Malaria

Malaria, caused by four species of Plasmodium protozoa and spread by mosquitoes, causes more deaths, worldwide, than any other vector-borne disease. Coping with malaria must be a two-pronged strategy of preventing and treating the disease in humans, and eradicating the disease-carrying mosquito vectors. The World Health Organization considers it the greatest problem among tropical diseases:

• Malaria is both preventable and curable.
• A child dies of malaria every 30 seconds.
• More than one million people die of malaria every year, mostly infants, young children and pregnant women and most of them in Africa

WHO, in its 2008 report on malaria, in no way minimizes the problem, but sees several areas of distinct progress. Some, however, are already showing difficulties." Half of the world's population is at risk of malaria, and an estimated 247 million cases led to nearly 881 000 deaths in 2006. The advent of long-lasting insecticidal nets and artemisinin-based combination therapy, plus a revival of support for indoor residual spraying of insecticide, presents a new opportunity for large-scale malaria control. "

Areas where malaria could re-establish in the U.S

Developed countries cannot be complacent. It has been assessed as a world threat in an U.S. National Intelligence Estimate.

The mosquito vector is present in many parts of the world, and refugees from endemic areas potentially can introduce it, as shown in he U.S. map with areas that have the appropriate mosquitoes. While malaria, in the U.S., there are 1500 cases of malaria annually in the U.S., which could get into the mosquito population. five cases of malaria were diagnosed in 2007, among Burundian refugees who had settled in the state of Washington, in the western United States.

Further, while mosquitoes are the natural vector, malaria certainly can be spread through shared hypodermic needles, either from intravenous drug abuse, or in areas where the healthcare system cannot afford either disposable hypodermics or proper sterilization.

Etiology

The protozoa, of the genus Plasmodium, are carried in the saliva of Anopheles mosquitoes, which reproduce in stagnant water. There are four species: P. falciparum, P. vivax, P. ovale, and P. malariae.

Prevention

Simple mechanical means are the starting point in controlling them: minimizing standing water and using netting. Appropriate insecticide and insect repellents have a role, although resistance to the main insecticides, DDT and pyrethrins, is increasing and there are no immediate alternatives. The basic techniques can be enhanced with :

• Indoor Residual Spraying of long-acting insecticide (IRS)
• Long-Lasting Insecticidal Nets (LLINs).

Integrated Vector Management (IVM) strategies to kill the developing larvae have to be tailored to each environment. These are long-term activities needing long-term funding and political commitment.

While there is no vaccine, chemoprophylaxis can be effective, although, as with the use of anti-malarial drugs to treat active infection, drug resistance is an increasing problem.

The Centers for Disease Control recommend that refugees from sub-Saharan Africa routinely be treated, before leaving Africa, with presumptive artemisinin-based combination therapy (ACT; e.g., artemether-lumefantrine).

Treatment

Drug treatment has been challenging. Many of the agents effective against parasites have significant toxicity, and Plasmodium sp. also become resistant. Even recently, major side effects such as increased psychosis became apparent only when a drug went into widespread use.

It is so common, in many areas of Africa, that fever and chills are routinely treated with antimalarial drugs. Misdiagnosis here adds not only to malaria drug resistance, but resistance to other drugs.

In the industrialized world, it is principally a disease of travelers. Clinicians encountering possible malaria must maintain a high index of suspicion, and be sure to take travel histories. Coinfection with other tropical diseases should add suspicion.

Early treatment

Malaria was one of the first drugs with a specific treatment, the alkaloid quinine, from cinchona tree bark, also called Jesuit's Bark. Quinine rarely is a complete cure but suppresses symptoms and is relatively toxic. With the advent of synthetic drugs in the Second World War, it was gradually replaced, although it still has a significant role as a backup drug for resistant forms.

Quinine is intensely bitter. Before tablet and capsule dosage forms were common, it had to be drunk. The British, in India, turned an unpleasant task of taking quinine for chemoprophylaxis into a pleasant daily ritual, by incorporating quinine into alcoholic drink mixer "tonics". One's gin-and-tonic was, aside from other attractions, the means of less painfully ingesting one's daily quinine dose.

First-generation synthetics

The first synthetic alternative to quinine was quinacrine, widely known by the trade name of Atabrine. First made in Germany in the 1930s, its distribution to U.S. troops at risk began in 1942. Compliance was a problem, as it turned the skin yellow, and casused nausea, vomiting, diarrhea, skin staining, psychosis, lichen planus, and exfoliative dermatitis. Weina observed that the first dose was often given to troops aboard a ship approaching a combat area, so anxiety, seasickness, and gastrointestinal upset were therefore blamed on the drug when other factors could have been responsible. Military folklore also claimed that quinacrine caused impotence.

The next major drug, chloroquine, was discovered by a German, Hans Andersag, in 1934 at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. He named his compound resochin. Through a series of lapses and confusion brought about during the war, chloroquine was finally recognized and established as an effective and safe antimalarial in 1946 by British and U.S. scientists. Chloroquine has activity against other parasites, and is, with derivatives, a member of the "antimalarial" subclass of disease-modifying antirheumatic drugs.

By 1947, comparisons were possible, and chloroquine was most preferred. Subsequent comparisons between chloroquine and hydroxychloroquine show the former is more effective, more toxic, and cheaper.

Antibiotics

More general antibiotics, including clindamycin, doxycycline and tetracycline have activity. Since their action against active parasites may be slower than that of other drugs, they tend to be preferred for prophylaxis, or in multidrug regimens where their specific modes of action are synergistic with faster-acting drugs.

Newer agents

Approved in 2000 was the fixed-combination, for prophylaxis and treatment, of atovaquone-proguanil.

Resistance concerns

Where the disease is not endemic, and the illness is not immediately life-threatening, laboratory diagnosis of the specific Plasmodium species, along with the travel history, will help guide the choice of the appropriate drug treatment. The disease must be reported to local and national public health authorities in non-endemic areas, especially in severe cases where organizations such as the CDC may stock drugs not normally available.

Plasmodium species	Evaluation
P. falciparum	Rapidly progressive illness or death	chloroquine or hydroxychloroquine, unless believed resistant; then quinine sulfate plus doxycycline, tetracycline, or clindamycin; or atovaquone-proguanil (Malarone).
P. vivax	May have dormant state requiring treatment	chloroquine or hydroxychloroquine, unless believed resistant; then quinine sulfate plus doxycycline, tetracycline, or clindamycin; or atovaquone-proguanil (Malarone).
P. ovale	May have dormant state requiring treatment	chloroquine or hydroxychloroquine, unless believed resistant; then quinine sulfate plus doxycycline, tetracycline, or clindamycin; or atovaquone-proguanil (Malarone).
P. malariae		chloroquine or hydroxychloroquine

Mild cases can be treated with oral therapy. The presence of any of the following factors may justify urgent parenteral therapy: who have one or more of the following clinical criteria

• impaired consciousness/coma or repeated generalized convulsions
• severe normocytic anemia
• renal failure
• pulmonary edema
• acute respiratory distress syndrome
• circulatory shock
• acidosis,
• disseminated intravascular coagulation or spontaneous bleeding or hemoglobinuria, *jaundice
• blood parasite load of > 5%

Artemisinin

Today's most valuable drug is artemisinin, which was first available as a Chinese herbal preparation. It has been synthesized to help meet demand. To minimize resistance formation, the standard of care defined by the World Health Organization is artemisin combination therapy (ACT), either with the original drug or a derivative. Artemisin itself has relatively low bioavailability and has been banned in some countries, to avoid resistance formation due to underdosage

Artesunate is a derivative that produces higher blood levels when given intravenously. In 2007, the U.S. Centers for Disease Control (CDC) received an exception from the Food and Drug Administration to Artesunate in the United States, specifically for treatment of malarial clinical emergencies; CDC will dispense it to requesting organizations that meet treatment criteria.

There is a significant drug counterfeiting problem, which is contributing to resistance.