Malaria

1. MALARIA
PROTOZOAL INFECTIONS

2. Laveran

5. Malaria remains the world's most devastating
human parasitic infection. Malaria affects over
40% of the world's population. WHO,
estimates that there are 350 - 500 million
cases of malaria worldwide.In India 2 million
cases and 1000 deaths annually

7. The malaria life cycle is a complex system with both sexual and asexual aspects .
cycle of all species that infect humans is basically the same. There is an exogenous
sexual phase in the mosquito called sporogony during which the parasite
multiplies. There is also an endogenous asexual phase that takes place in the
vertebrate or human host that is called schizogeny

8. A complex Life cycle

9. Human Cycle
1 Pre erythrocytic
schizogony
2 Erythrocytic
Schizogony
3 Gametogony
4 Exoerythrocytic
schizogony

10. Events in Humans start with Bite of
Mosquito
 Man – Intermediate
host.
 Mosquito – Definitive
host
– Sporozoites are
infective forms
 Present in the salivary
gland of female
anopheles mosquito
 After bite of infected
mosquito sporozoites are
introduced into blood
circulation.

11. Pre erythrocytic cycle
 Sprozoites undergo
developmental phase in
the liver cell
 Multiple nuclear divisions
develop to Schozonts
 A Schizont contains
20,000 – 50,000
merozoites.

12. Period of Pre erythrocytic cycle
 1 P.vivax 8 days
 2 P.falciparum – 6 days
 3 P.malariae - 13 – 16 days,
 4 P.ovale 9 days
On maturation Liver cells ruputure
Liberate Merozoites into blood stream

13. Erythrocyte cycle
 Merozoites released invade red cells
 P.vivax infects young erythrocytes
 P.malariae Infects old erythrocytes
 P.falciparum infects RBC of all ages
 The Merozoites are pear shaped 1-5 microns
in length
 The receptors for Merozoites are on red cells
in the glycoprotein

14. Erythrocytic Schizogony
 Liberated Merozoites
penetrate RBC
 Three stages occur
1 Trophozoites
2 Schizont
3 Merozoite

15. Exo-erythrocytic (tissue) phase
 P. malariae or P. falciparum sporozoites
do not form hypnotizes, develop directly
into pre-erythrocytic schizonts in the liver
 Schizonts rupture, releasing merozoites
which invade red blood cells (RBC) in liver

16. Gametogony
 Merozoites differentiate into Male and female
gametocytes
 They develop in the red cells
 Found in the peripheral blood smears
 Microgametocyte of all species are similar in
size
 Macro gametocytes are larger in size.

17. Mosquito cycle
Sexual cycle
 Sexual cycle will be initiated in the Humans by
the formation of Gametocytes
 Develop further in the female Anopheles
Mosquito
 Fertilization occurs when a Microgametocyte
penetrate into Macrogametocyte
 ZYGOTE is formed matures into OOKINETE
 OOKINETE to OOCYST
 OOCYST matures with large number of
Sporozoites ( A few hundred to thousands)

18. Mosquito cycle
A definitive Host – Mosquito

20. Malaria the disease
 9-14 day
incubation period

21. Early symptoms
 The common first symptoms –
fever, headache, chills and
vomiting – usually appear 10 to 15
days after a person is infected. If
not treated promptly with effective
medicines, malaria can cause
severe illness and is often fatal.

22. How Malaria present Clinically
 Stage 1(cold stage)
 Chills for 15 mt to 1 hour
 Caused due to rupture from the host red cells
escape into Blood
 Preset with nausea, vomitting,headache
 Stage 2(hotstage)
 Fever may reach upto 400c may last for
several hours starts invading newer red cells.

23. Clinical Malaria
 Stage 3(sweating stage)
Patent starts sweating, concludes the episode
Cycles are frequently Asynchronous
Paroxysms occur every 48 – 72 hours
In P.malariae pyrexia may last for 8 hours or
more and temperature my exceed 410c

24. Malaria stages of the disease

25. More commonly, the patient presents with a
combination of the following symptoms
 Fever
 Chills
 Sweats
 Headaches
 Nausea and vomiting
 Body aches
 General malaise.

26. Periodicity can be clue in Diagnosis
and species relation
 Malaria tertiana:
48h between fevers
(P. vivax and ovale)
 Malaria quartana:
72h between fevers
(P. malariae)
 Malaria tropica:
irregular high fever
(P. falciparum)

27. SEVERE COMPLICATED MALARIA
 Alteration in the level of consciousness (ranging from drowsiness to deep
coma)
 Cerebral malaria (unrousable coma not attributable to any other cause in a
patient with falciparum malaria)
 Respiratory distress (metabolic acidosis bicarb less than 15 meq/l)
 Multiple generalized convulsions (2 or more episodes within a 24 hour period)
 Shock (circulatory collapse, septicaemia)
 Pulmonary oedema
 Abnormal bleeding (Disseminated Intravascular coagulopathy)
 Jaundice
 Haemoglobinuria (black water fever)
 Acute renal failure - presenting as oliguria or anuria
 Severe anaemia (Haemoglobin < 5g/dl or Haematocrit < 15%)
 High fever
 Hypoglycaemia (blood glucose level < 2.2.mmol/l)
Confusion, or drowsiness with extreme weakness (prostration).
In addition, the following may develop:
defined as the detection of P. falciparum in the peripheral blood

28. Malaria the disease

29. Why Falciparum Infections are
Dangerous
 Can produce fatal complications,
1.Cerebral malaria
2.Malarial hyperpyrexia
3.Gastrointestinal disorders.
4.Algid malaria(SHOCK)
5 Black water fever can lead to death

30. Pernicious Malaria
 Is a life threatening complication in acute
falciparum malaria
 It is due to heavy parasitization
 Manifest with
1 Cerebral malaria – it presents with
hyperpyrexia, coma and paralysis. Brain is
congested
2 Algid malaria – presents with clammy skin
leading to peripheral circulatory failure.

31. Cerebral Malaria
Malignant malaria can
affect the brain and
the rest of the central
nervous system. It is
characterized by
changes in the level
of consciousness,
convulsions and
paralysis.

32. Cerebral Malaria
 Present with
Hyperpyrexia
 Can lead to Coma
 Paralysis and other
complications.
 Brain appears
congested

33. Pathogenesis of
Cerebral malaria
 High cytokine levels could be toxic on their own
 High levels of cytokine also enhance the second process
thought to be responsible for cerebral malaria: sequestration
of infected RBCs

34. Sequestration & cytoadherence
 Rosetting (adhesion of
infected RBCs to other
RBCs) and clumping
(adhesion between
infected cells) was first
observed in in vitro culture

35. Black Water Fever
 In malignant malaria a large
number of the red blood
corpuscles are destroyed.
Haemoglobin from the blood
corpuscles is excreted in the
urine, which therefore is dark
and almost the colour of cola

36. How long Malaria infection can lost in
Man
 Without treatment P.falciparum will terminate in
less than 1 year.
 But in P.vivax and P.ovale persist as
hypnozoites after the parasites have disppeared
from blood.
 Can prodce periodic relapses upto 5 years
 In P.malariae may last for 40 years
( Called as recrudescence X relapse )
Parasites survive in erythrocytes Liver ?

37. LABORATORY
DIAGNOSIS OF MALARIA

38. Diagnostic Tools
for Human Infections with Malaria
 Blood film examination(Microscopy)
 QBC system
 Rapid Diagnostic Tests" (RDTs)
 PCR

39. Thin and Thick smear

40. Microscopy
 Malaria parasites can be identified by
examining under the microscope a drop of the
patient's blood, spread out as a "blood smear"
on a microscope slide. Prior to examination, the
specimen is stained (most often with the
Giemsa stain) to give to the parasites a
distinctive appearance. This technique remains
the gold standard for laboratory confirmation of
malaria.

42. QBC system has evolved as rapid and
precise method in Diagnosis
 The QBC Malaria method is the simplest and
most sensitive method for diagnosing the
following diseases.
 Malaria
 Babesiosis
 Trypanosomiasis (Chagas disease, Sleeping
Sickness)
 Filariasis (Elephantiasis, Loa-Loa)
 Relapsing Fever (Borreliosis)

43. Appearance of Malarial parasite in
QBC system

44. Antigen Detection Methods are Rapid
and Precise
Antigen Detection
 Various test kits are available to detect antigens
derived from malaria parasites and provide results in
2-15 minutes. These "Rapid Diagnostic Tests"
(RDTs). Rapid diagnostic tests (RDTs) are
immunochromatographic tests based on detection of
specific parasite antigens. Tests which detect
histidine-rich protein 2 (HRP2) are specific for
P.falciparum while those that detect parasite
lactate dehydrogenase (pLDH)-OptiMAL
 or aldolase have the ability to differentiate between
P.falciparum and non-P.falciparum malaria

45. Newer Diagnostic methods
Molecular Diagnosis
 Parasite nucleic acids are detected using
polymerase chain reaction (PCR). This technique
is more accurate than microscopy. However, it is
expensive, and requires a specialized laboratory
(even though technical advances will likely result in
field-operated PCR machines).

46. Sensitivity of Tools for
Diagnosis of Malarial Infection
1. Most sensitive:
Antibody detection
2. PCR
3. Blood film examination

47. Malaria Relapses
 In P. vivax and P. ovale infections, patients
having recovered from the first episode of illness
may suffer several additional attacks
("relapses") after months or even years without
symptoms. Relapses occur because P. vivax
and P. ovale have dormant liver stage parasites
("hypnozoites") that may reactivate.

54. THE PHARMACOLOGY OF ANTIMALARIALS
Class
Definition
Examples
Class Definition Examples Class Definition Examples
Blood
schizonticidal
drugs
Act on (erythrocytic) stage of
the parasite thereby
terminating clinical illness
Quinine, artemisinins,
amodiaquine, chloroquine,
lumefantrine, tetracyclinea ,
atovaquone, sulphadoxine,
clindamycina , proguanila
Tissue
schizonticidal
drugs
Act on primary tissue forms of
plasmodia which initiate the
erythrocytic stage. They block
further
development of the
infection
Primaquine, pyrimethamine,
proguanil, tetracycline
Gametocytocid
al drugs
Destroy sexual forms of the
parasite thereby preventing
transmission of infection to
mosquitoes
Primaquine, artemisinins,
quinineb
a Slow acting, cannot be used alone to avert clinical symptoms
b Weakly gametocytocidal

55. THE PHARMACOLOGY OF ANTIMALARIALS (cont.)
Class Definition
Examples
Class Definition
Examples
Class Definition
Examples
Hypnozoitocidal
drugs
These act on persistent
liver stages of P.ovale
and P.vivax which cause
recurrent illness
Primaquine,
tafenoquine
Sporozontocidal
drugs
These act by affecting
further development of
gametocytes into
oocytes
within the mosquito thus
abating transmission
Primaquine, proguanil,
chlorguanil

58. 1. Treatment of severe falciparum malaria
Preferred regime Alternative regime
IV Artesunate (60mg): 2.4mg/kg on
admission, followed by 2.4mg/kg at 12h &
24h, then once daily for 7 days.
Once the patient can tolerate oral therapy,
treatment should be switched to a complete
dosage of Riamet (artemether/lumefantrine)
for 3 day.
IV Quinine loading 7mg salt /kg over 1hr
followed by infusion quinine 10mg salt/kg over
4 hrs, then 10mg salt/kg Q8H or IV Quinine
20mg/kg over 4 hrs, then 10mg/kg Q8H.
Plus
Adult & child >8yrs old: Doxycycline
(3.5mg/kg once daily)
or
Pregnant women & child < 8yrs old:
Clindamycin (10mg/kg twice daily). Both drug
can be given for 7 days.
Reconstitute with 5% Sodium Bicarbonate &
shake 2-3min until clear solution obtained.
Then add 5ml of D5% or 0.9%NaCl to create
total volume of 6ml.
Slow IV injection with rate of 3-4ml/min or
IM injection to the anterior thigh.
The solution should be prepared freshly for
each administration & should not be stored.
Dilute injection quinine in 250ml od D5%
and infused over 4hrs.
Infusion rate should not exceed 5 mg salt/kg
per hour.

59. 2. Treatment of uncomplicated p.falciparum
Preferred regime Alternative regime
Artemether plus lumefantrine(Riamet)
(1 tab: 20mg artemether/120mg lumefantrine)
Quinine sulphate (300mg/tab)
Weight
Group
Day 1 Day 2 Day3 Day 1-7: Quinine 10mg salt/kg PO
Q8H
Plus
*Doxycycline (3.5mg/kg once a
day)
OR
*Clindamycin (10mg/kg twice a
day)
*Any of these combinations should
be given for 7 days.
Doxycycline: Children>8yr
Clindamycin: Children<8yr
5-14kg 1 tab stat
then 8hr
later
1 tab
Q12H
1 tab
Q12H
15-24kg 2 tab stat
then 8hr
later
2 tab
Q12H
2 tab
Q12H
25-34kg 3 tab stat
then 8hr
later
3 tab
Q12H
3 tab
Q12H
>34kg 4 tab stat
then 8hr
later
4 tab
Q12H
4 tab
Q12H
Take immediately after a meal or drink
containing at least 1.2g fat to enhance

60. Dosage and administration Plasmodium falciparum for young infant
Age Group
Weight
group
Artesunate or *Quinine
0 - 4
months
<5 kg
** IM first dose
Artesunate 1.2
mg/kg or IM
Arthemeter 1.6
mg/kg)
***Oral
Artesunate
2mg/kg/day
day 2 to day 7
Oral
Quinine 10
mg/kgTDS
for 4 days
then 15-20
mg/kg TDS
for 4 days
Source: Malaria in Children, Department of tropical Pediatrics, Faculty of Tropical Medicine,
Mahidol University.
** Preferably Artesunate/Artemether IM on day 1 if available
*** When Artesunate/Artemether IM is unavailable, give oral Artesunate from day 1 to day 7
* Treat the young infant with Quinine when oral Artesunate is not available
Children under 5 kg or below 4 months should not be given Riamet
instead treat with the following regimen (see table).

61. 3. Treatment of malaria caused by p.knowlesi
& mixed infection (p. falciparum + p. vivax)
Treat as p. falciparum

62. 4. Treatment of of malaria caused by p.vivax, p. ovale or p.
malariae.
CHLOROQUINE
(150 mg base/tab) 25 mg
base/kg divided over 3 days
PRIMAQUINE
(7.5 mg base/tab)
Day 1 Day 2 Day 3 Start concurrently with
CHLOROQUINE 0.5 mg base/kg Q24H
for 2 weeks
Take with food
Check G6PD status before start
primaquine
In mild-to-moderate G6PD deficiency,
primaquine 0.75 mg base/kg body weight
given once a week for 8 weeks.
In severe G6PD deficiency, primaquine
is contraindicated and should not be
used.
10mg
base/kg
stat,
then
5mg
base/kg
5mg
base/kg
Q24H
5mg
base/kg
Q24H
1 tab of chloroquine phosphate 250mg equivalent to 150mg base. Calculation of
dose for chloroquine is based on BASE, not SALT form. 1 tab of primaquine
phosphate contains 7.5mg base.

63. Treatment in specific population & situations
Specific
populations
Preferred regime Alternative regime
Pregnancy Quinine plus clindamycin to be given for
7 day
Artesunate plus Clindamycin
for 7 days is indicated if first
line treatment fails
Lactating
women
Should receive standard antimalarial treatment (including ACTs) except for
dapsone, primaquine and tetracyclines, which should be withheld during
lactation
Hepatic
impairment
Chloroquine: 30-50% is modified by liver, appropriate dosage adjustment
is needed, monitor closely.
Quinine : Mild to moderate hepatic impairment-no dosage adjustment,
monitor closely.
Artemisinins : No dosage adjustment
Renal
Impairment
Chloroquine : ClCr<10ml/min-50% of normal dose.
Hemodialysis, peritoneal dialysis: 50% of normal dose.
Continuous Renal Replacement Therapy(CRRT) :100% of normal dose.
Quinine : .ClCr 10-50ml/min : Administer Q8-12H, CLCr<10ml/min :
administer Q24H,Severe chronic renal failure not on dialysis : initial dose:
600mg followed by 300mg Q12H, Hemo- or peritoneal dialysis: administer
Q24H ,Continuous arteriovenous or hemodialysis: Administer Q8-12H.
Artemisinin : no dosage adjustment.

64. Treatment of complications of malaria
 Severe & complicated falciparum or
knowlesi malaria is a medical emergency
that requires intervention and intensive care
as rapidly as possible.
 Fluid, electolyte glucose & acid-base balance
must be monitored.Intake & output should be
carefully recorded.

65. Immediate clinical management of severe manifestations and
complications of P. falciparum malaria
Definitive clinical
features
Immediate management/treatment
Come (Cerebral malaria) Monitor & record level of consciousness using Glaslow
coma scale, temperature, respiratory, and depth, BP and
vital signs.
Hyperpyrexia (rectal
body temperature
>40°C)
Treated by sponging, fanning &with an antipyretic drug.
Rectal paracetamol is preferred over more nephrotoxic
drugs (e.g. NSAIDs)
Convulsions A slow IV injection of diazepam(0.15mg/kg, maximum
20mg for adults).
Hypoglycaemia (glucose
conc. <2.8mmol/L)
Correct with 50% dextrose (as infusion fluids). Check
blood glucose Q4-6H in the first 48hrs.
Severe anaemia (hb <
7g/dl)
Transfuse with packed cells. Monitor carefully to avoid
fluid overload. Give small IV dose of frusemide, 20mg,
as necessary during blood transfusion to avoid
circulatory overload.
Acute pulmonary
oedema
Prop patient upright (45°), give oxygen, give IV diuretic
(but most patient response poorly to diuretics), stop
intravenous fluids. Early mechanical ventilation should

66. Immediate clinical management of severe manifestations and
complications of P. falciparum malaria (cont.)
Definitive clinical
features
Immediate management/treatment
Acute renal failure (urine
output <400ml in 24hrs
in adults or 0.5ml/kg/hr,
failing to improve after
rehydration & a serum
creatinine of
>265μmol/L)
Exclude pre-renal causes by assessing hydration status.
Rule out urinary tract obstruction by abdominal
examination or ultrasound.
Give intravenous normal saline
If in established renal failure add haemofiltration or
haemodialysis, or if unavailable, peritoneal dialysis.
Disseminated
intravascular
Coagulopathy (DIVC)
Transfuse with packed cell, clotting factors or platelet.
Usual regime: Cryoprecipitate 10units,platelets 4-8units,
fresh frozen plasma(10-15ml/kg).
For prolonged PT, give vitamin K, 10mg by slow IV
injection.
metabolic acidosis Infuse sodium bicarbonate 8.4% 1mg/kg over 30min
and repeat if needed.
if severe, add haemodialysis.
Shock (hypotension with
systolic blood pressure
Suspect septicaemia, take blood for cultures; give
parenteral broad-spectrum antimicrobials, correct

67. Monitoring & follow-up
 Blood smear should be repeated daily
(twice daily in severe infection). Within 48-
72 hr after start of treatment, patients
usually become afebrile and improve
clinically except in complicated cases.
 All patients should be investigated with
repeated blood film of malarial parasite
one month upon recovery of malarial
infection, to ensure no recrudescence.

68. Prevention
Avoid mosquito bites:
Wearing long sleeves,
trousers.
Insecticide Treated Bednets
Repellent creams or sprays.

69. Chemoprophylaxis
 Indicated for travellers travel to
endemic areas.
 Mefloquinine 250mg weekly (up to 1
year) or doxycycline 100mg daily (up
to 3 month), to start 1 week before
and continue till 4 weeks after leaving
the area.

70. Dosing schedule for mefloquine
Weight Age No of tablets
per
week
< 5 kg < 3 months Not
recommended
5 - 12 kg 3 - 23 months 1/4
13 - 24 kg 2 - 7 yrs 1/2
25 - 35 kg 8 - 10 yrs 3/4
36 and above 11 yrs and
above
1

71. Dosing schedule for doxycycline
Weight in
kg
Age in
years
No of tablets
< 25 < 8 Contraindicated
25 - 35 8 - 10 ½
36 - 50 11 - 13 ¾
50+ 14+ 1