Malaria -I

Malaria
Malaria is a vector-borne infectious disease that is widespread in tropical and subtropical regions. It infects between 300 and 500 million people every year and causes between one and three million deaths annually, mostly among young children in Sub-Saharan Africa. Malaria is not just a disease commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development.
Malaria is one of the most common infectious diseases and an enormous public-health problem. The disease is caused by protozoan parasites of the genus Plasmodium. The most serious forms of the disease are caused by Plasmodium falciparum and Plasmodium vivax, but other related species (Plasmodium ovale, Plasmodium malariae, and sometimes Plasmodium knowlesi) can also infect humans. This group of human-pathogenic Plasmodium species are usually referred to as malaria parasites.
Malaria parasites are transmitted by female Anopheles mosquitoes. The parasites multiply within red blood cells, causing symptoms that include symptoms of anemia (light headedness, shortness of breath, tachycardia etc.), as well as other general symptoms such as fever, chills, nausea, flu-like illness, and in severe cases, coma and death. Malaria transmission can be reduced by preventing mosquito bites with mosquito nets and insect repellents, or by mosquito control by spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs.
Unfortunately, no vaccine is currently available for malaria. Instead preventative drugs must be taken continuously to reduce the risk of infection. These prophylactic drug treatments are simply too expensive for most people living in endemic areas. Malaria infections are treated through the use of antimalarial drugs, such as chloroquine or pyrimethamine, although drug resistance is increasingly common.
History
Malaria has infected humans for over 50,000 years, and may have been a human pathogen for the entire history of our species. Indeed, close relatives of the human malaria parasites remain common in chimpanzees, our closest relatives. References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China during the Xia Dynasty. The term malaria originates from Medieval Italian: mala aria — "bad air"; and the disease was formerly called ague or marsh fever due to its association with swamps.
Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in Algeria named Charles Louis Alphonse Laveran observed parasites inside the red blood cells of people suffering from malaria. He therefore proposed that malaria was caused by this protozoan, the first time protozoa were identified as causing disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. The protozoan was called Plasmodium by the Italian scientists Ettore Marchiafava and Angelo Celli. A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, first suggested that mosquitoes were transmitting disease to humans. However, it was Britain's Sir Ronald Ross working in India who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly-established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius.[7] The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900, and its recommendations implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against this disease.
The first effective treatment for malaria was the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. This natural product was used by the inhabitants of Peru to control malaria, and the Jesuits introduced this practice to Europe during the 1640s where it was rapidly accepted. However, it was not until 1820 that the active ingredient quinine was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Caventou.
In the early twentieth century, before antibiotics, patients with syphilis were intentionally infected with malaria to create a fever. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable than the almost-certain death from syphilis.
Although the blood stage and mosquito stages of the malaria life cycle were established in the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed. The discovery of this latent form of the parasite finally explained why people could appear to be cured of malaria but still relapse years after the parasite had disappeared from their bloodstreams.
Distribution and impact
Malaria causes about 350–500 million infections in humans and approximately one to three million deaths annually — this represents at least one death every 30 seconds. The vast majority of cases occur in children under the age of 5 years; pregnant women are also especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has been little change in which areas are at risk of this disease since 1992. Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double in the next twenty years. Precise statistics are unknown because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. Consequently, the majority of cases are undocumented.
Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than with HIV/tuberculosis co-infection, due to the two diseases usually attacking different age-ranges, with malaria being most common in the young and active tuberculosis most common in the old. Although HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to each other's spread. This effect comes from malaria increasing viral load and HIV infection increasing a person's susceptibility to malaria infection.
Malaria is presently endemic in a broad band around the equator, in areas of South America, South and Southeast Asia, parts of the Middle East and Oceania, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur. The geographic distribution of malaria within large regions is complex, and malarial and malaria-free areas are often found close to each other. In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall. Malaria is more common in rural areas than in cities; this is in contrast to dengue fever where urban areas present the greater risk. For example, the cities of the Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in many rural regions. By contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities.
Socio-economic effects
Malaria is not just a disease commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development. The disease has been associated with major negative economic effects on regions where it is widespread. A comparison of average per capita GDP in 1995, adjusted to give parity of purchasing power, between malarious and non-malarious countries demonstrates a fivefold difference (US$1,526 versus US$8,268). Moreover, in countries where malaria is common, average per capita GDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries. In its entirety, the economic impact of malaria has been estimated to cost Africa US$12 billion every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism. In some countries with a heavy malaria burden, the disease may account for as much as 40% of public health expenditure, 30-50% of inpatient admissions, and up to 50% of outpatient visits.
Symptoms
Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia caused by hemolysis, hemoglobinuria, and convulsions. There may be the feeling of tingling in the skin, particularly with malaria caused by P. falciparum. The classical symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. falciparum, P. vivax and P. ovale infections, while every three for P. malariae. For reasons that are poorly understood, but which may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia during a period of rapid brain development and also direct brain damage from cerebral malaria to which children are more vulnerable.
Severe malaria is almost exclusively caused by P. falciparum infection and usually arises 6-14 days after infection. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), and hemoglobinuria with renal failure may occur. Renal failure may cause blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease fatality rates can exceed 20%, even with intensive care and treatment. In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.
Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can therefore be deceptive. The longest incubation period reported for a P. vivax infection is 30 years. Approximately one in five of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).
Hypoglycemia has four causes (direct and indirect) - 1) high parasitemia (parasite's inefficient use of glucose), 2) you don't eat as much because you lose your appetite, 3) depletion of liver glycogen and 4) inhibition of gluconeogenisis.
Causes
Malaria parasites
Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, and P. vivax. However, P. falciparum is the most important cause of disease and responsible for about 80% of infections and 90% of deaths. Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents. There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi, P. simiovale, P. brazilianum, P. schwetzi and P. simium; however these are mostly of limited public health importance. Although avian malaria can kill chickens and turkeys, this disease does not cause serious economic losses to poultry farmers. However, since being accidentally introduced by humans it has decimated the endemic birds of Hawaii, which evolved in its absence and lack any resistance to it.
Mosquito vectors and the Plasmodium life cycle
The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.
Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal. Malaria parasites can also be transmitted by blood transfusions, although this is rare.

To be continued;;;;

Dr Abdul Aziz Awan

Pathogenesis
Malaria
in humans develops via two phases: an exoerythrocytic (hepatic) and an
erythrocytic phase. When an infected mosquito pierces a person's skin
to take a blood meal, sporozoites in the mosquito's saliva enter the
bloodstream and migrate to the liver. Within 30 minutes of being
introduced into the human host, they infect hepatocytes, multiplying
asexually and asymptomatically for a period of 6–15 days. During this
so-called dormant time in the liver the sporozoites are often referred
to as hypnozoites. In the liver they differentiate to yield thousands
of merozoites which, following rupture of their host cells, escape into
the blood and infect red blood cells, thus beginning the erythrocytic
stage of its life cycle. The parasite escapes from the liver undetected
by wrapping itself in the cell membrane of the infected host liver
cell.
Within the red blood cells the parasites multiply further,
again asexually, periodically breaking out of their hosts to invade
fresh red blood cells. Several of such amplification cycles occur.
Thus, classical descriptions of waves of fever arise from simultaneous
waves of merozoites escaping and infecting red blood cells.
Some P.
vivax and P. ovale sporozoites do not immediately develop into
exoerythrocytic-phase merozoites, but instead produce hypnozoites that
remain dormant for periods ranging from several months (6–12 months is
typical) to as long as three years. After a period of dormancy, they
reactivate and produce merozoites. Hypnozoites are responsible for long
incubation and late relapses in these two species of malaria.
The
parasite is relatively protected from attack by the body's immune
system because for most of its human life cycle it resides within the
liver and blood cells and is relatively invisible to immune
surveillance. However, circulating infected blood cells are destroyed
in the spleen. To avoid this fate, the P. falciparum parasite displays
adhesive proteins on the surface of the infected blood cells, causing
the blood cells to stick to the walls of small blood vessels, thereby
sequestering the parasite from passage through the general circulation
and the spleen. This "stickiness" is the main factor giving rise to
hemorrhagic complications of malaria. High endothelial venules (the
smallest branches of the circulatory system) can be blocked by the
attachment of masses of these infected red blood cells. The blockage of
these vessels causes symptoms such as in placental and cerebral
malaria. In cerebral malaria the sequestrated red blood cells can
breach the blood brain barrier possibly leading to coma.
Although
the red blood cell surface adhesive proteins (called PfEMP1, for
Plasmodium falciparum erythrocyte membrane protein 1) are exposed to
the immune system they do not serve as good immune targets because of
their extreme diversity; there are at least 60 variations of the
protein within a single parasite and perhaps limitless versions within
parasite populations. Like a thief changing disguises or a spy with
multiple passports, the parasite switches between a broad repertoire of
PfEMP1 surface proteins, thus staying one step ahead of the pursuing
immune system.
Some merozoites turn into male and female
gametocytes. If a mosquito pierces the skin of an infected person, it
potentially picks up gametocytes within the blood. Fertilization and
sexual recombination of the parasite occurs in the mosquito's gut,
thereby defining the mosquito as the definitive host of the disease.
New sporozoites develop and travel to the mosquito's salivary gland,
completing the cycle. Pregnant women are especially attractive to the
mosquitoes, and malaria in pregnant women is an important cause of
stillbirths, infant mortality and low birth weight.
Evolutionary pressure of malaria on human genes
Malaria
is thought to have been the greatest selective pressure on the human
genome in recent history. This is due to the high levels of mortality
and morbidity caused by malaria, especially the P. falciparum species.
Sickle-cell disease
The
best-studied influence of the malaria parasite upon the human genome is
the blood disease, sickle-cell disease. In sickle-cell disease, there
is a mutation in the HBB gene, which encodes the beta globin subunit of
haemoglobin. The normal allele encodes a glutamate at position six of
the beta globin protein, while the sickle-cell allele encodes a valine.
This change from a hydrophilic to a hydrophobic amino acid encourages
binding between haemoglobin molecules, with polymerization of
haemoglobin deforming red blood cells into a sickle shape.
Individuals
homozygous for the mutation have full sickle-cell disease and rarely
live beyond adolescence. However, this allele has sustained gene
frequencies in populations where malaria is endemic of around 10%. This
is because individuals heterozygous for the mutated allele, known as
sickle-cell trait, have a low level of anaemia but also have a greatly
reduced chance of malaria infection. The existence of four haplotypes
of sickle-type hemoglobin suggests that this mutation has emerged
independently at least four times in malaria-endemic areas, further
demonstrating its evolutionary advantage in such affected regions.
There
are also other mutations of the HBB gene that produce haemoglobin
molecules capable of conferring similar resistance to malaria
infection. These mutations produce haemoglobin types HbE and HbC which
are common in Southeast Asia and Western Africa, respectively.
Thalassaemias
Another
well documented set of mutations found in the human genome associated
with malaria are those involved in causing blood disorders known as
thalassaemias. Studies in Sardinia and Papua New Guinea have found that
the gene frequency of β-thalassaemias is related to the level of
malarial endemicity in a given population. A study on more than 500
children in Liberia found that those with β-thalassaemia had a 50%
decreased chance of getting clinical malaria. Similar studies have
found links between gene frequency and malaria endemicity in the α+
form of α-thalassaemia.
Duffy antigens
The
Duffy antigens are antigens expressed on red blood cells and other
cells in the body acting as a chemokine receptor. The expression of
Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc
etc.). Plasmodium vivax malaria uses the Duffy antigen to enter blood
cells. However, it is possible to express no Duffy antigen on red blood
cells (Fy-/Fy-). This genotype confers complete resistance to P. vivax
infection. The genotype has not been found in Chinese populations, has
rarely been found in white populations, but is found in 68% of black
people. This is thought to be due to very high exposure to P. vivax in
Africa in the past.
G6PD
Glucose-6-phosphate
dehydrogenase (G6PD) is an enzyme which normally protects from the
effects of oxidative stress in red blood cells. However, a genetic
deficiency in this enzyme results in increased protection against
severe malaria.
HLA
HLA-B53 is associated
with low risk of severe malaria. This MHC class I molecule presents
liver stage and sporozoite antigens to T-Cells.
Diagnosis
The
preferred and most reliable diagnosis of malaria is microscopic
examination of blood films because each of the four major parasite
species has distinguishing characteristics. Two sorts of blood film are
traditionally used. Thin films are similar to usual blood films and
allow species identification because the parasite's appearance is best
preserved in this preparation. Thick films allow the microscopist to
screen a larger volume of blood and are about eleven times more
sensitive than the thin film, so picking up low levels of infection is
easier on the thick film, but the appearance of the parasite is much
more distorted and therefore distinguishing between the different
species can be much more difficult.
From the thick film, an
experienced microscopist can detect parasite levels (or parasitemia)
down to as low as 0.0000001% of red blood cells. Microscopic diagnosis
can be difficult because the early trophozoites ("ring form") of all
four species look identical and it is never possible to diagnose
species on the basis of a single ring form; species identification is
always based on several trophozoites. Please refer to the articles on
each parasite for their microscopic appearances: P. falciparum, P.
vivax, P. ovale, P. malariae.
In areas where microscopy is not
available, or where laboratory staff are not experienced at malaria
diagnosis, there are antigen detection tests that require only a drop
of blood. OptiMAL-IT® will reliably detect falciparum down to 0.01%
parasitemia and non-falciparum down to 0.1%. Paracheck-Pf® will detect
parasitemias down to 0.002% but will not distinguish between falciparum
and non-falciparum malaria. Parasite nucleic acids are detected using
polymerase chain reaction. This technique is more accurate than
microscopy. However, it is expensive, and requires a specialized
laboratory. Moreover, levels of parasitemia are not necessarily
correlative with the progression of disease, particularly when the
parasite is able to adhere to blood vessel walls. Therefore more
sensitive, low-tech diagnosis tools need to be developed in order to
detect low levels of parasitaemia in the field.
Molecular methods
are available in some clinical laboratories and rapid real-time assays
(for example, QT-NASBA based on the polymerase chain reaction) are
being developed with the hope of being able to deploy them in endemic
areas.
Severe malaria is commonly misdiagnosed in Africa, leading to
a failure to treat other life-threatening illnesses. In malaria-endemic
areas, parasitemia does not ensure a diagnosis of severe malaria
because parasitemia can be incidental to other concurrent disease.
Recent investigations suggest that malarial retinopathy is better
(collective sensitivity of 95% and specificity of 90%) than any other
clinical or laboratory feature in distinguishing malarial from
non-malarial coma.
Treatment
Active
malaria infection with P. falciparum is a medical emergency requiring
hospitalization. Infection with P. vivax, P. ovale or P. malariae can
often be treated on an outpatient basis. Treatment of malaria involves
supportive measures as well as specific antimalarial drugs. When
properly treated, someone with malaria can expect a complete cure.
Antimalarial drugs

There
are several families of drugs used to treat malaria. Chloroquine is
very cheap and until recently, was very effective, which made it the
antimalarial drug of choice for many years in most parts of the world.
However, resistance of Plasmodium falciparum to chloroquine has spread
recently from Asia to Africa, making the drug ineffective against the
most dangerous Plasmodium strain in many affected regions of the world.
In those areas where chloroquine is still effective it remains the
first choice. Unfortunately, chloroquine-resistance is associated with
reduced sensitivity to other drugs such as quinine and amodiaquine.
There
are several other substances which are used for treatment and,
partially, for prevention (prophylaxis). Many drugs may be used for
both purposes; larger doses are used to treat cases of malaria. Their
deployment depends mainly on the frequency of resistant parasites in
the area where the drug is used. One drug currently being investigated
for possible use as an anti-malarial, especially for treatment of
drug-resistant strains, is the beta blocker propranolol. Propranolol
has been shown to block Plasmodium's ability to gain access to the red
blood cell "password system" and thus join with and engulf the cell,
infecting it. A December 2006 study by Northwestern University
researchers suggested that propranolol may reduce the dosages required
for existing drugs to be effective against P. falciparum by 5- to
10-fold, suggesting a role in combination therapies.
Currently available anti-malarial drugs include:
• Artemether-lumefantrine (Therapy only, commercial names Coartem® and Riamet®)
• Artesunate-amodiaquine (Therapy only)
• Artesunate-mefloquine (Therapy only)
• Artesunate-Sulfadoxine/pyrimethamine (Therapy only)
• Atovaquone-proguanil, trade name Malarone (Therapy and prophylaxis)
• Quinine (Therapy only)
• Chloroquine (Therapy and prophylaxis; usefulness now reduced due to resistance)
• Cotrifazid (Therapy and prophylaxis)
• Doxycycline (Therapy and prophylaxis)
• Mefloquine, trade name Lariam (Therapy and prophylaxis)
• Primaquine (Therapy in P. vivax and P. ovale only; not for prophylaxis)
• Proguanil (Prophylaxis only)
•
Sulfadoxine-pyrimethamine (Therapy; prophylaxis for semi-immune
pregnant women in endemic countries as "Intermittent Preventive
Treatment" - IPT)
• Hydroxychloroquine, trade name Plaquenil (Therapy and prophylaxis)
Counterfeit drugs
Sophisticated
counterfeits have been found in Thailand, Vietnam, Cambodia and China,
and are an important cause of avoidable death in these countries. There
is no reliable way for doctors or lay people to detect counterfeit
drugs without help from a laboratory.

To be continued.....

Dr Abdul Aziz Awan

Prevention and disease control
Methods
used to prevent the spread of disease, or to protect individuals in
areas where malaria is endemic, include prophylactic drugs, mosquito
eradication, and the prevention of mosquito bites. There is currently
no vaccine that will prevent malaria, but this is an active field of
research.
Many researchers argue that prevention of malaria may be
more cost-effective than treatment of the disease in the long run, but
the capital costs required are out of reach of many of the world's
poorest people. Economic adviser Jeffrey Sachs estimates that malaria
can be controlled for US$3 billion in aid per year. It has been argued
that, in order to meet the Millennium Development Goals, money should
be redirected from HIV/AIDS treatment to malaria prevention, which for
the same amount of money would provide greater benefit to African
economies.
Efforts to eradicate malaria by eliminating mosquitoes
have been successful in some areas. Malaria was once common in the
United States and southern Europe, but the draining of wetland breeding
grounds and better sanitation, in conjunction with the monitoring and
treatment of infected humans, eliminated it from affluent regions. In
2002, there were 1,059 cases of malaria reported in the US, including
eight deaths. In five of those cases, the disease was contracted in the
United States. Malaria was eliminated from the northern parts of the
USA in the early twentieth century, and the use of the pesticide DDT
eliminated it from the South by 1951. In the 1950s and 1960s, there was
a major public health effort to eradicate malaria worldwide by
selectively targeting mosquitoes in areas where malaria was rampant.
However, these efforts have so far failed to eradicate malaria in many
parts of the developing world - the problem is most prevalent in Africa.
Brazil,
Eritrea, India, and Vietnam have, unlike many other developing nations,
successfully reduced the malaria burden. Common success factors
included conducive country conditions, a targeted technical approach
using a package of effective tools, data-driven decision-making, active
leadership at all levels of government, involvement of communities,
decentralized implementation and control of finances, skilled technical
and managerial capacity at national and sub-national levels, hands-on
technical and programmatic support from partner agencies, and
sufficient and flexible financing.
Prophylactic drugs
Several
drugs, most of which are also used for treatment of malaria, can be
taken preventively. Generally, these drugs are taken daily or weekly,
at a lower dose than would be used for treatment of a person who had
actually contracted the disease. Use of prophylactic drugs is seldom
practical for full-time residents of malaria-endemic areas, and their
use is usually restricted to short-term visitors and travelers to
malarial regions. This is due to the cost of purchasing the drugs,
negative side effects from long-term use, and because some effective
anti-malarial drugs are difficult to obtain outside of wealthy nations.
Quinine
was used starting in the seventeenth century as a prophylactic against
malaria. The development of more effective alternatives such as
quinacrine, chloroquine, and primaquine in the twentieth century
reduced the reliance on quinine. Today, quinine is still used to treat
chloroquine resistant Plasmodium falciparum, as well as severe and
cerebral stages of malaria, but is not generally used for prophylaxis.
Modern
drugs used preventively include mefloquine (Lariam®), doxycycline
(available generically), and the combination of atovaquone and
proguanil hydrochloride (Malarone®). The choice of which drug to use
depends on which drugs the parasites in the area are resistant to, as
well as side-effects and other considerations. The prophylactic effect
does not begin immediately upon starting taking the drugs, so people
temporarily visiting malaria-endemic areas usually begin taking the
drugs one to two weeks before arriving and must continue taking them
for 4 weeks after leaving (with the exception of atovaquone proguanil
that only needs be started 2 days prior and continued for 7 days
afterwards).
Indoor residual spraying
DDT was developed as the
first of the modern insecticides early in World War II. While it was
initially used to combat malaria, its use spread to agriculture where
it was used to eliminate insect pests. In time, pest-control, rather
than disease-control, came to dominate DDT use, particularly in the
developed world. During the 1960s, awareness of the negative
consequences of its indiscriminate use increased, and ultimately led to
bans in many countries in the 1970s. By this time, its large-scale use
had already led to the evolution of resistant mosquitoes in many
regions.
However, given the continuing toll to malaria, particularly
in developing countries, there is considerable controversy regarding
the restrictions placed on the use of DDT. Some advocates claim that
bans are responsible for tens of millions of deaths in tropical
countries where previously DDT was effective in controlling malaria.
Furthermore, most of the problems associated with DDT use stem
specifically from its industrial-scale application in agriculture,
rather than its use in public health.
The World Health Organization
(WHO) currently advises the use of DDT to combat malaria in endemic
areas. For instance, DDT-spraying the interior walls of living spaces,
where mosquitoes land, is an effective control. The WHO also recommends
a series of alternative insecticides to both combat malaria in areas
where mosquitoes are DDT-resistant, and to slow the evolution of
resistance. This public health use of small amounts of DDT is permitted
under the Stockholm Convention on persistent organic pollutants (POPs),
which prohibits the agricultural use of DDT for large-scale field
spraying. However, because of its legacy, many developed countries
discourage DDT use even in small quantities.
Mosquito nets and bedclothes
Mosquito
nets help keep mosquitoes away from people, and thus greatly reduce the
infection and transmission of malaria. The nets are not a perfect
barrier, so they are often treated with an insecticide designed to kill
the mosquito before it has time to search for a way past the net.
Insecticide-treated nets (ITN) are estimated to be twice as effective
as untreated nets, and offer greater than 70% protection compared with
no net. Since the Anopheles mosquitoes feed at night, the preferred
method is to hang a large "bed net" above the center of a bed such that
it drapes down and covers the bed completely.
The distribution of
mosquito nets impregnated with insecticide (often permethrin or
deltamethrin) has been shown to be an extremely effective method of
malaria prevention, and it is also one of the most cost-effective
methods of prevention. These nets can often be obtained for around
US$2.50 - $3.50 (2-3 euros) from the United Nations, the World Health
Organization, and others.
For maximum effectiveness, the nets should
be re-impregnated with insecticide every six months. This process poses
a significant logistical problem in rural areas. New technologies like
Olyset or DawaPlus allow for production of Long-Lasting Insecticidal
Mosquito Nets (LLINs), which release insecticide for approximately 5
years, and cost about US$5.50. ITN's have the advantage of protecting
people sleeping under the net and simultaneously killing mosquitoes
that contact the net. This has the effect of killing the most dangerous
mosquitoes. Some protection is also provided to others, including
people sleeping in the same room but not under the net.
Unfortunately,
the cost of treating malaria is high relative to income, and the
illness results in lost wages. Consequently, the financial burden means
that the cost of a mosquito net is often unaffordable to people in
developing countries, especially for those most at risk. Only 1 out of
20 people in Africa own a bed net. Although shipped into Africa mainly
from Europe as free development help, the nets quickly become expensive
trade goods. They are mainly used for fishing, and by combining
hundreds of donated mosquito nets, whole river sections can be
completely shut off, allowing not even the smallest fish to escape.
A
study among Afghan refugees in Pakistan found that treating top-sheets
and chaddars (head coverings) with permethrin has similar effectiveness
to using a treated net, but is much cheaper.
A new approach,
announced in Science on June 10, 2005, uses spores of the fungus
Beauveria bassiana, sprayed on walls and bed nets, to kill mosquitoes.
While some mosquitoes have developed resistance to chemicals, they have
not been found to develop a resistance to fungal infections.
Vaccination
Vaccines for malaria are under development, with no completely effective vaccine yet available.
The
first promising studies demonstrating the potential for a malaria
vaccine were performed in 1967 by immunizing mice with live,
radiation-attenuated sporozoites, providing protection to about 60% of
the mice upon subsequent injection with normal, viable sporozoites.
Since the 1970s, there has been a considerable effort to develop
similar vaccination strategies within humans. It was determined that an
individual can be protected from a P. falciparum infection if she
receives over 1000 bites from infected, irradiated mosquitoes.
Though
promising, it is generally accepted that it is hardly practical to
provide at-risk individuals with this vaccination strategy. Instead,
much work has been performed to try and understand the immunological
processes that provide protection after immunization with irradiated
sporozoites. After the mouse vaccination study in 1967, it was
hypothesized that the injected sporozoites themselves were being
recognized by the immune system, which was in turn creating antibodies
against the parasite. It was determined that the immune system was
creating antibodies against the circumsporozoite protein (CSP) which
coated the sporozoite. Moreover, antibodies against CSP prevented the
sporozoite from invading hepatocytes. CSP was therefore chosen as the
most promising protein on which to develop a vaccine against the
malaria sporozoite. It is for these historical reasons that vaccines
based on CSP are the most numerous of all malaria vaccines.
Presently,
there is a huge variety of vaccine candidates on the table.
Pre-erythrocytic vaccines (vaccines that target the parasite before it
reaches the blood), in particular vaccines based on CSP, make up the
largest group of research for the malaria vaccine. Other vaccine
candidates include: those that seek to induce immunity to the blood
stages of the infection; those that seek to avoid more severe
pathologies of malaria by preventing adherence of the parasite to blood
venules and placenta; and transmission-blocking vaccines that would
stop the development of the parasite in the mosquito right after the
mosquito has taken a bloodmeal from an infected person. It is hoped
that the sequencing of the P. falciparum genome will provide targets
for new drugs or vaccines.
The RTS,S/AS02A vaccine is the
candidate furthest along in vaccine trials. It is being developed by a
partnership between the PATH Malaria Vaccine Initiative (a grantee of
the Gates Foundation) and the pharmaceutical company, GlaxoSmithKline.
In the vaccine, a portion of CSP has been fused to the immunogenic "S
antigen" of the hepatitis B virus; this recombinant protein is injected
alongside the potent AS02A adjuvant. In October 2004, the RTS,S/AS02A
researchers announced results of a Phase IIb trial, indicating the
vaccine reduced infection risk by approximately 30% and severity of
infection by over 50%. The study looked at over 2,000 Mozambican
children. Further research will delay this vaccine from commercial
release until around 2011.
Other methods
Sterile insect
technique is emerging as a potential mosquito control method. Progress
towards transgenic, or genetically modified, insects suggest that wild
mosquito populations could be made malaria-resistant. Researchers at
Imperial College London created the world's first transgenic malaria
mosquito, with the first plasmodium-resistant species announced by a
team at Case Western Reserve University in Ohio in 2002.
Before DDT,
malaria was successfully eradicated or controlled also in several
tropical areas by removing or poisoning the breeding grounds of the
mosquitoes or the aquatic habitats of the larva stages, for example by
filling or applying oil to places with standing water. These methods
have seen little application in Africa for more than half a century.

Dr Abdul Aziz Awan

Download book- WHO guidelines for the treatment of Malaria (2006 edition).

http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf

A very Good Contribution!!