Malaria and Dengue

MMOOSSQQUUIITTOO--BBOORRNNEE
DDIISSEEAASSEESS

 Brief history &
pathophysiology by Iqra
Zulfiqar (R#33)

WWhhaatt iiss MMaallaarriiaa??
• Vector-borne infectious disease caused by
single-celled protozoan parasites of the
genus Plasmodium.
• Transmit by bite from an infective female
Anopheles mosquito.
• Widespread in tropical and subtropical
regions.
• Probably one of the oldest diseases
known to mankind that has had profound
impact on our history.

Alternative names:
oQuartan malaria
oFalciparum malaria
oBlackwater fever
oTertian malaria
At risk for malaria:
4400%% ooff tthhee wwoorrlldd’’ss ppooppuullaattiioonn
Female Anopheles are:
Anthropophilic : from humans
Zoophilic : from animals
Endophagic : prefer to bite indoors
Exophagic : prefer outdoor biting

WWhhaatt ccaauusseess MMaallaarriiaa??
• Malaria is caused by an infection by one of four single celled
Plasmodia species, they are: falciparum, vivax, malariae, and
ovale.
The most dangerous of the four is P.falciparum
• In the human body, the parasites multiply in the liver, and
then infect red blood cells.
• Transmission of Malaria do not occur <160C and >330C.
• Malaria is fourth leading cause of death
• In Pakistan majorly infectious species of plasmodium are:
P. vivax 70% P. falciparum 30%

Species IInnffeeccttiinngg HHuummaannss
Five Species known to infect Man
Plasmodium vivax – Benign Tertian,
Tertian Malaria(Grassi and Feletti)
P.ovale - Ovale tertian Malaria(Stephens)
P.malariae – Quartan malaria (Laveran)
P.falciparum – Falciparum malaria or
Malignant Tertian malaria(Welch)
P. knowlesi (Sinton and Muller)

Species IInnffeeccttiinngg HHuummaannss
Plasmodium falciparum
Malignant tertian (Cerebral)
Plasmodium vivax
Tertian
Plasmodium ovale
Tertian
Plasmodium malariae
Common & Severe
Quartan Rare & Mild

AN AANNCCIIEENNTT DDIISSEEAASSEE ––
TThhee HHiissttoorryy OOff MMaallaarriiaa
 Malaria parasites have been with us since the
dawn of time. They probably originated in
Africa (along with mankind), and fossils of
mosquitoes up to 30 million years old, show
that the malaria vector, the malaria mosquito,
was present well before the earliest history.

EEvveennttss oonn MMaallaarriiaa
Charles Louis
Alphose Lavern
discovered
malarial parasite
in wet mount
1880 1898 1948 1955 1970 1976
Roland Ross - Life
cycle of parasite
transmission,
wins Nobel Prize
in 1902
WHO starts world
wide malaria
eradication
programme using
DDT
Trager and Jensen
did in vitro
cultivation of
parasite
Site of
Exoerythrocytic
development in
Liver by Shortt
and Garnham
Mosquitos
develop
resistance to DDT
Programme fails

Nobel PPrriizzeess iinn MMaallaarriiaa

Pathophysiology- LLiiffee CCyyccllee ooff
Exo-erythrocytic
(hepatic) cycle
Hypnozoites
Sporozoites
Salivary Gland
Gametocytes
Erythrocytic
Cycle
Zygote
Oocyst
Stomach Wall
Pre-erythrocytic
(hepatic) cycle
MMaallaarriiaa

Animated IIlllluussttrraattiioonn OOff
PPaatthhoopphhyyssiioollooggyy

Period of Pre eerryytthhrrooccyyttiicc ccyyccllee
• P.vivax 8 days
• P.falciparum – 6 days
• P.malariae - 13 – 16 days,
• P.ovale 9 days
AAffffiinniittyy ooff PPaarraassiittee ttoo EErryytthhrrooccyytteess
• P.vivax Young red blood cells
• P.malariae Old red blood cells
• P.ovale Young red blood cells
• P.falciparum Infects all age groups

o Pregnant women have increased susceptibility to P.
falciparum malaria; in malaria-endemic countries, P.
falciparum contributes to 8-14% of low birth weight, which
in turn decreases the chance of a baby’s survival.
o Malarial parasite found mostly in warmer climates, malaria
breeds where there is an abundance of humidity and rain.
o Biologic characteristics and behavioral traits can influence
an individual's risk of developing malaria and, on a larger
scale, the intensity of transmission in a population.
o An experienced laboratory technician or pathologist can
distinguish between P. falciparum, P. vivax, P.
malariae and P. ovale based on the appearance of the
parasites and infected blood cells. Under the microscope, P.
knowlesi can resemble either P. falciparum or P. malariae.
Increasingly reference diagnostic tools like PCR
are employed to confirm malaria infection and to determine
definitively which species are involved.

o Patient’s Performa:
 Name – Mr. X
 Age – 26 yrs
 Gender – Male
 Date of admission – 06/10/12
 Date of discharge – 10/10/12
Chief complaints
Chills, intermittent fever, vomiting, back pain, fatigue, head ache
X 3days.
History of present illness
Back pain ,headache
Personal History
Non-alcoholic, Non-smoker
How we relate these sign & ssyymmppttoommss wwiitthh MMaallaarriiaa aanndd
wwhhaatt ssoorrtt ooff llaabb ddiiaaggnnoossiiss wwee ccaann ddoo,, ttoo ccoonnffiirrmm tthhee
ddiiaaggnnoossiiss ooff ppaattiieenntt??

Some important ffaaccttoorrss rreeggaarrddiinngg
ssyymmppttoommss……
TThhee ttiimmee ffrroomm tthhee iinniittiiaall mmaallaarriiaa iinnffeeccttiioonn uunnttiill ssyymmppttoommss
aappppeeaarr

SSyymmppttoommss....
CCOOMMMMOONN SSYYMMPPTTOOMMSS

Appearance of Common Symtoms..
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.
CClliinniiccaall eevveennttss
The symptoms often associated with malaria are due to bursting red blood cells
and clogged capillaries of major organs. Infection occurs when an infected
anopheles mosquito feeds on an individual releasing sporozites into the blood
stream. Mosquitos can carry more than one species and thus can infect peoples
with more than one species.
PPeerriiooddiicciittyy CClluueess
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)

SSyymmppttoommss....
CCLLAASSSSIICCAALL SSYYMMPPTTOOMMSS

Broad Clinical Manifestations
• Fever & Sweating
• Anemia
• Splenomagaly (enlarged spleen)
• Irratability
• Coma
• Retinal Hemorrages
• Algid Malaria ( a shock-like syndrome)
• Respiratory distress syndrome
CCoommpplliiccaattiioonnss
• Cerebral Malaria
• Pulmonary edema (fluid buildup in the lungs) or acute respiratory distress
syndrome (ARDS)
• Cardiovascular collapse and shock
• Black water Fever
• Acute kidney failure
• Metabolic acidosis (excessive acidity in the blood and tissue fluids), often in
association with hypoglycemia

DDIIAAGGNNOOSSIISS OOFF MMAALLAARRIIAA

CClliinniiccaall DDiiaaggnnoossiiss
Based on the patient's symptoms and on physical findings
at examination.

Microscopic DDiiaaggnnoossiiss

1. Blood Smear
• Malaria parasite
identified by examining
under the microscope a
drop of the patient's
blood, spread out blood
smear on a microscope
slide
Blood smear stained
with Giemsa’s stain
Microscopic
demonstration still the
Gold standard in
Diagnosis Blood Smear Stained
With Giensa Stain

Collection ooff BBlloooodd SSmmeeaarrss
4.
Slide must always be
grasped by its edges.
5.
Touch the drop of
blood to the slide
from below.
1.
The second or third
finger is usually
selected and
cleaned.
2.
Puncture at the side
of the ball of the
finger.
3.
Gently squeeze
toward the puncture
site.

Preparing thick aanndd tthhiinn ffiillmmss
1.
Touch one drop of
blood to a clean
slide.
2.
Spread the first
drop to make a 1
cm circle.
3.
Touch a fresh drop
of blood to the edge
of another slide.
4.
Carry the drop of blood
to the first slide and hold
at 45 degree angle.
5.
Pull the drop of blood
across the first slide in
one motion.
6.
Wait for both to
dry before fixing
and staining.

2. Fluorescent Microscopy
• Modification of light microscopy
• Fluorescent dyes detect RNA and DNA that is contained in parasites
• Requires Fluorescent microscope
• Nuclei of malaria parasites fluoresce bright green and cytoplasm red.
• Staining itself is cheap
• Sensitivities around 90%

3. Quantitative Buffy Coat
• Rapid and precise
method in Diagnosis
• Useful for screening
large numbers of sample
• Requires centrifuge,
special stains

AAnnttiiggeenn DDeetteeccttiioonn
• Immunochromatographic test (RDTs)
• Various test kits are available to detect
antigens derived from malaria parasites.
• Provide results in 2-15 minutes.
• These Rapid Diagnostic Tests (RDTs) offer a
useful alternative to microscopy in situations
where reliable microscopic diagnosis is not
available.
• RDTs Test Formats;
• Plastic Cassette
• Card
• Dipstick
• Hybrid Cassette Dipstick

MMoolleeccuullaarr DDiiaaggnnoossiiss
• Polymerase chain reaction (PCR)
• Molecular technique to identify
parasite genetic material
Lane S: Molecular base pair
standard (50-bp ladder). Black
arrows :size of standard bands.
Lane 1: P. vivax (size: 120 bp).
Lane 2: P. malariae (size: 144 bp).
Lane 3: P. falciparum (size: 205 bp).
Lane 4: P. ovale (size: 800 bp).

SSeerroollooggyy
• Serology detects antibodies against
malaria parasites
• Using either indirect
immunofluorescence (IFA) or enzyme-linked
immunosorbent assay (ELISA).
OOtthheerr LLaabboorraattoorryy FFiinnddiinnggss……..
¤Normocytic anemia of variable severity.
¤Liver function tests may be abnormal
¤Presence of protein and casts in the Urine of
children with P.malariae is suggestive of Quartan
nephrosis.
¤In severe Falciparum malaria with renal damage
may cause oliguria and appearance of casts, protein,
and red cells in the Urine

AANNTTIIMMAALLAARRIIAALL DDRRUUGGSS
• Antimalarial drugs are used for the treatment and prevention of
malaria infection.
• Most antimalarial drugs target the erythrocytic stage of malaria
infection, which is the phase of infection that causes symptomatic
illness.
• Treatment of the acute blood stage infection is necessary for
malaria caused by all malaria species.
• For infection due to Plasmodium ovale or P. vivax, terminal
prophylaxis is required with a drug active against hypnozoites
(which can remain dormant in the liver for months -- and
occasionally years -- after the initial infection.

DDrruugg CCllaassssiiffiiccaattiioonn
QQuuiinnoolloonneess
Tetracycline
Doxycycline
and
clindamycin
Artesunate
Artemether
Artelinic acid
Artemotil
AAnnttii ffoollaatteess AAnnttii
MMiiccrroobbiiaall
AArrtteemmiissiinniinnss
Chloroquine
Amodiaquine
Quinine
Quinidine
Mefloquine
Primaquine
Sulfonamides,
Pyrimethamine,
Proguanil
and
Dapsone

QQUUIINNOOLLIINNEE DDEERRIIVVAATTIIVVEESS
• Include chloroquine, amodiaquine, quinine,
quinidine, mefloquine, primaquine,
lumefantrine and halofantrine.
• These drugs have activity against the
erythrocytic stage of infection; primaquine also
kills intrahepatic forms and gametocytes.
• The drugs act by accumulating in the parasite
food vacuole and forming a complex with heme
that prevents crystallization in the plasmodium
food vacuole.
• Heme polymerase activity is inhibited, resulting
in accumulation of cytotoxic free heme.

4-aminoquinolines
• CChhlloorrooqquuiinnee:: has activity against the blood stages of
Plasmodium ovale, P. malariae, and susceptible strains of
P. vivax and P. falciparum.
• MMeecchhaanniissmm OOff AAccttiioonn :: Binds to and inhibits DNA and
RNA polymerase; interferes with metabolism and
hemoglobin utilization.
• Chloroquine concentrates within parasite acid vesicles
and raises internal pH resulting in inhibition of parasite
growth.

DDOOSSIINNGG:: AADDUULLTTSS
• Malaria, suppression or prophylaxis: Oral: 500 mg/week on the same day each
week; begin 1-2 weeks prior to exposure; continue for 4-6 weeks after leaving
endemic area; if suppressive therapy is not begun prior to exposure, double the
initial loading dose to 1 g and administer in 2 divided doses 6 hours apart,
followed by the usual dosage regimen.
• Malaria, acute attack: Oral: 1 g on day 1, followed by 500 mg 6 hours later,
followed by 500 mg on days 2 and 3.
• SSiiddee EEffffeeccttss
• Chloroquine is only administered orally; intravenous infusion is associated with
significant toxicity.
• Side effects of chloroquine include headaches, dizziness, abdominal discomfort,
vomiting, and diarrhea.

4-methanolquinolines
• QQuuiinniinnee && QQuuiinniiddiinnee:: Quinine is a derivative from the
bark of the South American Cinchona tree and exists in
oral and parenteral forms and is the most commonly
used parenteral antimalarial drug.
• Quinidine is a stereoisomer of quinine available in
parenteral formulation and is very effective for
treatment of severe malaria.
• MMeecchhaanniissmm ooff AAccttiioonn:: Depresses oxygen uptake and
carbohydrate metabolism; intercalates into DNA,
disrupting the parasite's replication and transcription

• DDoossiinngg--AAdduulltt ::
Treatment of chloroquine-resistant
malaria:
648 mg every 8 hours for 7
days with tetracycline,
doxycycline, or clindamycin.
• DDoossiinngg--AAdduulltt ::
Dosage expressed in terms of
the salt: 267 mg of
quinidine gluconate = 275
mg of quinidine
polygalacturonate = 200 mg
of quinidine sulfate.
UUSSEE::
Quinidine gluconate (I.V.
formulation) and quinidine
sulfate: Treatment of
malaria (Plasmodium

• AAddvveerrssee eeffffeeccttss of quinine and quinidine
include a complex of symptoms referred to as
cinchonism, includes:

• MMeeffllooqquuiinnee:: is an orally administered medication used in
the prevention and treatment of malaria.
• MMeecchhaanniissmm OOff AAccttiioonn :: The exact mechanism of action is
uncertain. However, it is proposed to share a similar
mechanism of action with chloroquine, which is
inhibition of heme polymerase.
• UUssee::Treatment of acute malarial infections and
prevention of malaria.

DDoossiinngg::
• AADDUULLTTSS:: Malaria treatment (mild-to-moderate infection): Oral: 5 tablets as a
single dose. If clinical improvement is not seen within 48-72 hours, an
alternative therapy should be used for retreatment.
• Malaria prophylaxis: Oral: 1 tablet (250 mg) weekly starting 1 week before
arrival in endemic area, continuing weekly during travel and for 4 weeks after
leaving endemic area
• PPEEDDIIAATTRRIICC:: Malaria treatment: Oral: 20-25 mg/kg in 2 divided doses, taken 6-8
hours apart (maximum: 1250 mg).
• If clinical improvement is not seen within 48-72 hours, an alternative therapy
should be used for retreatment.
• Malaria prophylaxis: Oral: 5 mg/kg/once weekly (maximum dose: 250 mg)
starting 1 week before arrival in endemic area, continuing weekly during travel
and for 4 weeks after leaving endemic area.

• AAddvveerrssee eeffffeeccttss includes:

8-aminoquinolines
• PPrriimmaaqquuiinnee:: is the only 8-aminoquinoline in clinical use.
• Largely used to prevent relapse of P. ovale and P. vivax
malaria by eliminating dormant hypnozoites, and it also
has activity against the pre-erythrocytic stage and
gametocytes of P. falciparum.
• MMeecchhaanniissmm OOff AAccttiioonn :: Eliminates the primary tissue
exoerythrocytic forms of P. falciparum; disrupts
mitochondria and binds to DNA.

DDoossiinngg::
ADULTS
The CDC recommends screening for G6PD deficiency prior to
initiating treatment with primaquine. (15 mg)
• It can cause hemolytic anemia in those with glucose-6-phosphate
dehydrogenase (G6PD) deficiency. Therefore, patients should
receive primaquine only if G6PD deficiency has been excluded.

AANNTTII--FFOOLLAATTEESS
• Antifolates include sulfonamides,
pyrimethamine, proguanil and dapsone.
• These drugs act synergistically to target
enzymes involved in folate synthesis, a pathway
required for parasite DNA synthesis.

SSuullffaaddooxxiinnee aanndd ppyyrriimmeetthhaammiinnee
•MMeecchhaanniissmm OOff AAccttiioonn :: Sulfadoxine interferes with
bacterial folic acid synthesis and growth via competitive
inhibition of para-aminiobenzoic acid; pyrimethamine
inhibits microbial dihydrofolate reductase, resulting in
inhibition of tetrahydrofolic acid synthesis
•UUssee:: Treatment of Plasmodium falciparum malaria in
patients in whom chloroquine resistance is suspected.

• DDoossee::
• AAdduullttss -- Treatment of acute malaria attacks: Oral: A single dose of
the following number of Fansidar® tablets is used in sequence with
quinine or alone: 3 tablets
• MMaallaarriiaa pprroopphhyyllaaxxiiss:: A single dose should be carried for self-treatment
in the event of febrile illness when medical attention is
not immediately available: Oral: 3 tablets
• AAddvveerrssee EEffffeeccttss::
• Mild adverse effects include gastrointestinal upset and headache.
Mild bone marrow suppression may occur, and sulfadoxine can
precipitate hemolysis in patients with G6PD deficiency.

AANNTTII--MMIICCRROOBBIIAALLSS
• Tetracycline, doxycycline, and clindamycin
target prokaryotic protein synthesis.
• In malaria parasites, these drugs appear to
target the apicoplast, an organelle derived from
prokaryotic ancestors.
• They have relatively slow antimalarial activity
because they exert their toxic effects in the
subsequent cycle of cell division.
• They are typically paired with fast-acting
antimalarials (usually quinine).
• Doxycycline has a longer half life than
tetracycline so is used more commonly.

• AAddvveerrssee eeffffeeccttss are common with the
tetracyclines
• Gastrointestinal discomfort and candidiasis are
the most frequent complaints.
• Doxycycline therapy also poses a risk of
esophageal ulceration.

AARRTTEEMMIISSIINNIINN
DDEERRIIVVAATTIIVVEESS
• The artemisinins are derived from the leaves of
the Chinese sweet wormwood plant, Artemisia
annua.
• They have been used in China for the treatment
of malaria for over 2000 years and came to
attention outside of China in the 1970s and
1980s.

• MMeecchhaanniissmm ooff AAccttiioonn:: Artemisinins 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, the parasite form
that is infectious to mosquitoes.
• Intravenous artesunate is used for the treatment of severe
malaria.

• DDoossiinngg:: If used alone (via the parenteral, rectal or oral
route), artesunate must be administered for 5-7 days.
• Artemisinins are generally well tolerated.
• Type 1 hypersensitivity to the artemisinin compounds
has been reported.
• AAddvveerrssee EEffffeeccttss of orally-administered artemisinins
demonstrated transient neurological
abnormalities( nystagmus and disturbances in balance)

 Brief history &
pathophysiology by Sana
Chauhdry (R#08)

WWhhaatt iiss DDeenngguuee FFeevveerr??
a debilitating viral disease of the tropics,
transmitted by mosquitoes, and causing
sudden fever and acute pains in the joints.
ALTERNATIVE NAMES
 Hemorrhagic dengue
 Dengue shock syndrome
 Philippine hemorrhagic
 Thai hemorrhagic fever
 Singapore hemorrhagic fever

OOrriiggiinn
The origin is still debatable.
Scientist proposed it originated from Asian
Forests.
Early outbreaks recorded:
• 992 in Chinese Encyclopedia
• 1635 in French West Indies
• 1699 in Panama.

11777711
• Dr. Jose Sabater
• Disease called “Break-
Bone Fever”
• Treated using small
quantities of Rum.

11778800
• Dr. Benjamin Rush
• Disease called “Bilious
Remitting Fever”

11880011
• People started calling it “Dengue”
• Dengue is Spanish word for “Fastidious”
• Some believe that name came from Swahili Phrase
“Ka Dinga Pepo”
(Disease caused by an evil spirit)

11995533
• First Epidemic of Severe
Dengue.
• Disease spread in South
East Asia during the next
20 years.

Main vector
Aedes Aegypti mosquito
Having white band and
scale patterns on its legs
Having white band and
scale patterns on its legs
and thorax.
and thorax.

DDOO YYOOUU KKNNOOWW????????
The mosquito is attracted by the body odors, carbon
dioxide and heat emitted from the animal or humans.
Aedes are day-biters, most active during dawn and dusk.

Diagnosis of dengue
• Travel history and symptom profile
• Detection of antibodies against the
virus
• Complete blood count
• Liver function test etc.

This is what yyoouu ccaann ddoo ttoo hheellpp……..

Preventive measure for traveler
• No vaccine or drugs are available for the prevention of
dengue
• Preventive measure should be taken to avoid the bite of
the mosquito
– Well screen accommodations or air conditioning
– Use of insecticide indoors
– Apply insect repellent to skin and clothing. The most effective
are the ones with DEET
– Empty , clean or cover any standing water that can be a
mosquito-breeding site

Final word of advice for travellers
• The times of higher risk of being bitten by the
female mosquito is 2 to 3 hours after daybreak
and 3 to 4 hours before nightfall
• The mosquito can feed indoors as well as
outdoors

RREEFFEERREENNCCEESS
 Katzung & Trevor's Pharmacology Examination and Board
Review
 Lippincott's Illustrated Reviews: Pharmacology
Comprehensive Pharmacy Review by Leon Shargel
 http://www.nytimes.com/health/guides/disease/malaria/overview.html
 http://www.cdc.gov/malaria/
 http://www.who.int
 http://www.who.int/tdr/publications/documents/dengue-life-cycle.swf
 http://realityviews.blogspot.com/2010/08/dengue-fever-know-25-dengue-natural. http://www.slideshare.net/brittgow/malaria-powerpoint
 http://www.slideshare.net/PietriGirl/dengue-1334860
 http://www.malariajournal.com/content

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