Malaria

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, 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.

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.

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 over wintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).

Causes

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 has 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.

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 a 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.

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, 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 for 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 as outpatients. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can be completely cured.

Antimalarial Drugs

There are several families of drugs used to treat malaria. As it was cheap and effective, chloroquine was 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 can 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.

Currently available anti-malarial drugs include:
Artemether-lumefantrine (Therapy only, commercial name Coartem)
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. 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 mitochondria 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.

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. Medecins Sans Frontieres estimates that the cost to treat a malaria-infected person in an endemic country is between US$0.25 and $2.40.

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.