Malaria

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Malaria
ICD-10 code: B50
ICD-9 code: 084
Red blood cell infected with P.vivax
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Red blood cell infected with P.vivax

Malaria (Italian: "bad air"; formerly called ague or marsh fever in English) is an infectious disease which in humans causes about 350-500 million infections and approximately 1.3 million deaths annually, mainly in the tropics. Sub-Saharan Africa accounts for 85% of these fatalities.[1]

Malaria is caused by the protozoan parasite, Plasmodium (one of the Apicomplexa) and the transmission vector for human malarial parasite is the Anopheles mosquito. The P. falciparum variety of the parasite accounts for 80% of cases and 90% of deaths. Pregnant women and infants under the age of five are most vulnerable to malaria.

For his discovery of the cause of malaria, French army doctor Charles Louis Alphonse Laveran was awarded the Nobel Prize for Physiology or Medicine in 1907. Britain's Sir Ronald Ross also received a Nobel prize (in 1902) for describing the life cycle of the malaria parasite as it develops in the bodies of its mosquito and human hosts.

Contents

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Symptoms

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia, and convulsions. There may be the feeling of tingling in the skin, particularly with malaria caused by P. falciparum. Complications of malaria include coma and death if untreated—young children are especially vulnerable. Splenomegaly (enlarged spleen), intense headaches, cerebral ischemia and hemoglobinuria with renal failure may occur.

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Mechanism of the disease

Infected female Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. If they bite a person, which they usually do starting at dusk and continuing throughout the night, the sporozoites enter the person's body via the mosquito's saliva, migrate to the liver where they multiply within hepatic liver cells. There they develop into merozoites which then enter red blood cells, where they multiply further, periodically breaking out of the red blood cells. The classical description of waves of fever coming every two or three days arises from simultaneous waves of merozoites breaking out of red blood cells during the same day.

The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it stays inside liver and blood cells. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the parasite produces certain surface proteins which infected blood cells present on their cell surface, causing the blood cells to stick to the walls of blood vessels. These surface proteins known as PfEMP1 are highly variable (there are at least 50 variations) and cannot serve as a reliable target for the immune system.

By the time the human immune system learns to recognise the protein and starts making antibodies against it, the parasite has switched to another form of the protein, making it difficult for the immune system to keep up.

The stickiness of the red blood cells is particularly pronounced in Plasmodium falciparum malaria and this is the main factor giving rise to hemorrhagic complications of malaria.

Some merozoites turn into male and female gametocytes. If a mosquito bites the infected person and picks up gametocytes with the blood, fertilization occurs in the mosquito's gut, 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.

The recognised species causing disease in humans are P. falciparum (which alone accounts for 80% of the recognised cases and ~90% of the deaths), P. vivax, P. ovale, and P. malariae. Infections with P. knowlesi and P. semiovale are also known to cause malaria but are of limited major public health importance.

High endothelial venules (the smallest branches of the circulatory system) can be occluded by the infected red blood cells, such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells affect the integrity of the blood brain barrier possibly leading to reversible coma. Even when treated, serious neurological consequences may result from cerebral malaria, especially in children.

Other mammals (bats, rodents, non-human primates) as well as birds and reptiles also suffer from malaria. However, the form of malaria found in animals is usually different than that found in humans. Three human forms (which account for most malaria cases) are completely exclusive to humans. Only one form, P. malariae, can cause malaria in both humans and higher primates. Other animal forms of malaria do not infect humans at all. Mosquitos which are "virgin" (i.e. have never bitten someone before) cannot transmit malaria, even if the eggs were laid by a female carrier of the disease.

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Sickle cell anemia and other genetic effects

Carriers of the sickle cell anemia gene are protected against malaria because of their particular hemoglobin mutation; this explains why sickle cell anemia is particularly common among people of African origin. They have a specific variant of the beta-globin gene. Some scientists hypothesize that another hemoglobin mutation, which causes the genetic disease thalassemia, may also give its carriers an enhanced immunity to malaria.

Another disease which is linked to protection against malaria is glucose-6-phosphate dehydrogenase deficiency (G6PD). It protects against malaria caused by Plasmodium falciparum as the presence of this enzyme is critical to survival of these parasites within red blood cells.

It is thought that humans have been affected by malaria for about 50,000 years, and several human genes responsible for blood cell proteins and the immune system have been shaped by the struggle against the parasite.

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Diagnosis

The gold standard for the diagnosis of malaria is microscopic examination of blood films. Two sorts of blood films are traditionally used: 1. thin films, and 2. thick films. Thin films are similar to usual blood films and allow the microscopist to speciate malaria. Thick films allow the microscopist to screen a larger volume of blood, so as to pick up low levels of infection. Blood films should be made within 20 minutes of taking the blood, parasite morphology changes as the blood cools to room temperature; this problem is exacerbated if anticoagulants such as EDTA or citrate are used.

In areas where microscopy is not available, there are antigen detection tests that require only a drop of blood [14]. OptiMAL-IT® will reliably detect falciparum down to 0.01% parasitaemia and non-falciparum down to 0.1%. Paracheck-Pf® will detect parasitaemias down to 0.002% but will not distinguish between falciparum and non-falciparum malaria. An experienced microscopist can detect parasite levels down to as low as 0.000001%

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Microscopic features

Diagnosis must be based on the features of a number of parasites. It is not possible to give a species one the basis of a single parasite. The early trophozoite ("ring form") of all four species looks identical and species identification should therefore NEVER be given on the basis of a single ring form.

P. falciparum
Only early trophozoites and gametocytes are seen in the peripheral blood. It is unusual to see mature trophozoites or schizonts in peripheral blood smears as these are usually sequestered in the tissues. The parasitised erythrocytes are not enlarged and it is common to see cells with more than one parasite within them (multiply parasitised erythrocytes). Occasionally, faint comma shaped red dots are seen on the red cell surface called "Maurer's dots". P. falciparum will parasitise erythrocytes of any age and up to 50% of all circulating erythrocytes may be parasitised. The banana-shaped gametocytes of P. falciparum are diagnostic of that species.
P. vivax
The parasitised erythrocyte is up to twice as large as a normal erythrocyte and fine pink "Schüffner's dots" are seen on the surface of the parasitised cell; the parasite within it is often wildly irregular in shape (described as "amoeboid"). Schizonts of P. vivax have up to 20 merozoites within them. It is rare to see cells with more than one parasite within them. Merozoites will only attach to reticulocytes (immature erythrocytes) and therefore it is unusual to see more than 3% of all circulating erythrocytes parasitised.
P. ovale
The microscopic appearance of P. ovale is very similar to that of P. vivax and if there are only a small number of parasites seen, it may be impossible to distinguish the two species. There is no difference between the medical treatment of P. ovale and P. vivax, and therefore the laboratory may report "P. vivax/ovale", and this is perfectly acceptable. Schüffner's dots are seen on the surface of the parasitised erythrocyte, but these are larger and darker than in P. vivax and are sometimes called "James's dots". The about 20% of the parasitised eythrocytes are oval in shape (hence the species name) and some of the oval erythrocytes also have fimbriated edges (the so-called "comet cell"). The matures schizonts of "P. ovale" never have more than 12 nuclei within them and this is the only reliable way of distinguishing between the two species.
P. malariae
The parasitised erythrocyte is never enlarged and may even appear smaller than that of a normal erythrocytes. The cytoplasm is not decolourised and no dots are visible on the cell surface. The food vacuole is small and the parasite is compact. Multiply parasitised erythrocytes are rare. Band forms (where the parasite forms a thick band across the width of the infected erythrocyte) are characteristic of this species. Large grains of malarial pigment are often seen in these parasites: more so than any other Plasmodium species.
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Treatment and prevention

If diagnosed early, malaria can be treated, but prevention is always much better.

For prevention, emphasis should be laid on 1. exposition prophylaxis (use of bednets and screening at night and use of repellents such as DEET and long-sleeved clothing) 2. chemo-prophylaxis using certain antimalarial drugs (especially for non-immune travellers)

The choice of drug for prevention and/or treatment does largely depend on the geographic area where infection is likely to occur. Travellers should consult a specialised physician for advice before taking prophylactic treatment.

Chloroquine was the antimalarial drug of choice for many years in most parts of the world. However, resistance of Plasmodium falciparum against 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.

There are several other substances which are used for treatment and, partially for prophylaxis. Their deployment depends mainly on the frequency of resitent parasites in the area where the drug should be used.

Quinine was used in the 17th century as a prophylactic against malaria. The development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the 20th 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 now recommended for malaria prophylaxis.

Popular antimalarial drugs include

  • Artemether-Lumefantrine (Therapy)
  • Artesunate-Amodiaquine (Therapy)
  • Atovaquon-Proguanil (Therapy and prophylaxis)
  • Quinine (Therapy)
  • Chloroquine (Therapy and prophylaxis; use restricted due to resistance)
  • Doxycycline (Therapy and prophylaxis)
  • Mefloquine (Therapy and prophylaxis)
  • Primaquine (Therapy in P. vivax and P. ovale only)
  • Proguanil (Prophylaxis only)
  • Sulfadoxine-Pyrimethamine (Therapy; prophylaxis for semi-immune pregnant women in endemic countries as "Intermittent Preventive Treatment" - IPT)

Extracts of the plant, Artemisia annua), containing the compound artemisinin or semi-synthetic derivatives (a substance unrelated to the quinine), offer over 90% efficacy rates but their supply is not meeting demand. On June 5, 2005 Nature (journal) released a study about possible drug resistance, although the finding could help the development of other drugs.[3]

Although efficacious antimalarial drugs are on the market, the disease poses a big threat for those people living in endemic areas having no proper and prompt access to effective drugs. Accessibility of drug sellers and health facilities as well as drug costs are major obstacles. Médecins sans Frontières estimates that the cost to treat a malaria-infected person in an endemic country is between $0.25 and $2.40. [2].

There is a problem of availability of effective malaria treatments in the U.S.A. Most hospitals in the U.S.A. do not stock intravenous quinine, and with the reduced use of quinidine by cardiologists, many US hospitals have no access to intravenous anti-malarial drugs at all.

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Disease control

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Background

Efforts to eradicate malaria by eliminating mosquitos 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. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the pesticide DDT during the 1950s eliminated it from the South. A major public health effort to eradicate malaria worldwide by selectively targeting mosquitos in areas where malaria was rampant was embarked upon in the 1950s and 1960s.[4] However, these efforts ultimately failed to eradicate malaria in many parts of the developing world. The problem still most rampantly exists in Africa.

DDT was developed as the first of the modern insecticides early in World War II. It was initially used with great effect to combat mosquitoes spreading malaria. It was banned for use in many countries in the 1970s due to its negative environmental impact. There is great controversy regarding this impact and the use of DDT to fight human diseases. Some claim that the ban is responsible for malaria deaths counted in tens of millions in tropical countries where the disease had been under control.

The World Bank estimates that malaria costs Africa $12bn a year in lost productivity. Yet international funding for malaria control is only $100m-$200m a year.[5] 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 much greater benefit to African economies.[6]

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Conventional means

Since most of the deaths today occur in poor rural areas of Africa which lack proper health care, the distribution of mosquito nets impregnated with insecticide has been suggested as the most effective and cost-effective prevention method. These nets can often be obtained for less than US$10 or 10 euros when purchased in bulk from the United Nations or other organizations. The nets need to be re-impregnated with the chemical about every six months. Insecticide-treated bednets (ITN) have the advantage of protecting people living under the net and simultaneously killing mosquitoes which get in contact with the net and thus protecting people sleeping in the same room but not under the net.

Spraying interior walls with DDT is also effective in areas where the mosquitoes are not already DDT-resistant. 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.[7]

Environmental management inculding elimination of mosquito habitats was an important measure to get rid of malaria in large parts of Europe. It is also an important option in many tropical (urban) settings.

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Vaccines and other new techniques

Vaccines for malaria are under development, with no completely effective vaccine yet available (as of September 2005). A team backed by the Gates Foundation and the pharma giant GlaxoSmithKline announced a partially successful field trial in October 2004, for RTS,S/AS02A, a vaccine which reduces infection risk by 30% and severity of infections by over 50%., although the numbers in this latter category of patients were rather small [8] Further research will delay this vaccine from commercial release until around 2010. In January 2005, Edinburgh University scientists announced the discovery of an antibody which protects against the disease. The scientists will lead a £17m European consortium of malaria researchers.[9] It is hoped that the genome sequence of the most deadly agent of malaria, Plasmodium falciparum, which was completed in 2002, will provide targets for new drugs or vaccines. [10]

Sterile insect technique is emerging as a potential method to control malaria-carrying mosquitos. Progress towards transgenic, or genetically modified insects suggests that wild mosquito populations could be made malaria-resistant. Researchers at Imperial College London created the world's first transgenic malaria mosquito[11], with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002[12].

A very promising approach was announced in Science on June 10, 2005. It uses inert spores of the fungus Beauveria bassiana to kill mosquitoes, sprayed on walls and bed nets. Unlike chemicals, mosquitoes have never been found to develop a resistance to fungal infections.[13]

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Travel to malaria-risk zones

The countries where malaria is known to occur are shown in red. Source: CDC.
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The countries where malaria is known to occur are shown in red. Source: CDC.

Travelers to malaria-risk zones should first contact a physician whose speciality is in travel medicine. Most often a general practitioner cannot prescribe medications or give vaccinations for third-world travel. Seldom will malaria be the sole health concern, and the physician will need to assess all the health risks the traveler will face. Even before considering prophylactic medications, there are important anti-insect measures that should be used, such as impregnated bed nets and appropriate insect repellents. There are several drugs available for malaria prevention (many are also used in higher doses for treatment) including mefloquine, doxycycline, and Malarone. There is no one drug that is right for all travelers to all destinations. The choice of a malaria prophylaxis should be made carefully with one's physician taking into account drug resistance in the traveler's destination; possible side effects, interactions, and contraindications; and finally the preferred frequency per dose (daily, weekly, etc.).

Travel to rural areas always involves more potential exposure to malaria than in the larger cities. (This is in contrast to dengue fever where cities present the greater risk.) For example, the capital cities of the Philippines, Thailand and Sri Lanka are essentially malaria-free. However, malaria is present in many other places (especially rural areas) of these countries. By contrast, in West Africa, Ghana and Nigeria have malaria throughout the entire country. However, the risk will always be lower in the larger cities. Travelers should never assume that their choice of malaria prophylaxis is available in the country that they will be visiting. Quinine is not recommended as a prophlactic antimalarial.

Any malaria prophylaxis must be taken before, during, and (especially) after traveling to a malaria-risk zone. The exact frequency will vary by which drug is chosen. There has been some debate recently over whether pre-travel malaria prophylaxis is being started early enough. For example, mefloquine is normally taken one week prior to travel. Some feel this is inadequate if the person is unfortunate enough to be exposed to malaria shortly upon arrival. Those who have concerns may wish to discuss with their physician about doubling the time period (not the dosage) that their malaria prophylaxis will be taken prior to travel. In addition to providing better protection, there will be more time to switch to another anti-malaria medication, if necessary.

No malaria prophylaxis is 100% effective in prevention. Avoiding mosquito bites (i.e. using DEET, screens, and proper bed netting) when mosquitos are obviously present is important as well. If a person who has visited a malaria risk zone contracts a fever within one year, their physician should be informed of the possibility of malaria. Note that lesser forms of malaria (such as P. vivax) can mimic the symptoms of the flu. Physicians who rarely, if ever, examine malaria patients may need to be reminded of this fact. The standard laboratory test for malaria is a thick and thin blood smear on a glass slide viewed under the microscope.

Aspirin must never be taken as an antipyretic when malaria or dengue fever is a possibility. (Continuing daily low-dose 81 mg aspirin therapy during and after third-world travel should be discussed with your physician.) Acetaminophen and ibuprofen are considered safe alternatives provided all of their precautions are observed. Malaria, dengue fever, and typhoid fever all tend to have somewhat similar symptoms at first and should not be self-diagnosed.

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References

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External links

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Vaccine and other research

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DDT

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Animations, images and photos

Retrieved from "http://en.wikipedia.org/wiki/Malaria"
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