malaria background

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QUESTION

where did malaria come from?

ANSWER

Malaria is a disease caused by a single-celled parasite called Plasmodium. There are many species of Plasmodium, which infect many other animals as well as humans. The types of malaria which infect humans probably evolved from similar Plasmodium species in monkeys and apes; for example, P. vivax is closely related to several species of malaria that infect macaque monkeys in south-east Asia, while P. falciparum, the most severe and deadly kind of malaria, probably evolved from similar infections in chimpanzees and gorillas in central Africa. This transition from other primates to humans occurred many thousands of years ago; further back in time, the types of Plasmodium which infect mammals (rodents can also be infected with Plasmodium) are thought to have jumped over from Plasmodium species which infect birds and reptiles. Even before that, Plasmodium itself seems to have evolved from other types of blood-borne parasites which infect birds and reptiles.

Antimalarial Drugs During pPregnancy

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QUESTION

What is the safest antimalarial drug to be used by a pregnant woman in her second trimester?

ANSWER

With regards to treating malaria, intravenous artesunate (or quinine, if artesunate is not available) should be used for the treatment of severe/complicated Plasmodium falciparum malaria. Signs of severe and/or complicated malaria include impaired consciousness, organ failure, abnormal bleeding, hypoglycemia, severe anemia and/or inability to ingest medication orally. Treatment for uncomplicated malaria (where the above signs are absent) in pregnant women is usually chloroquine for P. vivax, P. ovale, P. knowlesi and P. malariae, as well as for P. falciparum if there are no reports of this parasite being resistant to chloroquine in the area. In places where P. falciparum is resistant to chloroquine, quinine and clindamycin should be used to treat this parasite in pregnant women.

As for preventative anti-malarials (chemoprophylaxis), if a pregnant woman is travelling to an area where only P. vivax, P. ovale, P. knowlesi, P. malariae or chloroquine-sensitive P. falciparum is transmitted, then she should take chloroquine to prevent malaria. In areas where P. falciparum is resistant to chloroquine, mefloquine is also suitable during pregnancy. Note that in some areas of south-east Asia, there are areas where P. falciparum is resistant to mefloquine, which may prevent its suitability as a prophylactic in this region. Preventing malaria during pregnancy is crucial, since the mother, particularly if it is her first baby, is especially vulnerable to the parasite. Moreover, malaria can have a negative impact on the fetus.

Newly Sequenced Malaria Genomes Show Genetic Variability

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Genetic variability revealed in malaria genomes newly sequenced by two multi-national research teams points to new challenges in efforts to eradicate the parasite, but also offers a clearer and more detailed picture of its genetic composition, providing an initial roadmap in the development of pharmaceuticals and vaccines to combat malaria.

The research appears in two studies published in the latest issue of the journal Nature Genetics. They focus on Plasmodium vivax (P. vivax), a species of malaria that afflicts humans and the most prevalent human malaria parasite outside Africa, and Plasmodium cynomolgi (P. cynomolgi), a close relative that infects Asian Old World monkeys.

“The bad news is there is significantly more genetic variation in P. vivax than we’d thought, which could make it quite adept at evading whatever arsenal of drugs and vaccines we throw at it,” said Professor Jane Carlton, senior author on both studies and part of New York University’s Center for Genomics and Systems Biology. “However, now that we have a better understanding of the challenges we face, we can move forward with a deeper analysis of its genomic variation in pursuing more effective remedies.”

In one study, the researchers examined P. vivax strains from different geographic locations in West Africa, South America, and Asia, providing the researchers with the first genome-wide perspective of global variability within this species. Their analysis showed that P. vivax has twice as much genetic diversity as the world-wide Plasmodium falciparum (P. falciparum) strains, revealing an unexpected ability to evolve and, therefore, presenting new challenges in the search for treatments.

The second study, performed jointly with Professor Kazuyuki Tanabe at Osaka University, Japan, sequenced three genomes of P. cynomolgi. The researchers compared its genetic make-up to P. vivax and to Plasmodium knowlesi (P. knowlesi), a previously sequenced malaria parasite that affects both monkeys and humans in parts of Southeast Asia.

Their work marked the first time P. cynomolgi genomes have been sequenced, allowing researchers to identify genetic diversity in this parasite. Its similarity to P. vivax means that their results will also benefit future efforts to understand and fight against forms of malaria that afflict humans.

“We have generated a genetic map of P. cynomolgi, the sister species to P. vivax, so we can now push forward in creating a robust model system to study P. vivax,” explained Tanabe. “This is important because we can’t grow P. vivax in the lab, and researchers desperately need a model system to circumvent this.”

Much of the work occurred under a seven-year grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The funding has established 10 International Centers of Excellence for Malaria Research (ICEMR). Carlton is heading an ICEMR based in India, where malaria – and P. vivax in particular — is a significant public health burden. A particular aim of this Center of Excellence is to support and help train scientists in India who can then work to combat infectious diseases, such as malaria, where they are most prominent. The P. vivax sequencing was funded by NIAID as part of the NIAID funded Genomic Sequencing Center for Infectious Diseases at the Broad Institute under Contract No. HHSN272200900018C. The Burroughs Wellcome Fund was instrumental in providing pilot funds for the P. cynomolgi sequencing.

Researchers at the following institutions were also part of the P. vivax sequencing: The Broad Institute, the National Institute of Malaria Research in India, Arizona State University, and the Centers for Disease Control and Prevention.

Researchers at the following institutions were also part of the work on P. cynomolgi: Osaka University, Dokkyo Medical University, Japan’s Corporation for Production and Research of Laboratory Primates, Nagasaki University, Juntendo University’s School of Medicine, the University of Tokyo, the National Institute of Biomedical Innovation, the Centers for Disease Control and Prevention, and Arizona State University.

Source: New York University

About Malaria Proteins

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QUESTION

Please tell about about malarial causitive proteins.

ANSWER

I’m not sure what your question is, as malaria is not caused by a protein, but rather by a single-celled parasite called Plasmodium, which contains many different types of proteins. Some of these are indeed used for entering host cells and thus causing disease. Many of these proteins, and particularly ones on the surface of the malaria parasite, induce the host’s immune system, and so are called antigens. One of the most well known malaria antigens is called the Duffy antigen, and it is found on two types of malaria (Plasmodium knowlesi and Plasmodium vivax). It is used by the parasite to invade host red blood cells, and it is interesting because many populations of people in Africa have genetic changes in the parts of the red blood cell which the Duffy antigen binds to. This means these people, called Duffy negative, are much less susceptible to these types of malaria than people who are so-called Duffy positive and have normal red blood cells.

Malaria Prophylaxis for Indonesia

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QUESTION

I have been working a 4-week rotation between the USA and East Kalimantan (Borneo) for about 2 years. While on Borneo, I am in the jungle much of the time. I have never contracted malaria. I am embarrassed to say I thought I had been inoculated for malaria when I first started working here. I just spent 10 days in a hospital last month fighting a blood degenerating viral infection not unlike hemophiliac dengue. Is there a preferred Rx I should take for malaria? I have no allergies to medicines that I am aware of. I am 57 year-old male.

ANSWER

Given the amount of time you spend in rural areas of Borneo, you probably should consider anti-malarial medication to prevent infection. There are three types of drug which are recommended against malaria in Indonesia: atovaquone-proguanil (sold as Malarone), mefloquine (sold as Lariam) and doxycycline. Each has pros and cons: Malarone and doxy have to be taken every day, while Lariam is only taken weekly, which might make it more convenient. However, both doxy and Lariam should be taken for a full 4 weeks after leaving the malarial area, while Malarone is only taken for a week after leaving.

In my opinion, Malarone has the fewest and mildest side effects (though some people complain of upset stomachs and disturbed sleep patterns), while doxycycline is sometimes a problem in the tropics since it can cause sun sensitivity. Lariam is not recommended for people with a history of mental illness, and has been reported to have psychiatric side effects, including nightmares, hallucinations and even altered behavior. Of the three, Malarone is the most expensive, and doxycycline usually the cheapest.

In terms of taking them long term, I don’t know of any studies that look at long term usage of Malarone (it is expensive enough that I doubt anyone takes it for very long trips!), while people do safely take doxycycline for periods of several months, and Peace Corps volunteers and American expats routinely take Lariam for periods of several years.

Of course, many people living long term in malarial areas do not find it convenient to take pills to prevent malaria, and focus on other preventative measures, mainly revolving around killing mosquitoes and avoiding being bitten. Sleeping under a long-lasting insecticide treated bednet is one such method, which is cheap, easy and very effective.

Incidentally, the area you are in is interesting from a malaria point of view since it is one of the few places where transmission of Plasmodium knowlesi occurs. This is a type of malaria which was thought to be only present in macaque monkeys, until human cases started becoming more prevalent a few years ago. Now it is considered a “human” type of malaria, and an emerging threat in south-east Asia. It’s important to be aware of it as the mosquitoes which transmit it tend to be forest-dwelling (since that is where the macaques live), and although very easily treated with chloroquine or other anti-malarials, an infection can progress rapidly into quite severe disease.

If you suspect you might have malaria at any point, therefore, it is crucial to get out and get tested at a clinic or hospital, where they can promptly treat you if you test positive. Be aware also that if tested via microscopy, P. knowlesi can often be confused with P. malariae or P. vivax; while the initial treatment is likely to be the same for all three, if you had P. vivax you might be told about taking an additional medication, called primaquine, to prevent future relapses, whereas relapses do not occur with P. knowlesi.

Recurrence of Malaria Symptoms

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QUESTION

If a person suffering from malaria is given the proper treatment and he gets well but he again develops the symptoms of malaria..? These symptoms would arise from liver or blood? Who’ll be responsible for the recurrence of the symptoms?

ANSWER

Malaria can come back in three ways: first of all, the person could have been successfully treated, but then re-infected again by being bitten by an infected mosquito. In these cases, the person should focus on improved malaria prevention, such as sleeping under a long-lasting insecticide treated bednet.

Secondly, the patient could have recrudescence: when the patient takes medication, the treatment kills most of the malaria parasites in the blood, and enough so the patient feels better again, but some parasites still remain. Then, after the treatment finished, the parasite is able to replicate again, they increase in number in the blood and the patient feels ill again. In this case, you would say the infection came back from the blood, and the patient should take another dose of anti-malarials, but of a different kind to that which they originally had, in order to kill all of the parasites.

Finally, there is what is called relapse, which only occurs with two types of malaria: Plasmodium vivax and Plasmodium ovale. These are able to form dormant stages in the liver, so even when all the parasites are killed in the blood by the malarial treatment, these dormant forms survive. Many weeks, months or even years later, these dormant liver stages can re-activate and enter the blood again, causing new malaria symptoms. In this case, the liver was the source of the parasites. Again, the active blood infection should be treated with anti-malarials, but the patient should also talk to their doctor about taking primaquine, a drug which can kill any remaining dormant liver forms and thus prevent future relapses.

Trophozoites of Plasmodium Vivax

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QUESTION

What should I take in this condition? After treatment I came to know that Rechocin should be taken for 6 months 2  weekly.

ANSWER

I am not sure I understand your question, but if you have been diagnosed with trophozoites of Plasmodium vivax in your blood, then you can be treated with normal anti-malarials (the World Health Organization recommends artemisinin-based combination therapies for first line treatment of uncomplicated malaria, but depending where you are, you might even just be able to take chloroquine), as these kill the blood stages of malaria. To prevent relapse, caused by hypnozoites dormant in the liver, you should talk to your doctor about the possibility of also taking a course of primaquine, which usually lasts 14 days. This drug is not suitable for people with G6DP deficiency, however, so you may need a test for this condition before you can take the treatment.

New Malaria Parasites

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QUESTION

I heard researchers have found a new malaria parasite—what is the name?

ANSWER

New malaria parasites are found quite regularly—the parasite that causes malaria, Plasmodium, actually infects birds, reptiles, rodents and non-human primates like monkeys and apes as well as humans. As such, non-human forms of malaria are discovered relatively frequently in other species. For example, a few years ago, some researchers looked at malaria in apes in Central Africa, and found a new species in gorillas, which is so new it has not even been fully described to science yet, and so remains unnamed! It is thought to be very closely related to Plasmodium falciparum, which is the most dangerous type of malaria in humans. Also recently, two new species were observed in chimpanzees, also in Central Africa, and names P. billcollinsi and P. billbrayi.

Even in humans, new infections are sometimes observed. One which has gained a lot of recent attention is not a new species, but what seems to be increasing numbers of cases of a monkey type of malaria (called P. knowlesi) in humans. It is unclear whether this is due to changes within the parasite, or changes to the landscape which might be creating more favorable conditions for the transmission of this malaria to humans. It is even possible that this malaria has always infected humans, and so this is not a new development, but due to diagnostic issues, it was mistaken for other, human malaria species, such as P. vivax and/or P. malariae.

How is Malaria Prevented?

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QUESTION

What are the methods to prevent malaria?

ANSWER

Malaria prevention consists of a combination of mosquito avoidance measures and chemoprophylaxis. Although very efficacious, none of the recommended interventions are 100% effective.

Mosquito Avoidance Measures

  • Because of the nocturnal feeding habits of Anopheles mosquitoes, malaria transmission occurs primarily between dusk and dawn.
  • Contact with mosquitoes can be reduced by remaining in well-screened areas, using mosquito bed nets (preferably insecticide-treated nets), using a pyrethroid-containing flying-insect spray in living and sleeping areas during evening and nighttime hours, and wearing clothes that cover most of the body.
  • All travelers should use an effective mosquito repellent.
  • The most effective repellent against a wide range of vectors is DEET (N,N-diethylmetatoluamide), an ingredient in many commercially available insect repellents. The actual concentration of DEET varies widely among repellents. DEET formulations as high as 50% are recommended for both adults and children older than 2 months of age (see the Protection Against Mosquitoes, Ticks, and Other Insects and Arthropods section later in this chapter). DEET should be applied to the exposed parts of the skin when mosquitoes are likely to be present.
  • In addition to using a topical insect repellent, a permethrin-containing product may be applied to bed nets and clothing for additional protection against mosquitoes.

Chemoprophylaxis

  • All currently recommended primary chemoprophylaxis regimens involve taking a medicine before travel, during travel, and for a period of time after leaving the malaria endemic area. Beginning the drug before travel allows the antimalarial agent to be in the blood before the traveler is exposed to malaria parasites.
  • Presumptive antirelapse therapy (also known as terminal prophylaxis) uses a medication towards the end of the exposure period (or immediately thereafter) to prevent relapses or delayed-onset clinical presentations of malaria caused by hypnozoites (dormant liver stages) of P. vivax or P. ovale. Because most malarious areas of the world (except the Caribbean) have at least one species of relapsing malaria, travelers to these areas have some risk for acquiring either P. vivax or P. ovale, although the actual risk for an individual traveler is difficult to define. Presumptive anti-relapse therapy is generally indicated only for persons who have had prolonged exposure in malaria-endemic areas (e.g., missionaries, volunteers).
  • In choosing an appropriate chemoprophylactic regimen before travel, the traveler and the health-care provider should consider several factors. The travel itinerary should be reviewed in detail and compared with the information on where malaria transmission occurs within a given country (see the Malaria Risk Information and Prophylaxis, by Country, section later in this chapter) to determine whether the traveler will actually be traveling in a part of the country where malaria occurs and if significant antimalarial drug resistance has been reported in that location.
  • The resistance of P. falciparum to chloroquine has been confirmed in all areas with P. falciparum malaria except the Caribbean, Central America west of the Panama Canal, and some countries in the Middle East. In addition, resistance to sulfadoxine–pyrimethamine (e.g., Fansidar) is widespread in the Amazon River Basin area of South America, much of Southeast Asia, other parts of Asia, and in large parts of Africa. Resistance to mefloquine has been confirmed on the borders of Thailand with Burma (Myanmar) and Cambodia, in the western provinces of Cambodia, in the eastern states of Burma (Myanmar), on the border between Burma and China, along the borders of Laos and Burma, and the adjacent parts of the Thailand–Cambodia border, as well as in southern Vietnam.
  • Additional factors to consider are the patient’s other medical conditions, medications being taken (to assess potential drug–drug interactions), the cost of the medicines, and the potential side effects.
      The medications recommended for chemoprophylaxis of malaria may also be available at overseas destinations. However, combinations of these medications and additional drugs that are not recommended may be commonly prescribed and used in other countries. Travelers should be strongly discouraged from obtaining chemoprophylactic medications while abroad. The quality of these products is not known, and they may not be protective and may be dangerous. These medications may have been produced by substandard manufacturing practices, may be counterfeit, or may contain contaminants. Additional information on this topic can be found in an FDA document

Purchasing Medications Outside the United States

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Death from Malaria: Humans and Other Primates

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QUESTION

If not treated in some form, do most who acquire malaria die? What about primates, such as orangutans that live in the wild and would not be treated as such. Do they die or do they become chronically ill within period of remission?

ANSWER

That’s a really good question, and the answer is: it depends! In humans, the most deadly form of malaria is Plasmodium falciparum—when infected for the first time, if not given prompt treatment, many people will die from this infection. However, after repeated infections, people develop acquired immunity to the P. falciparum parasite which means they are increasingly able to survive subsequent infections without treatment. This reason of acquired immunity is why young children, who do not yet have immunity, and visitors to malarial areas tend to have the most severe infections and most require treatment in order to survive.

The other three major forms of human malaria, P. vivax, P. malariae and P. ovale, are generally less deadly, though they can also result in death in some circumstances if the person does not have immunity and is not treated. Although much less common than P. falciparum, P. knowlesi is the fifth type of malaria to infect humans (it is more commonly an infection of macaque monkeys in south-east Asia), and because it replicates in a 24-hour cycle (the other types of human malaria have either a 48 or 72 hour cycle), high parasite loads can establish very quickly, leading to severe disease. As such, P. knowlesi is also quite dangerous and a high proportion of untreated cases result in death.

It is great that you ask about malaria in other primate species—as with humans, some forms of malaria are tolerated reasonably well while others are more deadly. It varies depending on the type of malaria as well as the species of primate. So, for example, P. knowlesi in long-tailed macaques is rarely observed to cause severe disease. In fact, infected macaques sometimes don’t even appear to have any symptoms. In contrast, if rhesus macaques are experimentally infected with P. knowlesi (the transmission range of this type of malaria does not overlap with the natural range of rhesus macaques), almost 100% of them will die without treatment.

You ask specifically about orangutans: one problem is that it is unclear which, and how many, species of malaria infect these apes. Past research has uncovered two species which are thought to be unique to orangutans (namely P. silvaticum and P. pitheci) while molecular studies have also shown non-specific species, namely human P. vivax and macaque P. cynomolgi and P. inui. As such, while originally orangutan malaria was thought to be not very dangerous to these apes, more recently there have been reports of orangutans showing very human-like symptoms suggestive of more advanced disease. However, rarely do studies link symptoms and observations of parasites in the blood, so it is unclear which parasites are causing these symptoms, if indeed it is malaria at all (in some sanctuary/rehabilitation center settings, orangutans exhibiting malaria symptoms have responded positively to treatment with anti-malarials, though this is not definitive evidence that their symptoms were caused by malaria).

So, in short, more research should be done on wild primates, particularly using molecular tools, to ascertain accurately what species of malaria they are infected with, and whether they are associated with symptoms and/or severe disease.