisting for
>30 min after generalized convulsion,GCS <11
Acidemia/acidosis
Arterial pH of <7.25, base deficit >8 meq/L, or plasma bicarbonate level of <15
mmol/L; venous lactate level of >5 mmol/L; manifests as labored deep breathing,
often termed “respiratory distress”
Severe normochromic,
normocytic anemia
(Hb< 5g/dl, packed cell volume < 15% in children; <7g/dl, PCV < 20% in adults)
Renal failure
Serum or plasma creatinine level of >265 μmol/L (>3 mg/dL); urine output (24 h) of
<400 mL for adults or <12 mL/kg for children; no improvement with rehydration
Pulmonary edema/ARDS
Noncardiogenic pulmonary edema, often aggravated by overhydration,(Oxygen
saturation < 92% on room air with a respiratory rate > 30/min,often with chest
indrawing and crepitations on auscultations)
Hypotension/ shock
Systolic blood pressure of <50 mmHg in children 1–5 years or <80 mmHg in adults;
core/skin temperature difference of >10°C; capillary refill >2 s
Convulsions
More than two generalized seizures in 24 h; signs of continued seizure activity,
sometimes subtle (e.g., tonic clonic eye movements without limb or face movement)

39. Severe falciparum malaria
Hemoglobinuria
Macroscopic black, brown, or red urine; not associated
with effects of oxidant drugs and red blood cell enzyme
defects (such as G6PD deficiency)
Bleeding/DIC
Significant bleeding and hemorrhage from the gums, nose,
and gastrointestinal tract and/or evidence of DIC
Hypoglycemia Plasma glucose level of <2.2 mmol/L (<40 mg/dL)
Extreme
weakness
Prostration; inability to sit unaided
Hyperparasitemia
Parasitemia level of >5% in nonimmune patients (>10% in
any patient)
Jaundice
Serum bilirubin level of >50 mmol/L (>3 mg/dL) if
combined with a parasite density of 100,000/μL or other
evidence of vital-organ dysfunction

40. Severe Falciparum Malaria
• Cerebral Malaria is a characteristic and ominous feature
of falciparum malaria and, even with treatment, has been associated
with death rates of ~20% among adults and 15% among children.
• Cerebral malaria is a syndrome characterized by diminished
consciousness, seizures, or both.
• Risk factors for cerebral malaria include age (children and older
adults), pregnancy, poor nutritional status, host genetic susceptibility,
and history of spleenectomy..

41. Cerebral Malaria
• Cerebral malaria manifests as diffuse symmetric encephalopathy;
focal neurologic signs are unusual.
• Some passive resistance to head flexion may be detected, signs of
meningeal irritation are absent
• Muscle tone may be either increased or decreased
• The tendon reflexes are variable, and the plantar reflexes may be
flexor or extensor
• Flexor or extensor posturing may be seen

42. Cerebral Malaria
• 30–40% retinal hemorrhages
• Convulsions: usually generalized but can be subtle, partial motor with
secondary generalisation occur in ~10% of adults and upto 50% of
children with cerebral malaria.
• The incidence of epilepsy is increased and life expectancy
decreased among children.

43. Cerebral Malaria
• Laboratory examination of cerebrospinal fluid (CSF) is generally
normal.
• Cerebral edema and elevated intracranial pressure may contribute to
a fatal outcome.
• A CSF glucose concentration below 3.4 mmol/L (61 mg/dL) was the
best discriminator of cerebral malaria from presumed viral
encephalitis.
• Residual deficits may include hemiplegia, cerebral palsy, cortical
blindness, deafness, epilepsy, language deficit, and impaired
cognition .

44. Biochemistry
Hypoglycemia (<2.2 mmol/L)
Hyperlactatemia (>5 mmol/L)
Acidemia (arterial pH <7.25, base
deficit >8 meq/L, or serum HCO3
<15 mmol/L)
Elevated serum creatinine (>265
μmol/L)
Elevated total bilirubin (>50
μmol/L)
Elevated liver enzymes (AST/ALT 3
times upper limit of normal)
Elevated muscle enzymes (CPK ↑,
myoglobin ↑)
Elevated urate (>600 μmol/L)
Features Indicating a
Poor Prognosis in Severe
Falciparum Malaria
Marked agitation
Hyperventilation
(respiratory distress)
Low core temperature
(<36.5°C; <97.7°F)
Bleeding
Deep coma
Repeated convulsions
Anuria
Shock
Hematology
Leukocytosis
(>12,000/μL)
Severe anemia (PCV
<15%)
Coagulopathy
Decreased platelet
count (<50,000/μL)
Prolonged
prothrombin time
(>3 s)
Prolonged partial
thromboplastin time
Decreased fibrinogen
(<200 mg/dL)
Parasitology
Hyperparasitemia
Increased mortality
at >100,000/μL
High mortality at
>500,000/μL
>20% of parasites
identified as
pigment-containing
trophozoites and
schizonts
>5% of neutrophils
contain visible
malaria pigment

45. Differential diagnosis
• Influenza: Prominent upper respiratory symptoms (rhinorrhea, sore throat,
or dry cough) may help to distinguish influenza from malaria.
• Enteric Fever: Prominent gastrointestinal symptoms (abdominal pain,
constipation or diarrhea), the findings of rose spots or relative bradycardia,
and a history of unsanitary food or water consumption
• Dengue Fever: Myalgias tend to be much more severe than those
experienced during malaria episodes.
• Incubation period is 4-5 days in dengue ,usually more than 7 days in
malaria
• Centrifugal rash, petechiae, lymphadenopathy, conjunctival injection,
pharyngeal erythema, and relative bradycardia

46. Differential diagnosis
• Leptospirosis: findings of conjunctival suffusion or rash but
may progress to hepatic and renal insufficiency marked by hemorrhagic
manifestations and extremely high bilirubin (Weil syndrome)
• Bacteremia/Sepsis:The fever, hypotension, evidence of poor peripheral
perfusion, altered mental status, and multiorgan dysfunction that
characterize bacteremia and sepsis can mimic severe malaria
• Acute Schistosomiasis (Katayama Fever) :generalized urticaria and the
findings of a pruritic rash at the site of cercarial penetration (usually on the
legs), lymphadenopathy, and blood eosinophilia
• Yellow Fever:conjunctival suffusion or relative bradycardia and
short incubation period (average, 3–6 days)

47. Diagnosis
• Thick and Thin Blood Smears
• Thick smears concentrate red cell layers approximately 40-fold and
are used to screen a relatively large amount of blood for the presence
of parasite
• Giemsa-stained thin smears are prepared from a much smaller amount of blood
than thick smears and are used to determine the Plasmodium species
• P. falciparum infection may not be apparent on an initial blood smear if the
parasites are predominantly mature cytoadherent forms (i.e.,trophozoite and
schizont-infected erythrocytes) and are sequestered in the microvasculature
• If the initial blood smear is negative and malaria remains possible, the smear
should be repeated every 12 hours for a total of three sets before ruling out
malaria .

48. Thick blood films of
Plasmodium falciparum. A.
Trophozoites. B. Gametocytes
Thick blood films of Plasmodium
vivax. A. Trophozoites. B.
Schizonts. C. Gametocytes

50. Rapid Diagnostic Tests
• The first type is based on the detection of Plasmodium histidine-rich
protein-2 (HRP-2): had 96% sensitivity and 99% specificity
for Plasmodium infection when compared with microscopy
• The second type of RDT is based on detection of P. falciparum–specific
lactate dehydrogenase (LDH) and pan-Plasmodium LDH:test had 80%
sensitivity and 98% specificity for Plasmodium infection
when compared with microscopy
• Molecular diagnosis by polymerase chain reaction (PCR) amplification of
parasite nucleic acid is more sensitive than microscopy or rapid
diagnostic tests for detecting malaria parasites and defining malarial
species used in making the distinction between recrudescence and re-
infection, as well as in other specialized epidemiological investigations.

51. Treatment
Hospitalization is appropriate for patients in the following categories,
who may deteriorate rapidly
• Young children
• Immunocompromised patients
• Individuals with no acquired immunity (ie, individuals from
nonendemic areas)
• Patients with hyperparasitemia (4 to 10 percent) but no signs of
severe infection such patients are at increased risk for progression to
severe malaria and/or treatment failure.

52. Treatment

53. Treatment
• The 4 major drug classes currently used to treat malaria includes
• Quinoline-related compounds
• Antifolates- sulfonamides, pyrimethamine, proguanil, and dapsone
• Artemisinin derivatives- Artemether, Arteether, dihydroartemisinin,
and Artesunate
• Antimicrobials-Tetracycline, doxycycline and clindamycin

54. Quinoline derivatives
Chloroquine,amodiaquine,quinine, quinidine, mefloquine, primaquine,
lumefantrine, tafenoquine and halofantrine.
Drugs act by accumulating in the parasite food vacuole and forming a
complex with heme that prevents crystallization in the Plasmodium food
vacuole.
• These drugs have activity against the erythrocytic stage of infection;
primaquine also kills intrahepatic forms and gametocytes.
• Tafenoquine is a new drug,is a long-acting 8-aminoquinoline that targets P.
vivax hypnozoites.
• It can be used as single-dose for prevention of P. vivax relapse and for
prophylaxis of malaria, including P. falciparum and P. vivax.

55. Quinoline derivatives
• Side effects of chloroquine include headaches, dizziness, abdominal
discomfort, vomiting, and diarrhea
• The adverse effects of quinine and quinidine include a complex of
symptoms referred to as cinchonism: tinnitus, nausea, headaches,
dizziness, and disturbed vision
• Adverse effects of mefloquine include vomiting and dizziness.
• Mefloquine is contraindicated for individuals with neurologic and
psychiatric disorders.
• Both primaquine and tafenoquine can cause hemolytic anemia in
patients with G6PD deficiency;

56. Artemisinin derivatives-
• The artemisinins are derived from the leaves of the Chinese sweet
wormwood plant, Artemisia annua.
• Artemisinins appear to act by binding iron, breaking down peroxide
bridges, leading to the generation of free radicals that damage
parasite proteins .
• They act rapidly, killing blood stages of all Plasmodium species and
reducing the parasite biomass.
• Artemisinins have the fastest parasite clearance times of any
antimalarial.
• Artemisinins are active against gametocytes.

57. Adverse effects
• Transient neurologic abnormalities, including nystagmus and
disturbances in balance
• Transient neutropenia
• Hypersensitivity reactions
• Possible Teratogenic in first trimester
Artemisinin-based combination therapy combines the highly effective
short-acting artemisinins with a longer-acting partner to protect
against artemisinin resistance and to facilitate dosing convenience.

58. Treatment
• Treatment of uncomplicated P.vivax, P.ovale, P.malariae or P.knowlesi
• First line treatment
The first line treatment is chloroquine (CQ) for 3 days.
Day 1: chloroquine is given at an initial dose of 10 mg base/kg body weight.
Day 2: followed by 10 mg/kg body weight.
Day 3: 5 mg/kg body weight
• Second line treatment
The recommended 2nd line option in Nepal is dihydroartemisinin +
piperaquine (DHA/PPQ)
• DHA/PPQ is given over 3 days : dihydroartemisinin at a dose of 4 mg/kg
bw per day and 18 mg/kg bw per day piperaquine once a day for 3 days

59. • A second line antimalarial (DHA/PPQ) should be used in the following
situations:
• Where a patient does not tolerate or has adverse reactions to the first
line medicine.
• Recrudescence (treatment failure) - reappearance of symptoms and
parasites within 28 days following initial antimalarial treatment of
the 1st line drug
• Suspected chloroquine resistant vivax infection – all cases imported
from areas with chloroquine-resistant infections (Mekong Region,
Countries in South America and Africa, Indonesia, Timor Leste and PNG)
should be considered as potentially CQ resistant and treated with 2nd
line medicine.

60. • Anti-relapse treatment
P. vivax malaria should be treated in children and
adults (except pregnant women, infants aged <6 months, and women
breastfeeding infants <6 months) with a 14-day course of primaquine
at 0.25 mg/kg body weight per day
• Primaquine generates reactive intermediate metabolites that are
oxidant and cause variable haemolysis in G6PD-deficient individuals.
The severity of haemolytic anaemia depends on the dose of
primaquine and on the variant of the G6PD enzyme.

61. Treatment of P. falciparum malaria
• Uncomplicated falciparum malaria
• World Health Organization (WHO) recommends use of artemisinin
combination therapy (ACT) for treatment of uncomplicated P.
falciparum malaria (irrespective of chloroquine sensitivity)
• First line treatment:The first line treatment for falciparum malaria is
artemether + lumefantrine (AL) given over three days and a single dose
primaquine (0.25 mg/kg single dose) on the first day of malaria
treatment to nonpregnant adults and children ≥6 months
• Target dose range of artemether + lumefantrine (AL): Total dose of 5-24
mg/kg -artemether and 29-144 mg /kg lumefamtrine

62. Treatment of P. falciparum malaria
• Second line treatment
• dihydroartemisinin + piperaquine (DHA/PPQ) at a dose of
dihydroartemisinin 4 mg/kg bw per day and 18 mg/kg bw per day
piperaquine once a day for 3 Days and a single dose primaquine.
• A second line antimalarial should be used in the following
situations:
• Patients not tolerating or adverse reactions to the first line medicine.
• Recrudescence (treatment failure) - reappearance of symptoms and
parasites within 28 days following initial antimalarial treatment of the
1st line drug.

63. Severe Falciparum malaria
• The antimalarial medicine recommended for the treatment of severe
malaria is an initial treatment with injectable (IV/IM) artesunate
followed by a full course of AL as soon as the patient is stable enough
and able to tolerate oral medication
• Artesunate
• Recommended Dosage for injectable artesunate:
• Children less than 20kg – artesunate 3.0 mg/kg bw
• Older children and adults – artesunate 2.4mg/kg bw
Dosage regimen - Give 3 parenteral doses of
injection artesunate in the first 24 hours
• first dose on admission (time zero),
• second dose 8 hours after the first dose and
• third dose at 24 hours after the first dose.
• Thereafter every 24 hours until patient is able
to tolerate oral medication

64. Severe Falciparum malaria
• ACTs have a low side effect profile, are potent against all blood stages
(asexual forms) of malaria, and have the most rapid clearance time
relative to other antimalarial drugs.
• Artemisinins should be administered with a second agent that has a
longer half-life than the artemisinin drug.
• Administration of artemisinins alone would result in recrudescence
(treatment failure).
• No ACT has been proven to be superior to any other.

66. Malaria in pregnancy
• ƒ
Non falciparum malaria should be treated with CQ as in non-pregnant
women ,however the use of primaquine to prevent relapse is
contraindicated in pregnancy and lactating mothers
• Chloroquine (25mg/kg) over 3 days to cure the current blood stage
infection, then
• CQ 300mg every week as chemoprophylaxis for the remaining duration of
the pregnancy and until the breastfed baby is up to 6 months of age.
• This is to prevent development of clinical disease by hypnozoites released
intermittently from the liver.
• Once the breastfeed baby is older than 6 months of age, the mother should
receive a 14 course of primaquine to ensure radical cure.

67. Falciparum malaria in pregnancy
• Uncomplicated Falciparum malaria is treated in pregnant women all
trimesters and lactating mothers with the first line ACT (AL) as in non-
pregnant women.
• During the first trimester, the World Health Organization (WHO)
recommends treatment of uncomplicated P. falciparum malaria
with quinine plus clindamycin for seven days
• ACT in second and third trimester.
• Complicated falciparum malaria -Parenteral artesunate is the
treatment of choice in all trimesters.

68. MALARIA PREVENTION
• PERSONAL PROTECTION AGAINST MALARIA:
• avoidance of exposure to mosquitoes at their peak feeding times
(usually dusk to dawn)
• the use of insect repellents containing 10–35% DEET (or, if DEET is
unacceptable, 7% picaridin),
• Suitable clothing, and ITNs or other insecticide-impregnated
materials.

69. CHEMOPROPHYLAXIS
Administration of a medicine, at predefined intervals, to prevent either
the development of an infection or progression of an infection to
manifest disease.
• The choice of prophylaxis depends on the several factors including
the species, resistant profile to antimalarial medicine in the
destination country
• Mefloquine:250 mg (one tablet) once per week.
• It is preferable to start 2–3 weeks before arrival in the malaria-risk
area to achieve higher pre-travel blood levels and to allow side effects
to be detected before travel so that possible alternatives can be
considered
• Continue the drug for 4 weeks after leaving malaria-risk zone

70. CHEMOPROPHYLAXIS
• Minor side effects (fairly common): Headache, nausea, dizziness,
sleep
disturbance, anxiety, vivid dreams, visual disturbance. Do not usually
require stopping the drug.
Rare side effects: Seizures, depression, psychosis.
Stop the drug if serious ADR occur.
• Can be used in pregnancy

71. Doxycycline: 100 mg once daily. Should be taken at same time each day
• Begin 1 or 2 days before arrival in the malaria-risk and Continue for 4
weeks after leaving malaria-risk area
• Minor side effects (fairly common): Sun sensitivity, vaginal yeast
infection, nausea, gastro-esophageal reflux
• Contraindications: <8yr,pregnancy
Atovaquone/Proguanil (Malarone):250 mg/100mg
• Should be started 1-2 days prior to travel and continued for 1 week
after the visit to the malaria-risk area
• rare side effects but high cost
Chloroquine: 300 mg base weekly in 1 dose.
• Start 1 week before departure and continue for 4 weeks after return
• Recommended for prophylaxis to areas with only vivax transmission

72. Vaccination
• RTS,S/ASO1 vaccine:WHO approved the RTS,S vaccine in October 2021 for
children in Sub-Sahara Africa and other regions with high transmission
• "RTS" stands for "repeat T epitopes" derived from the circumsporozoite
protein, "S" stands for the S antigen derived from hepatitis B surface
antigen (HBSAg), and AS01 is a proprietary adjuvant
• recombinant fusion protein created based on an antigen target consisting
of a repetitive sequence of four amino acids in the circumsporozoite
antigen on the surface of the P. falciparum sporozoite
• 4 doses in children from 5 months of age
• R21/MM vaccine:the R21 vaccine is a virus-like particle based on the
circumsporozoite protein from P. falciparum strain NF54, fused to the N-
terminus of HBsAg; it is manufactured using Matrix-M, a proprietary
adjuvant

73. • Recrudescence occurs most often within days or weeks
• Relapse occurs within weeks or months.
• In recrudescence, parasites remain in the bloodstream undetected due to
ineffective treatment or host immunological response (or both).
• In relapse, new blood stage parasites are released from dormant parasite
stages (hypnozoites) in liver cells, causing a repeat episode of peripheral
parasitemia.
• P. falciparum is the usual cause of recrudescent infection, although P.
malariae can remain present at low levels of parasitemia for years prior to
clinical presentation.
• P. vivax and P. ovale may cause relapse months after the primary blood
stage infection is cured, as these species have hypnozoite forms.

74. HIV and malaria
• HIV and malaria often coexist.
• HIV infection is associated with increased susceptibility to malaria,
higher parasitemia, and increased risk for recurrent malaria infection,
particularly in patients with CD4 counts <200 cells/microL.
• HIV and malaria independently lead to anemia. Coinfection may be
associated with anemia of greater severity among children P.
falciparum infection in children.
• In addition, malaria infection in patients with HIV infection has been
associated with more rapid CD4 cell decline relative to patients with
HIV infection in the absence of malaria.

75. • References
• Mandell, Douglous Principle of practice of infectious disease
• Harrison Principle of Medicine
• National Guideline of Nepal

76. Thank You