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MALARIA

Dr.T.V.Rao MD

DR.T.V.RAO MD

HISTORY AND FUTURE RESEARCH


One of the oldest known diseases.

King Tut died of malaria.


Malaria has been infecting humans for over 50,000 years. References to malaria have been recorded for nearly 6000 years, starting in China. Used to be common in Europe and North America. First advances in malaria were made in 1880 by a French army doctor named Charles Laveran. He looked into infected red blood cells and discovered the parasite was a protist. This was the first time a protist was discovered to cause a disease.

Carlos Finlay discovered that mosquitoes transmitted diseases.


DR.T.V.RAO MD

MALARIA HISTORY WHO MADE IT

Alphonse Laveran

Sir Patrick Manson

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Sir Ronald Ross

Giovanni Grassi
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It was discovered more than 100 years ago


A French army doctor in Algeria observed parasites inside red blood cells of malaria patients and proposed for the first time that a protozoan caused disease
Charles Louis Alphonse Laveran
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RONALD ROSS DISCOVERS THE ROLE OF MOSQUITOS AND TRANSMISSION


Ronald Ross discovered that mosquitoes transmitted malaria in 1898. First effective medicine was discovered by Pierre Pelletier and Joseph Caventou. This medicine is called quinine, which comes from the bark of cinchona trees in Peru. No effective vaccine: only immunity is a result of multiple infections.

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MALARIA HOT SPOTS GEOGRAPHIC DISTRIBUTION

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PRESENT GEOGRAPHICAL DISTRIBUTION OF MALARIA

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DR.T.V.RAO MD

MALARIA in 40% of the worlds population lives


endemic areas 3-500 million clinical cases per year 1.5-2.7 million deaths (90% Africa) increasing problem (re-emerging disease)
resurgence in some areas drug resistance ( mortality)

causative agent = Plasmodium species


protozoan parasite member of Apicomplexa 4 species infecting humans
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P. falciparum P. vivax P. malariae P. ovale


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transmitted by anopholine mosquitoes

WHAT IS MALARIA?
Malaria is a parasite that enters the blood. This parasite is a protozoan called plasmodium. 3 to 700 million people get malaria each year, but only kills 1 to 2 million

40% of the worlds population lives in malaria zones


Malaria zones are: Africa, India, Middle East, Southeast Asia, Central and South America, Eastern Europe, and the South Pacific (slide 13).
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WHAT DETERMINES THE SPREAD OF MALARIA?


Malaria spread depends on:

Rainfall pattern
(How does this affect mosquito breeding?) Types of mosquitoes in the area How close are people to the breeding sites? Some areas constantly have a high rate of malaria. Other areas have malaria seasons or occasional epidemics of malaria.
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MALARIA BURDEN CLINICAL MANIFESTATIONS


Hypoglycemia

Anemia
Acute febrile illness Infected Mosquito Severe illness Respiratory distress Cerebral malaria Death

Anemia Chronic effects Infected Human Neurologic/ cognitive Developmental Impaired growth and development Malnutrition

Fetus Pregnancy Maternal


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Low birth weight Acute illness Anemia

Infant mortality
Impaired 12 productivity

MALARIA PARASITE (PLASMODIUM) Pathogen of malaria P.vivax ; P.falciparum ;P.malariae ; P.ovale P.vivax ; P.falciparum are more common Plasmodium is a wide distribution in many tropical or subtropical regions of the world
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MALARIA VECTORS

Anopheles balabacensis

A. gambiae

A. freeborni
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A. stephensi
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CHARACTERISTIC OF LIFE CYCLE


Intermediate host : human

Final host : mosquito


Infective stage : sporozoite Infective way : mosquito bite skin of human Parasitic position : liver and red blood cells Transmitted stage : gametocytes

Schizogonic cycle in red cells : 48 hrs/P.v


Sporozoite : tachysporozite and bradysporozite
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MOSQUITOES AND MALARIA


The spread of malaria depends on the life cycle of the mosquito. Adult mosquitoes lay their eggs on water. The eggs hatch to become larvae and then pupae, before turning into adults. Adult females mosquitoes only live 2 to 4 weeks. So you can reduce malaria by attacking any of these four stages of the mosquito.
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Life Cycle
sporozoites injected during mosquito feeding invade liver cells exoerythrocytic schizogony (merozoites) merozoites invade RBCs repeated erythrocytic schizogony cycles gametocytes infective for mosquito fusion of gametes in gut sporogony on gut wall in hemocoel sporozoites invade salivary glands
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Invasive Stages

Merozoite erythrocytes Sporozoite salivary glands hepatocytes Ookinete epithelium


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SPECIES CHARACTERISTICS
PV PO PM PF

Periodicity(hrs.)
Parasites/Ml RBC Age

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20-50 Young

50
9-30 Young

72
6-20 Old

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50-2000 Any

Hyponozoite
Duration (yrs.)

Yes
1.5-5

Yes
1.5-5

No
3->50

No
1-2

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MORPHOLOGY
Malarial parasite trophozoites are generally ring shaped, 1-2 microns in size, although other forms (ameboid and band) may also exist. The sexual forms of the parasite (gametocytes) are much larger and 7-14 microns in size. P. falciparum is the largest and is banana shaped, while others are smaller and round.

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EXO-ERYTHROCYTIC
S
HYPNOZOITES

GAMETOCYTES

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ERYTHROCYTIC

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Exoerythrocytic Schizogony
hepatocyte invasion asexual replication 6-15 days 1000-10,000 merozoites no overt pathology

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Hyponozoite Forms
some EE forms exhibit delayed replication (ie, dormant) merozoites produced months after initial infection only P. vivax and P. ovale

relapse = hypnozoite
recrudescence = subpatentt

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IS IT FALCIPARUM?
WHAT DOES THE SMEAR SHOW?

>3% PARASITEMIA
MONOTONOUS SMALL RINGS NO TROPHOZOITES OR SCHIZONTS BANANA SHAPED GAMETOCYTES MULTIPLY INFECTED CELLS APPLIQUE FORMS CELLS OF ALL SIZES INFECTED

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HOW THE PARASITE APPEARS IN BLOOD SMEAR

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P. FALCIPARUM BLOOD STAGES

Uninfected RBC

4 hr.

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2 hr.

12 hr.
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erythrocytic schizogony 48 hr in Pf, Pv, Po 72 hr in Pm gametocytes

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Gametocytogenesis
alternative to asexual replication induction factors not known ring gametocyte
drug treatment #'s immune response #'s

Pf : ~10 days others: ~same as schizogony

sexual dimorphism
microgametocytes macrogametocytes

no pathology infective stage for mosquito


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GAMETOCYTES

Male gametocyte

Female gametocyte

Note: compact cytoplasm and absence of nuclear division.


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GAMETOCYTE OF P. FALCIPARUM

banana shaped gametocyte ( P. falciparum)

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Gametogenesis
occurs in mosquito gut exflagellation most obvious
3X nuclear replication 8 microgametes formed

exposure to air induces


temperature (2-3oC) pH (8-8.3) result of pCO2

gametoctye activating factor in mosquito


xanthurenic acid
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Sporogony
occurs in mosquito (9-21 d) fusion of micro- and macrogametes zygote ookinete (~24 hr) ookinete transverses gut epithelium ('trans-invasion')

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Sporogony
ookinete oocyst

asexual replication sporozoites sporozoites released

between epithelium and basal lamina

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Sporogony
sporozoites migrate through hemocoel sporozoites 'invade' salivary glands

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INCUBATION PERIOD

Following the infective bite by the Anopheles mosquito a period of time (the "incubation period") goes by before the first symptoms appear. The incubation period in most cases varies from 7 to 30 days.
The shorter periods are observed most frequently with P. falciparum and the longer ones with P. malariae.

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Clinical Features characterized by acute febrile attacks (malaria


paroxysms)
periodic episodes of fever alternating with symptom-free periods

manifestations and severity depend on species and host status


immunity, general health, nutritional state, genetics

recrudescences and relapses can occur over months or years

can develop severe complications (especially P. falciparum)


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Malaria Paroxysm
paroxysms associated with synchrony of merozoite release between paroxysms temperature is normal and patient feels well falciparum may not exhibit classic paroxysms (continuous fever) tertian malaria quartan malaria
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CLINICAL MANIFESTATIONS
1 Anemia 2 Splenomegaly

3 Cerebral malaria
4 Malaria nephropathy 5 Congenital malaria usually fatal 6 black water fever

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WHAT ARE THE SIGNS AND SYMPTOMS OF MALARIA?

Symptoms of malaria include fever and flu-like illness, including shaking chills, headache, muscle aches, and tiredness. Nausea, vomiting, and diarrhea may also occur. Malaria may cause anemia and jaundice (yellow coloring of the skin and eyes) because of the loss of red blood cells. Infection with one type of malaria, Plasmodium falciparum, if not promptly treated, may cause kidney failure, seizures, mental confusion, coma, and death.

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UNCOMPLICATED MALARIA
The classical (but rarely observed) malaria attack lasts 6-10 hours.
It consists of a cold stage (sensation of cold, shivering) ; a hot stage (fever, headaches, vomiting; seizures in young children) and finally a sweating stage (sweats, return to normal temperature, tiredness)
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IS IT FALCIPARUM?
WHAT DOES THE SMEAR SHOW?

>3% PARASITEMIA
MONOTONOUS SMALL RINGS NO TROPHOZOITES OR SCHIZONTS BANANA SHAPED GAMETOCYTES MULTIPLY INFECTED CELLS APPLIQUE FORMS CELLS OF ALL SIZES INFECTED

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----a

specific attack that it is up to months or even years after the primary attacks. ----The bradysporozoites in the liver spend a rest and sleeping times of months or even years , then they start develop in Exoerythrocytic stage and erythrocytic stage. at this time, the patient occurs paroxysm , showing as periodic fever like the primary attacks, it is called relapse. ----Relapse only occurs in
DR.T.V.RAO MD

RELAPSE

P.vivax

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MALIGNANT MALARIA
Malaria caused by P.falciparum. is more severe than that caused by other plasmodia. ----The serious complication of P.falciparum. involves cerebral malaria (involving the brain); massive haemoglobinuria (blackwater fever) in which the urine becomes dark in color, because of acute hemolysis of RBC; acute respiratory distress syndrome; severe gastrointestinal symptoms; shock and renal failure which may cause death.
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LABORATORY DIAGNOSIS
----

laboratory diagnosis of malaria is confirmed by the demonstration of malarial parasites in

the blood film under microscopic


examination.

Thin film
Thick film
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ANTIGEN DETECTION METHODS


Various test kits are available to detect antigens derived from malaria parasites. Such immunologic ("immunochromatographic") tests most often use a dipstick or cassette format, and 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

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SEROLOGY IN MALARIA
Serology detects antibodies against malaria parasites, using either indirect immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA). Serology does not detect current infection but rather measures past exposure.

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MOLECULAR DIAGNOSIS OF MALARIA


Parasite nucleic acids are detected using polymerase chain reaction (PCR). Although this technique may be slightly more sensitive than smear microscopy, it is of limited utility for the diagnosis of acutely ill patients in the standard healthcare setting. PCR results are often not available quickly enough to be of value in establishing the diagnosis of malaria infection.

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PCR IS USEFUL IN SPECIES DETECTION


PCR is most useful for confirming the species of malarial parasite after the diagnosis has been established by either smear microscopy or RDT.
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TREATMENT
Faciparum?

Yes

No

Fansidar or Artemeter/Lumefantrine

Vivax or Ovale

Malariae

Chloroquine Check G6PD Primaquine

Chloroquine

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TREATMENT
HALOFANTRINE MALARONE ATOVAQUONE/PROGUANIL

TAFENOQUINE
QUININE based regimens CHLOROQUINE/PROGUANIL

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WHAT ARE WAYS TO PREVENT MOSQUITO BITES?


Use mosquito repellants. Wear long pants and long sleeves. Wear light-colored clothes.

Use window screens


Use bed nets.
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INSECTICIDE-TREATED NETS (ITNS)


What is happening here? What needs to happen within six months? Can you think of any practical challenges?
Source: HEPFDC, 2009.

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ORIGINAL ERADICATION PLANS


Interruption of transmission of main species infecting humans by DDT spraying
Malaria disappears spontaneously in under 3 years
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Source: Gabaldon

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OTHER WAYS TO PREVENT MALARIA


Who is at the highest risk of malaria? Travelers to an area high in malaria

Travelers often take prophylactic (preventive) medicines to prevent malaria.


Pregnant women (especially those with HIV)

Pregnant women are given intermittent preventive treatment. They are given at least 2 doses of a malaria drug during their pregnancy. Young children
How can you protect young children?
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MALARIA VACCINE
Scientists are working on a new malaria vaccine. The vaccine would help protect children from deadly malaria. The vaccine boosts the immune response against malaria. However, the vaccine is still being tested.
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Programme Created by Dr.T.V.Rao MD for Medical and Health Care Workers in the Developing World
Email
doctortvrao@gmail.com

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