PROTOZOAL INFECTIONS

MALARIA
Laveran
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
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
A complex Life cycle
Human Cycle

1 Pre erythrocytic
schizogony
2 Erythrocytic
Schizogony
3 Gametogony
4 Exoerythrocytic
schizogony
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.
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.
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
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
Erythrocytic Schizogony
 Liberated Merozoites
penetrate RBC
 Three stages occur

1 Trophozoites
2 Schizont
3 Merozoite
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
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.
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)
Mosquito cycle
A definitive Host – Mosquito
Malaria the disease

 9-14 day
incubation period
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.
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.
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
Malaria stages of the disease
More commonly, the patient presents with a
combination of the following symptoms

 Fever
 Chills
 Sweats
 Headaches
 Nausea and vomiting
 Body aches
 General malaise.
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)
 SEVERE COMPLICATED MALARIA
Confusion, or drowsiness with extreme weakness (prostration).
In addition, the following may develop:
 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)

defined as the detection of P. falciparum in the peripheral blood

Malaria the disease
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
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.
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.
Cerebral Malaria

 Present with
Hyperpyrexia
 Can lead to Coma
 Paralysis and other
complications.
 Brain appears
congested
 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
Sequestration & cytoadherence

 Rosetting (adhesion of
infected RBCs to other
RBCs) and clumping
(adhesion between
infected cells) was first
observed in in vitro culture
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
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 ?
LABORATORY
DIAGNOSIS OF MALARIA
Diagnostic Tools
for Human Infections with Malaria

 Blood film examination(Microscopy)

 QBC system

 Rapid Diagnostic Tests" (RDTs)

 PCR
Thin and Thick smear
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.
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)
Appearance of Malarial parasite in
QBC system
 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
 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).
Sensitivity of Tools for
Diagnosis of Malarial Infection

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

Class Definition Class Definition Class Definition

Examples Examples Examples
Hypnozoitocidal These act on persistent Primaquine,
drugs liver stages of P.ovale tafenoquine
and P.vivax which cause
recurrent illness
Sporozontocidal These act by affecting Primaquine, proguanil,
drugs further development of chlorguanil
gametocytes into
oocytes
within the mosquito thus
abating transmission
 1. Treatment of severe falciparum malaria
Preferred 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.
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.
Alternative regime
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.
Dilute injection quinine in 250ml od D5%
and infused over 4hrs.
Infusion rate should not exceed 5 mg salt/kg
per hour.
 2. Treatment of uncomplicated p.falciparum
Preferred regime Alternative regime
Artemether plus lumefantrine(Riamet) Quinine sulphate (300mg/tab)
(1 tab: 20mg artemether/120mg lumefantrine)
Weight Day 1 Day 2 Day3 Day 1-7: Quinine 10mg salt/kg PO
Group Q8H
5-14kg 1 tab stat 1 tab 1 tab
then 8hr Q12H Q12H Plus
later *Doxycycline (3.5mg/kg once a
day)
15-24kg 2 tab stat 2 tab 2 tab
then 8hr Q12H Q12H OR
later
25-34kg 3 tab stat 3 tab 3 tab *Clindamycin (10mg/kg twice a
then 8hr Q12H Q12H day)
later
>34kg 4 tab stat 4 tab 4 tab *Any of these combinations should
then 8hr Q12H Q12H be given for 7 days.
later Doxycycline: Children>8yr
Clindamycin: Children<8yr
Take immediately after a meal or drink
containing at least 1.2g fat to enhance
 Children under 5 kg or below 4 months should not be given Riamet
instead treat with the following regimen (see table).
Dosage and administration Plasmodium falciparum for young infant

Weight
Age Group Artesunate or *Quinine
group

Oral
** IM first dose Quinine 10
***Oral
Artesunate 1.2 mg/kgTDS
0-4 Artesunate
<5 kg mg/kg or IM for 4 days
months 2mg/kg/day
Arthemeter 1.6 then 15-20
day 2 to day 7
mg/kg) 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
3. Treatment of malaria caused by p.knowlesi
& mixed infection (p. falciparum + p. vivax)

 Treat as p. falciparum
 4. Treatment of of malaria caused by p.vivax, p. ovale or p.
malariae.

CHLOROQUINE
PRIMAQUINE
(150 mg base/tab) 25 mg
(7.5 mg base/tab)
base/kg divided over 3 days

Day 1 Day 2 Day 3 Start concurrently with

CHLOROQUINE 0.5 mg base/kg Q24H
for 2 weeks
Take with food
10mg Check G6PD status before start
base/kg primaquine
5mg 5mg
stat, In mild-to-moderate G6PD deficiency,
base/kg base/kg
then primaquine 0.75 mg base/kg body weight
Q24H Q24H
5mg given once a week for 8 weeks.
base/kg In severe G6PD deficiency, primaquine
is contraindicated and should not be
used.
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.
Treatment in specific population & situations
Specific Preferred regime Alternative regime
populations
Pregnancy Quinine plus clindamycin to be given for Artesunate plus Clindamycin
7 day for 7 days is indicated if first
line treatment fails
Lactating Should receive standard antimalarial treatment (including ACTs) except for
women dapsone, primaquine and tetracyclines, which should be withheld during
lactation
Hepatic Chloroquine: 30-50% is modified by liver, appropriate dosage adjustment
impairment is needed, monitor closely.
Quinine : Mild to moderate hepatic impairment-no dosage adjustment,
monitor closely.
Artemisinins : No dosage adjustment
Renal Chloroquine : ClCr<10ml/min-50% of normal dose.
Impairment 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.
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.
 Immediate clinical management of severe manifestations and
complications of P. falciparum malaria

Definitive clinical Immediate management/treatment

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

Definitive clinical Immediate management/treatment

features
Acute renal failure (urine Exclude pre-renal causes by assessing hydration status.
output <400ml in 24hrs Rule out urinary tract obstruction by abdominal
in adults or 0.5ml/kg/hr, examination or ultrasound.
failing to improve after Give intravenous normal saline
rehydration & a serum If in established renal failure add haemofiltration or
creatinine of haemodialysis, or if unavailable, peritoneal dialysis.
>265μmol/L)
Disseminated Transfuse with packed cell, clotting factors or platelet.
intravascular Usual regime: Cryoprecipitate 10units,platelets 4-8units,
Coagulopathy (DIVC) 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 Suspect septicaemia, take blood for cultures; give
systolic blood pressure parenteral broad-spectrum antimicrobials, correct
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.
Prevention

 Avoid mosquito bites:

Wearing long sleeves,

trousers.
Insecticide Treated Bednets

Repellent creams or sprays.

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