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Dr.T.V.Rao MD 1
Malaria Teaching Basics
Dr.T.V.Rao MD
Dr.T.V.Rao MD 2
History of Malaria • 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.
Lavern and Ronald RossPioneered the Events on Malaria
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Malaria – Historywho made it
Patrick MansonSir Alphonse Laveran
Sir Ronald Ross Giovanni Grassi
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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
It was discovered more than 100 years
ago
Charles Louis Alphonse Laveran
Dr.T.V.Rao MD 6
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.
Nature of parasite as Drawn by Lavern
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Malaria – Hot spots Geographic distribution
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Present geographical distribution of malaria
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MALARIA• 40% of the world’s population lives in
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)
•P. falciparum•P. vivax•P. malariae•P. ovale
• causative agent = Plasmodium species• protozoan parasite• member of Apicomplexa• 4 species infecting humans
• transmitted by anopholine mosquitoes
Plasmodium species which infect humans
Plasmodium vivax (tertian)
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartian)
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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.
Exo-erythrocytic (hepatic) cycle
Sporozoites
Mosquito Salivary Gland
Malaria Life CycleLife Cycle
Gametocytes
Oocyst
Erythrocytic Cycle
Zygote
Schizogony
Sporogony
Hypnozoites(for P. vivax and P. ovale)
Exo-erythrocytic (hepatic) cycle
Hypnozoites
Sporozoites
Salivary Gland
LIFE CYCLE OF MALARIA
Gametocytes
Erythrocytic Cycle
Zygote
Adapted from:
Oocyst
Stomach Wall
Pre-erythrocytic (hepatic) cycle
Malaria Transmission Cycle
Parasite undergoes sexual reproduction in the mosquito
Some merozoites differentiate into male or female gametocyctes
Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts
Dormant liver stages (hypnozoites) of P. vivax and P. ovale
Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood
MOSQUITO HUMAN
Sporozoires injected into human host during blood meal
Parasites mature in mosquito midgut and migrate to salivary glands
Components of the Malaria Life Cycle
Mosquito Vector
Human Host
Sporogonic cycle
Infective Period
Mosquito bitesgametocytemic person
Mosquito bitesuninfected person
Prepatent Period
Incubation Period
Clinical Illness
Parasites visible
Recovery
Symptom onset
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Malaria Burden Clinical Manifestations
Infected Mosquito
Infected Human
Chronic effects
AnemiaNeurologic/
cognitiveDevelopmental
Impaired growth and
development
Malnutrition
Acute febrile illness
Severe illness
Hypoglycemia
Anemia
Cerebral malaria
DeathRespiratory distress
Pregnancy
Fetus
MaternalAcute illness
AnemiaImpaired
productivity
Low birth weight Infantmortality
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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. freeborni
A. gambiae
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• erythrocytesSporozoite• salivary glands• hepatocytesOokinete• epithelium
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Species CharacteristicsPV PO PM PF
Periodicity(hrs.) 48 50 72 48Parasites/Ml 20-50 9-30 6-20 50-2000 RBC Age Young Young Old AnyHyponozoite Yes Yes No NoDuration (yrs.) 1.5-5 1.5-5 3->50 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.
Dr.T.V.Rao MD 29ERYTHROCYTIC
HYPNOZOITESS
GAMETOCYTES
EXO-ERYTHROCYTIC
Exoerythrocytic (tissue) phase
• Blood is infected with sporozoites about 30 minutes after the mosquito bite
• The sporozoites are eaten by macrophages or enter the liver cells where they multiply – pre-erythrocytic schizogeny
• P. vivax and P. ovale sporozoites form parasites in the liver called hypnozoites
Exoerythrocytic (tissue) phase
• P. malariae or P. falciparum sporozoites do not form hypnozites, develop directly into pre-erythrocytic schizonts in the liver
• Pre-erythrocytic schizogeny takes 6-16 days post infection
• Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver
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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
Relapsing malaria
• P. vivax and P. ovale hypnozoites remain dormant for months
• They develop and undergoe pre-erythrocytic sporogeny
• The schizonts rupture, releasing merozoites and produce clinical relapse
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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
2 hr.
4 hr.
12 hr.
Exoerythrocytic (tissue) phase
• P. vivax and P. ovale hypnozoites remain dormant for months
• They develop and undergoe pre-erythrocytic sporogeny
• The schizonts rupture, releasing merozoites and producing clinical relapse
Erythrocytic phasestages of parasite in RBC
• Trophozoites are early stages with ring form the youngest
• Tropohozoite nucleus and cytoplasm divide forming a schizont
• Segmentation of schizont’s nucleus and cytoplasm forms merozoites
• Schizogeny complete when schizont ruptures, releasing merozoites into blood stream, causing fever
• These are asexual forms
Erythrocytic phasestages of parasite in RBC
• Merozoites invade other RBCs and schizongeny is repeated
• Parasite density increases until host’s immune response slows it down
• Merozoites may develop into gametocytes, the sexual forms of the parasite
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gametocytes
erythrocytic schizogony• 48 hr in Pf, Pv, Po• 72 hr in Pm
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Gametocytogenesis• alternative to asexual replication• induction factors not known
• drug treatment #'s• immune response #'s
• ring gametocyte• 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
• between epithelium and basal lamina
•asexual replication sporozoites
• sporozoites released
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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.
Schizogenic periodicity and fever patterns
• Schizogenic periodicity is length of asexual erythrocytic phase– 48 hours in P.f., P.v., and P.o. (tertian)– 72 hours in P.m. (quartian)
• Initially may not see characteristic fever pattern if schizogeny not synchronous
• With synchrony, periods of fever or febrile paroxsyms assume a more definite 3 (tertian)- or 4 (quartian)- day pattern
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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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• paroxysms associated with synchrony of merozoite release
• between paroxysms temper-ature is normal and patient feels well
• falciparum may not exhibit classic paroxysms (continuous fever)
Malaria Paroxysm
tertian malariaquartan malaria
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Clinical manifestations1 Anemia 2 Splenomegaly3 Cerebral malaria4 Malaria nephropathy 5 Congenital malaria usually fatal6 black water fever…
Clinical presentation
• Acute febrile illness, may have periodic febrile paroxysms every 48 – 72 hours with
• Afebrile asymptomatic intervals• Tendency to recrudesce or relapse over months to
years• Anemia, thrombocytopenia, jaundice,
hepatosplenomegaly, respiratory distress syndrome, renal dysfunction, hypoglycemia, mental status changes, tropical splenomegaly syndrome
Clinical presentation
• Early symptoms– Headache– Malaise– Fatigue– Nausea– Muscular pains– Slight diarrhea– Slight fever, usually not intermittent
• Could mistake for influenza or gastrointestinal infection
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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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Relapse ----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 P.vivax less in P.ovale
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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
Blood collected with sterile technique
Making of Thick smear
How a thick smear looks
Appearance of Thick and Thin Smears
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
Microscopic demonstration still the Gold standard in Diagnosis
Blood smear stained with
Giemsa’s stain
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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
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)
Principle of QBC System
Appearance of Malarial parasite in QBC system
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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.
Newer Diagnostic methodsMolecular Diagnosi
• 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).
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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.
Other Laboratory Findings• 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
Treatment
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Faciparum?
Yes
Fansidar orArtemeter/Lumefantrine
No
Vivax or Ovale
ChloroquineCheck G6PDPrimaquine
Malariae
Chloroquine
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TREATMENT • HALOFANTRINE• MALARONE
– ATOVAQUONE/PROGUANIL• TAFENOQUINE• QUININE based regimens• CHLOROQUINE/PROGUANIL IS AN INFERIOR
REGIMEN AND SHOULD NOT BE USED
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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
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.
Vaccines for Malaria• This degree of protection would be extremely
difficult to achieve and might not be technically feasible with current vaccinology art and science. Many vaccine developers have therefore focused their efforts on creating a vaccine that limits the ability of the parasite to successfully infect large numbers of red blood cells. This would not prevent infection but would limit the severity of the disease and help prevent malaria deaths.…Vaccine Challenges
Current Initiatives The PATH Malaria Vaccine Initiative and
partner, GlaxoSmithKline Biologicals, published recent Phase 2 trial results showing that the vaccine candidate, RTS,S, has a promising safety and tolerability profile and reduces malaria parasite infection and clinical illness due to malaria. This was the first RTS,S vaccine trial in African infants.
World Malaria Day• World Malaria Day (previously Africa Malaria
Day) will now be commemorated every year on 25 April. The declaration of the 2008 1st World Malaria Day reflects the emphasis the world now attaches to the burden of this disease and its impact on the lives of those who live in malaria endemic countries, especially children under five years and pregnant women
