Malaria

Compiled and Summarized by Anthony
Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, it causes disease in approximately 650 million people and kills between one and three million, most of them young children in Sub-Saharan Africa. Malaria is 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 is 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.

No vaccine is currently available for malaria; preventative drugs must be taken continuously to reduce the risk of infection. These prophylactic drug treatments are often too expensive for most people living in endemic areas. Most adults from endemic areas have a degree of long-term recurrent infection and also of partial resistance; the resistance reduces with time and such adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas. They are strongly recommended to take full precautions if they return to an endemic area. Malaria infections are treated through the use of antimalarial drugs, such as quinine or artemisinin derivatives, although drug resistance is increasingly common.

Signs and 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. vivax and P. ovale infections, while every three for P. malariae. P. falciparum can have recurrent fever every 36-48 hours or a less pronounced and almost continuous fever. 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. This neurologic damage results 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), hypoglycemia, 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).

Causative Agent

Single-celled protozoan parasites of the genus Plasmodium. Four species infect humans by entering the bloodstream.

P. falciparum: found throughout tropical Africa, Asia and Latin America

P. vivax: worldwide in tropical and some temperate zones

P. ovale: mainly in tropical west Africa

P. malariae: worldwide but very patchy distribution

Mode of Transmission

Inoculation via the bite of infected blood-feeding female mosquitoes of the genus Anopheles, which transfer parasites from human to human. Male mosquitoes do not bite. In humans, parasites multiply exponentially in the liver and then in infected red blood cells. Mosquitoes ingest parasites with a blood meal, the parasites undergoing another reproductive phase inside the mosquito before being passed on to another human.

Diagnosis

The most economic, preferred, and 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. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis.

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.

See 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. Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).

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.

Incubation Period

In the case of malaria, the incubation period for the disease (the period between infection and the beginning of symptoms) typically lasts between 10 days to four weeks. In some cases, the malaria incubation period may be as short as seven days or as long as several years. Factors that affect the incubation period for malaria include the type of Plasmodium parasite responsible for the infection. When antimalarial drugs are used to prevent the spread of the disease, they may also increase the length of the malaria incubation period by weeks or months.

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. Once in the liver these organisms 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 the 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 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.

Pathophysiology

The vector, the Anopheles species mosquito, passes plasmodia, which is contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating erythrocytes (RBCs) and feed on the hemoglobin and other proteins within the cells. One brood of parasites becomes dominant and is responsible for the synchronous nature of the clinical symptoms of malaria.

This protozoan brood replicates inside the cell. This replication induces RBC cytolysis and causes the release of toxic metabolic byproducts into the bloodstream; therefore, the host experiences flulike symptoms. These symptoms include chills, headache, myalgias, and malaise, and they occur in a cyclic pattern. The parasite also may cause jaundice and anemia. P. falciparum, the most malignant of the 4 species of Plasmodium, may induce kidney failure, coma, and death. Malaria-induced death is preventable if the proper treatment is sought and implemented.

P. vivax and P. ovale may produce a dormant form that persists in the liver of infected individuals and emerges at a later time. Therefore, infection by these species requires treatment to kill any dormant protozoan as well as the actively infecting organisms.

Malaria-causing Plasmodium species metabolize hemoglobin and other RBC proteins to create a toxic pigment termed hemozoin. The parasites derive their energy solely from glucose, and they metabolize it 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis. The plasmodia also cause lysis of infected and uninfected RBCs, suppression of hematopoiesis, and increased clearance of RBCs by the spleen, which leads to anemia. Over time, malaria infection also causes thrombocytopenia and hepatosplenomegaly.

The morbidity and mortality caused by P. falciparum are increased greatly over that caused by other Plasmodium species because of the increased parasitemia of P. falciparum and its ability to cytoadhere. When an RBC becomes infected with P. falciparum, it produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, leading to much of the damage incurred by the parasite.

Prevention

-Avoid endemic regions.

-Take the proper prophylactic drugs at proper intervals if traveling to endemic regions.

-Use topical insect repellent (30-35% diethyltoluamide [DEET]), especially from dusk to dawn.

-Wear long-sleeved permethrin-coated clothing if not allergic to permethrin; spray under beds, chairs, tables, and along walls.

-Sleep under fine-nylon netting impregnated with permethrin.

-Avoid wearing perfumes and colognes.

-Seek out medical attention immediately upon contracting any tropical fever or flulike illness.

-Chemoprophylaxis is available in many different forms.

· The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicate the use of a specific drug.

· Before traveling, people should consult their physician and consult the CDC's Malaria and Traveler's Web site to determine the most appropriate chemoprophylaxis.

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.

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 both Plasmodium's ability to enter red blood cell and establish an infection, as well as parasite replication. 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)

The development of drugs was facilitated when Plasmodium falciparum was successfully cultured. This allowed in vitro testing of new drug candidates.

Extracts of the plant Artemisia annua, containing the compound artemisinin or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply is not meeting demand. One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with artesunate, rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted. Since 2001 the World Health Organization has recommended using artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent WHO treatment guidelines for malaria recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that SERCA, a calcium pump in the endoplasmic reticulum may be associated with artemisinin resistance. Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA. However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.

In February 2002, the journal Science and other press outlets announced progress on a new treatment for infected individuals. A team of French and South African researchers had identified a new drug they were calling "G25". It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. In 2005 the same team of researchers published their research on achieving an oral form, which they refer to as "TE3" or "te3". As of early 2006, there is no information in the mainstream press as to when this family of drugs will become commercially available.

In 1996, Professor Geoff McFadden stumbled upon the work of British biologist Ian Wilson, who had discovered that the plasmodia responsible for causing malaria retained parts of chloroplasts, an organelle usually found in plants, complete with their own functioning genomes. This led Professor McFadden to the realization that any number of herbicides may in fact be successful in the fight against malaria, and so he set to trial large numbers of them, and enjoyed a 75% success rate.

These "apicoplasts" are thought to have originated through the endosymbiosis of algae and play a crucial role in fatty acid bio-synthesis in plasmodia. To date, 466 proteins have been found to be produced by apicoplasts and these are now being looked at as possible targets for novel anti-malarial drugs.

Although effective anti-malarial drugs are on the market, the disease remains a threat to people living in endemic areas who have no proper and prompt access to effective drugs. Access to pharmacies and health facilities, as well as drug costs, are major obstacles. Médecins Sans Frontières estimates that the cost of treating a malaria-infected person in an endemic country was between US$0.25 and $2.40 per dose in 2002

Complications

Most complications are caused by P. falciparum, and they may include the following:

- Coma (cerebral malaria)

· Defined as coma, altered mental status, or multiple seizures with P. falciparum in the blood, cerebral malaria is the most common cause of death in malaria patients. If untreated, this complication is lethal.

· Even with treatment, 15% of children and 20% of adults who develop cerebral malaria die.

· The symptoms of cerebral malaria are similar to those of toxic encephalopathy.

- Seizures

- Renal failure: As many as 30% of non-immune adults infected with P. falciparum suffer acute renal failure.

- Hemoglobinuria (blackwater fever)

· Blackwater fever is the passage of dark, Madeira-colored urine.

· Hemolysis, hemoglobinemia, and the subsequent hemoglobinuria and hemozoinuria cause this condition.

- Noncardiogenic pulmonary edema: This affliction is most common in pregnant women and results in death in 80% of patients.

- Profound hypoglycemia: Hypoglycemia often occurs in young children and pregnant women. It often is difficult to diagnose since adrenergic signs are not always present and since stupor already may have occurred in the patient.

- Lactic acidosis: This occurs when the microvasculature becomes clogged with P. falciparum. If the venous lactate level reaches 45 mg/dL, a poor prognosis is very likely.

- Hemolysis resulting in severe anemia and jaundice

- Bleeding (coagulopathy)

References

http://www.wikipedia.org
Source for primary information.

http://www.emedicine.com
Contains additional information.

http://www.who.int
Supplied additional information.

http://malaria.emedtv.com
Supplied additional information.

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