MALARIA, CAUSE, PREVENTION AND CURE

What is malaria?
Malaria is an infectious disease caused by a parasite, Plasmodium, which infects red blood cells. Malaria is characterized by cycles of chills, fever, pain and sweating. Historical records suggest malaria has infected humans since the beginning of mankind. The name "mal 'aria" (meaning "bad air" in Italian) was first used in English in 1740 by H. Walpole when describing the disease. The term was shortened to "malaria" in the 20th century. C. Laveran in 1880 was the first to identify the parasites in human blood. In 1889, R. Ross discovered that mosquitoes transmitted malaria. Of the four species of malaria, the most serious type is Plasmodium falciparum malaria. It can be life-threatening. The other three species of malaria (P. vivax, P. malariae, and P. ovale) are generally less serious and are not life-threatening.
How is malaria transmitted?
The life cycle of the parasite is complicated (for life cycle details, see http://www.cdc.gov/malaria/biology/life_cycle.htm) and involves two hosts, humans and Anopheles mosquitoes. The disease is transmitted to humans when an infected Anopheles mosquito bites a person and injects the malaria parasites (sporozoites) into the blood. Sporozoites travel through the bloodstream to the liver, mature, and eventually infect the human red blood cells. While in red blood cells, the parasites again develop until a mosquito takes a blood meal from an infected human and ingests human red blood cells containing the parasites. Then the parasites reach the Anopheles mosquito's stomach and eventually invade the mosquito salivary glands. When an Anopheles mosquito bites a human, these sporozoites complete and repeat the complex Plasmodium life cycle. P. ovale and P. vivax can further complicate the cycle by producing dormant stages (hypnozoites) that may not develop for weeks to years.
Where is malaria a particular problem?
Malaria is a particular problem and a major one in areas of Asia, Africa, and Central and South America. Unless precautions are taken, anyone living in or traveling to a country where malaria is present can get the disease. Malaria occurs in about 100 countries; approximately 40% of the world population is at risk for contracting malaria. To get information on countries that have current malaria infection problems, the CDC (Centers for Disease Control) has a constantly updated website that lists the problem areas in detail: http://www.cdc.gov/malaria/travel/index.htm#riskareas.
What are the signs and symptoms of malaria?
The symptoms characteristic of malaria include flu-like illness with fever, chills, muscle aches, and headache. Some patients develop nausea, vomiting, cough, and diarrhea. Cycles of chills, fever, and sweating that repeat every one, two, or three days are typical. There can sometimes be vomiting, diarrhea, coughing, and yellowing (jaundice) of the skin and whites of the eyes due to destruction of red blood cells and liver cells. People with severe P. falciparum malaria can develop bleeding problems, shock, liver or kidney failure, central nervous system problems, coma, and can die from the infection or its complications. Cerebral malaria (coma, or altered mental status or seizures) can occur with severe P. falciparum infection. It is lethal if not treated quickly; even with treatment, about 15%-20% die.
What is the incubation period for malaria?
The period between the mosquito bite and the onset of the malarial illness is usually one to three weeks (seven to 21 days). This initial time period is highly variable as reports suggest that the range of incubation periods may range from four days to one year. The usual incubation period may be increased when a person has taken an inadequate course of malaria prevention medications. Certain types of malaria (P. vivax and P. ovale) parasites can also take much longer, as long as eight to 10 months, to cause symptoms. These parasites remain dormant (inactive or hibernating) in the liver cells during this time. Unfortunately, some of these dormant parasites can remain even after a patient recovers from malaria, so the patient can get sick again. This situation is termed relapsing malaria.
How is malaria diagnosed?
Clinical symptoms listed above, when associated with travel to countries that have identified malarial risk, suggest malaria as a diagnosis. Malaria tests are not routinely ordered by most physicians in developed countries so recognition of travel history is essential.
The classic and most used test is the blood smear on a microscope slide that is stained (Giemsa stain) to show the parasites inside red blood cells. Although this test is easily done, correct results are dependent on the technical skill of the lab technician who prepares and examines the slides with a microscope. Other tests based on immunologic principles exist; including RDT's (rapid diagnostic tests) approved for use in the U.S. in 2007 and the polymerase chain reaction (PCR) tests. These are not yet widely available and are more expensive than the traditional Giemsa blood smear. Some investigators suggest such immunologic based tests be confirmed with a Giemsa blood smear.
How is malaria treated?
Three main factors determine treatments: the infecting species of Plasmodium parasite, the clinical situation of the patient (for example, adult, child, or pregnant female with either mild or severe malaria), and the drug susceptibility of the infecting parasites. Drug susceptibility is determined by the geographic area where the infection was acquired. Different areas of the world have malaria types that are resistant to certain medications. The correct drugs for each type of malaria must be prescribed by a doctor who is familiar with malaria treatment protocols. Since people infected with P. falciparum malaria can die (often because of delayed treatment), immediate treatment for P. falciparum malaria is necessary.
Mild malaria can be treated with oral medication; severe malaria (one or more symptoms of either impaired consciousness/coma, severe anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria [hemoglobin in the urine], jaundice, repeated generalized convulsions, and/or parasitemia [parasites in the blood] of > 5%) requires intravenous (IV) drug treatment and fluids.
Drug treatment of malaria is not always easy. Chloroquine phosphate is the drug of choice for all malarial parasites except for chloroquine-resistant Plasmodium strains. Although almost all strains of P. malariae are susceptible to chloroquine, P. falciparum, P. vivax and even some P. ovale strains have been reported as resistant to chloroquine. Unfortunately, resistance is usually noted by drug-treatment failure in the individual patient. There are, however, multiple drug-treatment protocols for treatment of drug resistant Plasmodium strains (for example, quinine sulfate plus doxycycline [Vibramycin, Oracea, Adoxa, Atridox] or tetracycline [Achromycin], or clindamycin [Cleocin], or atovaquone-proguanil [Malarone]). There are specialized labs that can test the patient's parasites for resistance, but this is not done frequently. Consequently, treatment is usually based on the majority of Plasmodium species diagnosed and its general drug-resistance pattern for the country or world region where the patient became infested. For example, P. falciparum acquired in the Middle East countries is usually susceptible to chloroquine, but if acquired in sub-Sahara African countries, is usually resistant to chloroquine.
Is malaria a particular problem during pregnancy?
Yes. Malaria may pose a serious threat to a pregnant woman and her pregnancy. Malaria infection in pregnant women may be more severe than in women who are not pregnant. Malaria may also increase the risk of problems with the pregnancy, including prematurity, abortion, and stillbirth. Statistics indicate that in sub-Saharan Africa, between 75,000-200,000 infants die from malaria per year; worldwide estimates indicate over 1 million children die from malaria each year. Therefore, all pregnant women who are living in or traveling to a malaria-risk area should consult a doctor and take prescription drugs (for example, sulfadoxine-pyrimethamine) to avoid contracting malaria. Treatment of malaria in the pregnant female is similar to the usual treatment described above; however, drugs such as primaquine (Primaquine), tetracycline (Achromycin, Sumycin), doxycycline, and halofantrine (Halfan) are not recommended as they may harm the fetus. In addition to monitoring the patient for anemia, an OB-GYN specialist is consulted for further management.
Is malaria a particular problem for children?
Yes. All children, including young infants, living in or traveling to malaria-risk areas should take antimalarial drugs (for example, chloroquine and mefloquine [Lariam]). Although the recommendations for most antimalarial drugs are the same as for adults, it is crucial to use the correct dosage for the child. The dosage of drug depends on the age and weight of the child. Since an overdose of an antimalarial drug can be fatal, all antimalarial (and all other) drugs should be stored in childproof containers well out of the child's reach.
How do I keep from getting malaria?
If you are traveling to an area known to have malaria, find out which medications you need to take, and take them as prescribed. Current CDC recommendations suggest individuals begin taking antimalarial drugs about one to two weeks before traveling to a malaria infested area and for four weeks after leaving the area. Your doctor, travel clinic, or the health department can advise you as to what medicines to take to keep from getting malaria. Currently, there is no vaccine available for malaria, but researchers are trying to develop one.
What other precautions should I take to avoid malaria?
If possible, avoid travel to or through countries where malaria occurs. If you must go to areas where malaria occurs, take the prescribed preventive medicine. In addition, the 2008 CDC international travel recommendations suggest the following precautions be taken in malaria infested areas:
Avoid exposure to mosquitoes during the early morning and early evening hours between the hours of dusk and dawn (the hours of greatest mosquito activity).
Wear appropriate clothing (long-sleeved shirts and long pants, for examples) especially when you are outdoors.
Apply insect repellent to the exposed skin. The CDC recommended insect repellent should contains up to 50% DEET (N, N-diethyl-m-toluamide), which is the most effective mosquito repellent for adults and children over 2 months of age.
Spray mosquito repellents on clothing to prevent mosquitoes from biting through thin clothing.
• Use a permethrin-coated (or similar repellant) mosquito net over your all beds.
• Have screens over cover windows and doors.
• Spray permethrin or a similar insecticide in the bedroom before going to bed.
Where can I get more information about malaria?
http://www.cdc.gov/malaria/history/index.htm#discoverymalariaparasite
http://www.cdc.gov/malaria/biology/life_cycle.htm
http://gis.hhs.gov/website/mrisk9/viewer.htm
http://www.traveldoctor.co.uk/malaria.htm
http://www.malariasite.com/malaria/history_parasite.htm
http://www.cdc.gov/malaria/faq.htm#4
http://www.cdc.gov/malaria/diagnosis_treatment/clinicians2.htm



Background
Two important currently used antimalarial drugs are derived from plants whose medicinal values had been noted for centuries: artemisinin from the Qinghao plant (Artemisia annua L, China, 4th century) and quinine from the cinchona tree (South America, 17th century).(2)
Malaria treatment milestones
Quinine
Quinine comes from the bark of a tree native to South America. According to legend it was first brought to Europe by a Countess who had been treated with it in Peru in the 1600s. The bark was named cinchona in 1742 by Linnaeus. In 1820, two French chemists isolated quinine from the cinchona bark and quinine became a treatment of reference for intermittent fever throughout the world. Quinine remains an important and effective treatment for malaria today, despite sporadic observations of quinine resistance.(1)
Chloroquine
Research by German scientists to discover a substitute for quinine led to the synthesis in 1934 of Resochin (chloroquine) and Sontochin (3-methyl-chloroquine). These compounds belonged to a new class of antimalarials, the four-amino quinolines. The German research went no further and the formula for Resochin was passed to a US sister company. During World War II, French soldiers happened upon a stash of German-manufactured Sontochin in Tunis and handed it over to the Americans. American researchers made slight adjustments to the captured drug to enhance its efficacy. The new formulation was called chloroquine. Only after comparing chloroquine to the older and supposedly toxic Resochin, did they realize that the two chemical compounds were identical.(1)
Following the war, chloroquine and DDT emerged as the two principal weapons in WHO’s global eradication malaria campaign. Subsequently, chloroquine resistant P. falciparum probably arose in four separate locations starting with the Thai-Cambodian border around 1957; in Venezuela and parts of Colombia around 1960; in Papua New Guinea in the mid-1970s and in Africa starting in 1978 in Kenya and Tanzania and spreading by 1983 to Sudan, Uganda, Zambia and Malawi.(1)
Sulfadoxine/Pyrimethamine
A pyrimidine derivative, proguanil, also emerged from the antimalarial pipeline during World War II. Proguanil’s success in treating humans led to further study of its chemical class and to the development of pyrimethamine. Resistance to the two monotherapies appeared quickly (within one year in the case of proguanil). Sulfones and sulfonamides were then combined with proguanil or pyrimethamine in hopes of increasing efficacy and forestalling or preventing resistance. By 1953, P. falciparum resistance had already been noted in Tanzania. When Sulfadoxine/Pyrimethamine (SP) was introduced in Thailand in 1967, resistance appeared that same year and resistance spread quickly throughout South-East Asia. Resistance to SP in Africa remained low until the late 1990s but since then it has spread rapidly.(1)
Mefloquine
The development of mefloquine was a collaborative achievement of the US Army Medical Research and Development Command, WHO/TDR and Hoffman-La Roche, Inc. Mefloquine’s efficacy in preventing falciparum malaria when taken regularly was shown in 1974 and its potential as a successful treatment agent was shown soon after. Resistance to mefloquine began to appear in Asia in 1985, around the time the drug became generally available.(1)
Artemisinin
Artemisinin was isolated by Chinese scientists in 1972 from Artemisia annua (sweet wormwood), better known to Chinese herbalists for more than 2000 years as Qinghao. In the early 1970s, initial testing by Chinese scientists of Qinghao extracts in mice infected with malaria showed it to be as effective as chloroquine and quinine in clearing the parasite. Mao Tse Tung’s scientists then began testing in humans and in 1979 published their findings in the Chinese Medical Journal.(1)
Artemisinin and other artemether-group drugs have been the main line of defense against drug resistant malaria in many parts of South-East Asia. Artemisinin has been a very potent and effective antimalarial drug, especially when used in combination with other malaria medicines.(3) Combining an artemisinin drug with a partner drug that has a longer half-life was found to improve the efficacy of the artemisinin. It also reduced treatment duration with the artemisinin and appeared to reduce the likelihood of development of resistance to the partner drug. In the early part of this century, Artemisinin-based combination therapy (ACT) had been shown to improve treatment efficacy and was thought to be a key to containing resistance in Southeast Asia. Read more about the MMV artemisinin programme.
Tackling resistance
However, in 2009, evidence of resistance to artemisinin-based combination therapy (ACT) was reported. Initially in the Thai-Cambodia border region, and now increasingly in Southeast Asia, ACTs are taking longer and longer to clear the parasite from patients. MMV’s first step is to determine whether resistance is only to artemisinin, or whether all artemisinin-like molecules (i.e. endoperoxides) in our pipeline are compromised. Find out more about how MMV is tackling resistance.


REFERENCES
(1) Text, where referenced, was adapted with permission of the US Institute of Medicine (IOM) from the report, {Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance}, 2004, pp. 126-128