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.
Malaria and Man
Hippocrates and Malaria
Hippocrates, a physician born in ancient Greece, today regarded as the "Father of Medicine", was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived.
Name is derived from Italian
Mal’ aria or bad air
Malaria continues to be most important cause of fever and morbidity in the Tropical world
Malaria has been eradicated from Europe, Most of North America, USA South America Korea and Japan,
History – Events on Malaria
1880 - Charles Louis Alphose Lavern discovered malarial parasite in wet mount
1883 - Methylene blue stain - Marchafava
1891 - Polychrome stain- Romanowsky
1898 - Roland Ross - Life cycle of parasite transmission, wins Nobel Prize in 1902
1948 - Site of Exoerythrocytic development in Liver by Shortt and Garnham
Major Developments in 20 th Century
1955 - WHO starts world wide malaria eradication programme using DDT
1970 – Mosquitos develop resistance to DDT Programme fails
1976 – Trager and Jensen in vitro cultivation of parasite
1948 - Site of E1948 - Site of Exoerythrocytic dev in Liver by Shortt and Garnham
xoerythrocytic dev in Liver by Shortt and Garnham
Lavern and Ronald Ross Pioneered the Events on Malaria
Nature of parasite as Drawn by Lavern
Nobel Prizes in Malaria
The discovery of this parasite in mosquitoes earned the British scientist Ronald Ross the Nobel Prize in Physiology or Medicine in 1902. In 1907, Alphonse Lavern received the Nobel prize for his findings that the parasite was present in human blood.
Malaria is probably one of the oldest diseases known to mankind that has had profound impact on our history.
It is a huge social, economical and health problem, particularly in the tropical countries.
Malaria is a vector -borne infectious disease caused by single-celled protozoan parasites of the genus Plasmodium.
Malaria is transmitted from person to person by the bite of female mosquitoes.
Female Anopheles Mosquitos transmit Malaria
What causes Malaria
Malaria is caused by a parasite called Plasmodium , which is transmitted via the bites of infected mosquitoes. In the human body, the parasites multiply in the liver, and then infect red blood cells.
Transmission of Malaria do not occur <16 0 c and >33 0 c
Do not occur > 2000 meters altitude.
Parasites Cause of Malaria
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
Falciparum most Dangerous
Falciparum accounts for 90% of deaths due to malaria and vivax is the most widely spread species because it exists in both temperate and tropical climates (Encarta). The malaria life cycle is a complex system with both sexual and asexual aspects .
Why it is important in Medicine
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, of which 270 - 400 million are Falciparum malaria, the most severe form of the disease.
Malaria Kills more people than AIDS
Malaria kills in one year what AIDS kills in 15 years. For every death due to HIV/AIDS there are about 50 deaths due to malaria. To add to the problem is the increasing drug resistance to the established drug.
4 P.falciparum – Falciparum malaria or Malignant Tertian malaria.
Structure of Malarial parasite
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.
1 Pre erythrocytic schizogony
2 Erythrocytic Schizogony
4 Exoerythrocytic schizogony
Pre erythrocytic cycle
Sprozoites undergo developemtnal phase in the liver cell
Sprozoites are elongated and spindle shaped become rounded inside the liver parenchyma
Multiple nuclear divisions develop to Schozonts
A Schizont contains 20,000 – 50,000 merozoites.
Life Cycle of Malaria
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
Affinity of Parasite to Erythrocytes
P.malariae Infectes only young or
P.ovale Old Erythocytes
P.falciparum Infects all age groups
Also adhere to the endothelial lining of Blood vessesl
Causes the obstruction, Thrombosis and Local Ischemias
Liberated Merozoites penetrate RBC
Three stages occur
Ruptured red cells release Merozoites which attack new red cells
Continue with Schizogony
Repeated cycles will continue
In P.falciparum - infected erythrocytes with Schizonts aggregate in the capillaries of brain and other internal organs
Only ring forms are seen in the blood smears
After invasion grow and feed on hemoglobin
Blue cytoplasm and red nucleus, Called as Signet ring appearance
Hence called ring form
When the Trophozoite is fully developed becomes compact.
Malarial pigments are scattered through the cytoplasm
The Nucleus is large and lies at the periphery starts dividing.
Exo Erythrocytic Schizogony
Some Sprozoites do not undergo sporogony in the first instance
But go into resting stage called as Hypnozoites,( hibernation )
Within 2 years reactivate to form Schizonts release Merozoites and attack red cell and produce relapses
Absent in P falciparum
Merozoites differentiate into Male and female gametocytes
Macrogametocytes also called female gametocytes
Microgametocyte also called as male 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 A definitive Host – Mosquito
Mosquito cycle Sexual cycle
Sexual cycle will be initiated in the Humans by the formation of Gametocytes
Develop further in the female Anopheles Mosquito
Only mature sexual forms are capable of further development in Mosquito
In midgut one Microgametocyte develops into 4-8 thread like filamentous structures named Micro gametes
From one macrogametocyte only one macrogamete is formed
Events in Mosquitos
Fertilization occurs when a Microgametocyte penetrate into Macrogametocyte
Fertilized macrogametocyte is known as ZYGOTE
ZYGOTE matures into OOKINETE
OOKINETE to OOCYST
Formation of Sporozoites in Mosquitos.
OOCYST matures with large number of Sporozoites ( A few hundred to thousands.)
OOCYST ruptures and release SPOROZOITES in the body cavity of Mosquito
There is a specific predilection for salivary glands
Now capable to transmit the infection to new Host
Pathology and Pathogenesis
Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum.
Events start with bite of Infected Anopheles Mosquitoes
Sporoozoites enter liver, in 1 hour infect the parenchymal cell.
Pathogenesis in Pre Erythrocyte cycle
Numerous asexual progeny – Merozoites ruputure and leave from liver cells
Enter the Blood and invade Erythrocytes
Erythrocytic cycle starts – Multiply in species specific fashion
Broods of Merozoites appearing at 48 hour interval in P.ovale, P.vivax , P.falciparum
P.malariae appear in 72 hour cycles,
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
Chooses to enter the RBC
Specific for each species
They pit on red cells
By endocytosis enters the RBC
Becomes a Trophozoites
What happens in RBC
Size of Trophozoites is 1/3 of the RBC except in P.falciparum which is 1/5 of RBC
Feed on Hemoglobin but donot totally metabolize and forms the Malarial pigment
When the Trophozoite is fully developed becomes compact.
Malarial pigments are scattered through the cytoplasm
The Nucleus is large and lies at the periphery starts dividing.
Schizont’s are 9 -10 microns
Divide and produce 8-32 Merozoites
Arranged in Rossets in two rows.
Mature schizonts rupture and release Merozoites
Causes the paroxysms of fever.
Merozoites invade fresh RBC Cycles repeats
Cycles differs in Different species
Cycle repeats every 48 hours in
Repeats every 72 hours In
Incubation period varies according to species
Which includes Exo eythrocytic cycle time and one or two erythocytic cycles,
P.vivax and P.falciparum 10 – 15 days (can vary from weeks to months)
P.malariae infection can start after 28 days.
Clinical Features of Malaria
Clinical Manifestations are related to cycle of events in relation to RBC
What are the characteristics of a malaria attack
Fever and shivering. The attack begins with fever, with the temperature rising as high as 40ºC and falling again over a period of several hours.
A poor general condition, feeling unwell and having headaches like influenza.
Diarrhea, nausea and vomiting often occur as well.
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
Broad clinical manifestations of Malaria
Splenomagaly (enlarged spleen)
Coma, Retinal Hemorrages
Algid Malaria ( a shocklike syndrome)
Respiratory distress syndrome
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.
Present with Hyperpyrexia
Can lead to Coma
Paralysis and other complications.
Brain appears congested
Black water fever
In malignant malaria a large number of the red blood corpuscles are destroyed. Hemoglobin from the blood corpuscles is excreted in the urine, which therefore is dark and almost the color 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 ?
Why Falciparum Infections are Dangerous
Can produce fatal complications,
5 Black water fever can lead to death
Complication of P.malariae
Can produce Nephrotic syndrome
Affects mainly children of years age
Pernicious Malaria Carries a High Mortality
On few occasions life threading complications can occur.
Occurs in infections with P.falciparum
Associated with Heavy parasitaztion
Grouped into three types
1. Cerebral Malaria
2 Algid malaria
3 Black water fever
How Malaria present Clinically
Chills for 15 mt to 1 hour
Caused due to rupture from the host red cells escape into Blood
Preset with nausea, vomitting,headache
Fever may reach upto 40 0 c may last for several hours starts invading newer red cells.
patent starts sweating, concludes the episode
Cycles are frequently Asynchronous
Paroxysms occur every 48 – 72 hours
In P.malariae pyrexia may lost for 8 hours or more and temperature my exceed 41 0 c
A.normocytic anemia devlops due repeated ruputure of RBC’s
Laboratory Diagnosis of Malaria
Laboratory diagnosis of malaria can be made through microscopic examination of thick and thin blood smears. Thick blood smears are more sensitive in detecting malaria parasites because the blood is more concentrated allowing for a greater volume of blood to be examined ; however, thick smears are more difficult to read
Blood collected with sterile technique
Making of Thick smear
How a thick smear looks
Appearance of Thick and Thin Smears
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
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.
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. Malaria RDTs are currently used in some clinical settings
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 experience.
Newer Diagnostic methods
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).
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
Still the Choroquine continues to be Drug of choice in all forms of susceptible in all forms of Acute Malaria
1.5 grams of Chloroquine ( Base ) in over 3 days peroid in adults
1.8 grams of Chloroquine in over 4 days.
In children dose to be calculated according to weight
In cases of P.falcipqrum leading to coma need to be treated with Quinidine gluconate till the oral treatment is feasible.
Treatment (cont )
P.vivax with Chloroquine resistance is on raise But Chloroquine is preferred till drug resistance is established.
Early decisions on P.falciparum treatment with appropriate drug is highly essential in view of the rapid detoriation with complications.
Primaquin and 8 Aminoquilone eliminates Exoeythrocytic forms ( Relapsing forms )
Individuals deficient in Glucose -6 phosphate dehydrogenase with Primaquin treatment leads to hemolytic complications. Avoid use of Primaquin or give in low doses
People living in Eastern Mediterrian regions or Some Blacks are prone.
Treating Drug Resistance in P.falciparum
Should be treated with
Quinine sulphate plus single dose of Combination Drug Pyramethamine and Sulphodoxine ( Fansidar )
1 Quinine plus Doxycycline or Tetracycline
2 Quinine plus Clindamycin
1 Mefloquine and Halofantril.
Popular drugs include, Chloroquine, Amodiaquine.
Mefloquine is drug of choice in Chloroquine resistant areas of the world
Prophylactic drugs are chosen on the basis of scientific studies on resistance, availaility,and individual accepatability
CDC – on Current Recommendations
The current guidelance on issues related to Malaraia prevention can be searched at
http://www.cdc.gov ( travelers health )
Malaria continues to be one of the most important and devastating infectious diseases in developing areas of the world. Worldwide, over 40% of the population lives in areas where malaria transmission occurs (i.e., parts of Africa, Asia, the Middle East, Central and South America, Hispaniola, and Oceania)
Major cause of Morbidity and Morality
1 It is estimated that 300-500 million cases of malaria occur each year resulting in 7,50,000-2 million deaths.
Control of Malaria
Elimination of Mosquito breeding places,
National improvements on health and Hygiene.
Use of Mosquito nets, treated with Pyrithrin
Clothing with sleeves, and long trousers
Use of Mosquito repellents
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
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.
Current successful Trails
The most successful candidate developed to date is the RTS,S recombinant vaccine. The RTS,S/AS02A, one of the key vaccines produced using this technique, has been used in field trials in The Gambia. Three repeat doses were administered in the 6 months leading up to the period of highest malaria transmission. The vaccine efficacy was reported at approximately 71% (with 95% confidence intervals spanning from 46 to 85%) during the first 2 months of follow-up, but falling to 0% in the last 6 weeks in 250 male volunteers.
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
Bill Gates greatest contribution to Malaria eradication
The Bill & Melinda Gates Foundation announced three grants totaling $258.3 million in 2005 for advanced development of a malaria vaccine, new drugs, and innovative mosquito control methods to help defeat malaria, a disease that kills 2,000 African children every day
Bill Gates and Melinda Gates contribution is Immense – In Malaria
Created for Universal Education on Malaria Dr.T.V.Rao MD Email [email_address]