Malaria Deaths 2x Greater than Previously Reported

by

Malaria is killing more people worldwide than previously thought, but the number of deaths has fallen rapidly as efforts to combat the disease have ramped up, according to new research from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington.
More than 1.2 million people died from malaria worldwide in 2010, twice the number found in the most recent comprehensive study of the disease. IHME researchers say that deaths from malaria have been missed by previous studies because of the assumption that the disease mainly kills children under 5. IHME found that more than 78,000 children aged 5 to 14 and more than 445,000 people aged 15 and older died from malaria in 2010, meaning that 42% of all malaria deaths were in people aged 5 and older.
“You learn in medical school that people exposed to malaria as children develop immunity and rarely die from malaria as adults,” said Dr. Christopher Murray, IHME Director and the study’s lead author. “What we have found in hospital records, death records, surveys, and other sources shows that just is not the case.”
The study also found that while the overall number of malaria deaths is higher than earlier reports, the trend in malaria deaths followed a similar downward pattern. Starting in 1985, malaria deaths grew every year before peaking in 2004 at 1.8 million deaths worldwide. Since then, the number of deaths fell annually, and between 2007 and 2010, the decline in deaths was more than 7% each year.
The new findings are being published today in The Lancet in “Global malaria mortality between 1980 and 2010: a systematic analysis.” The work is part of the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. Other research from this study, global trends in child mortality, maternal mortality, breast cancer, and cervical cancer, were released last year, and more trends will be released in the coming months.
Researchers say the biggest drivers of the decline in malaria deaths have been the scale-up of insecticide-treated bed nets and artemisinin-combination treatments (ACTs). This has been accomplished through the advent of the Global Fund to Fight AIDS, Tuberculosis and Malaria in 2001 and the creation of organizations focused on fighting malaria, such as the World Health Organization’s Roll Back Malaria, Malaria No More, and Nothing But Nets. Overall funding for malaria efforts grew from less than $0.25 billion annually in 2001 to more than $2 billion in 2009, according to IHME’s latest estimates. IHME reported in September 2011 that homes owning at least one bed net were associated with a 23% reduction in child mortality.
“We have seen a huge increase both in funding and in policy attention given to malaria over the past decade, and it’s having a real impact,” said Dr. Alan Lopez, Head of the School of Population Health at the University of Queensland and one of the study’s co-authors. “Reliably demonstrating just how big an impact is important to drive further investments in malaria control programs. This makes it even more critical for us to generate accurate estimates for all deaths, not just in young children and not just in sub-Saharan Africa.”
One of the most important factors in identifying the new malaria estimates was the use of verbal autopsy data. In a verbal autopsy, researchers interview the relatives of someone who has recently died to identify the cause of death. IHME and collaborators around the world published a series of articles in a special edition of Population Health Metrics in August 2011 focused on advancing the science of verbal autopsy. Verbal autopsy data were especially important in India, where malaria deaths have been vastly undercounted in both children and adults. IHME found that more than 37,000 people over the age of 15 in India died from malaria in 2010, and the chances of someone dying from malaria in India have fallen rapidly since 1980.
Progress in fighting malaria can be seen everywhere. Countries such as Zambia and Tanzania saw malaria deaths fall by more than 30% between 2004 and 2010. The progress being seen in Africa is especially significant, given that malaria deaths there accounted for a quarter of all deaths in children under 5 in 2010.
But the researchers warn that those gains could be reversed if global economic troubles continue to stifle funding efforts. IHME reported in December that growth in development assistance for health slowed greatly between 2009 and 2011. The announcement by the Global Fund in November that it would cancel its next round of funding casts a cloud over the future of malaria programs, the researchers say.
“If the Global Fund is weakened, the world could lose 40% of all the funding dedicated to fighting malaria,” said Dr. Stephen Lim, Associate Professor of Global Health at IHME and a co-author on the study. “That kind of loss of funding poses a definite threat to the health of people in countries with a high malaria burden, which in many cases are some of the poorest countries in the world. We need to think of ways to fill funding deficits in order to ensure continued progress on malaria mortality.”

Source: IHME

Scientists Develop Method to Synthesize Artemisinin Inexpensively and in Large Quantities

by

Prof. Dr. Peter H. Seeberger and Dr. François Lévesque. Copyright © MPI of Colloids and Interfaces

In future it should be possible to produce the best anti-malaria drug, artemisinin, more economically and in sufficient volumes for all patients.

The most effective anti-malaria drug can now be produced inexpensively and in large quantities. This means that it will be possible to provide medication for the 225 million malaria patients in developing countries at an affordable price.

Researchers at the Max Planck Institute of Colloids and Interfaces in Potsdam and the Freie Universität Berlin have developed a very simple process using oxygen and light for the synthesis of artemisinin, the active ingredient that pharmaceutical companies could only obtain from plants up to now. The chemists use a waste product from current artemisinin production as their starting substance. This substance can also be produced biotechnologically in yeast, which the scientists convert into the active ingredient using a simple yet very ingenious method.

There is an effective treatment against malaria, but it is not accessible to all of the more than 200 million people worldwide who are affected by the disease. Millions, especially in the developing world, cannot afford the combination drug preparation, which consists mainly of artemisinin. Moreover, the price for the medication varies, as this substance is isolated from sweet wormwood (Artemisia annua) which grows mainly in China and Vietnam, and varies seasonally in its availability.

To make the drug affordable for at least some patients in developing countries, the Clinton Foundation, for example, subsidises its cost to the tune of several million dollars per year. Nevertheless, over one million people die of malaria each year because they do not have access to effective drugs.

This may be about to change. Peter H. Seeberger, Director at the Max Planck Institute of Colloids and Interfaces in Potsdam and Professor of Chemistry at the Freie Universität Berlin and his colleague François Lévesque have discovered a very simple way of synthesising the artemisinin molecule, which is known as an anti-malaria drug from traditional Chinese medicine and has an extremely complex chemical structure. “The production of the drug is therefore no longer dependent on obtaining the active ingredient from plants,” says Peter Seeberger.

Synthesis from a by-product of artemisinin production

As a starting point, the chemists use artemisinic acid – a substance produced as a hitherto unused by-product from the isolation of artemisinin from sweet wormwood, which is produced in volumes ten times greater than the active ingredient itself. Moreover, artemisinic acid can easily be produced in genetically modified yeast as it has a much simpler structure.

“We convert the artemisinic acid into artemisinin in a single step,” says Peter Seeberger. “And we have developed a simple apparatus for this process, which enables the production of large volumes of the substance under very controlled conditions.” The only reaction sequence known up to now required several steps, following each of which the intermediate products had to be isolated laboriously—a method that was far too expensive to offer as a viable alternative to the production of the drug from plants.

The striking simplification of artemisinin synthesis required not only a keen sense for an elegant combination of the correct partial reactions to enable the process to take place in a single step; it also took a degree of courage, as the chemists departed from the paths typically taken by industry up to now. The effect of the molecule, which not only targets malaria but possibly also other infections and even breast cancer, is due to, among other things, a very reactive chemical group formed by two neighbouring oxygen atoms, which chemists refer to as an endoperoxide.

Peter Seeberger and François Lévesque use photochemistry to incorporate this structural element into the artemisinic acid. Ultraviolet light converts oxygen into a form that can react with molecules to form peroxides.

800 photoreactors should suffice to cover the global requirement for artemisinin

“Photochemistry is a simple and cost-effective method. However, the pharmaceutical industry has not used it to date because it was so difficult to control and implement on a large scale,” explains Peter Seeberger. In the large reaction vessels with which industrial manufacturers work, flashes of light do not penetrate deeply enough from outside and the reactive form of oxygen is not produced in sufficient volumes.

The Potsdam-based scientists have succeeded in resolving this problem using an ingenious trick: They channel the reaction mixture containing all of the required ingredients through a thin tube that they have wrapped around a UV lamp. In this structure, the light penetrates the entire reaction medium and triggers the chemical conversion process with optimum efficiency.

“The fact that we do not carry out the synthesis as a one-pot reaction in a single vessel, but in a continuous-flow reactor enables us to define the reaction conditions down to the last detail,” explains Peter Seeberger. After just four and a half minutes a solution flows out of the tube, in which 40 percent of the artemisinic acid has become artemisinin. “We assume that 800 of our simple photoreactors would suffice to cover the global requirement for artemisinin,” says Peter Seeberger.

And it could all happen very quickly. Peter Seeberger estimates that the innovative synthesis process could be ready for technical use in a matter of six months. This would alleviate the global shortage of artemisinin and exert considerable downward pressure on the price of the associated drugs.

Reference: François Lévesque and Peter H. Seeberger
“Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin”
Angewandte Chemie international edition, 17. January 2012; DOI: 10.1002/anie.201107446

Source: Max Planck Institute of Colloids and Interfaces

Counterfeit Anitmalarial Drugs Threaten Crisis in Africa

by

Hopes of at last controlling malaria in Africa could be dashed by the emergence of poor-quality and fraudulent antimalarial medicines, warn experts writing in Malaria Journal. Unless urgent action is taken both within Africa and internationally, they argue, millions of lives could be put at risk. [Read more…]

Artemisinin Hailed as One of the Greatest Advances in Fight Against Malaria

by

The Chinese drug artemisinin has been hailed as one of the greatest advances in fighting malaria, the scourge of the tropics, since the discovery of quinine centuries ago. Artemisinin’s discovery is being talked about as a candidate for a Nobel Prize in Medicine. Millions of American taxpayer dollars are spent on it for Africa every year. But few people realize that in one of the paradoxes of history, the drug was discovered thanks to Mao Zedong, who was acting to help the North Vietnamese in their jungle war against the Americans. Or that it languished for 30 years thanks to China’s isolation and the indifference of Western donors, health agencies and drug companies. [Read more…]

Mosquito Immune System Can Be Engineered to Block Malaria

by

Researchers have demonstrated for the first time that the Anopheles mosquito’s innate immune system could be genetically engineered to block the transmission of the malaria-causing parasite to humans. In addition, they showed that the genetic modification had little impact on the mosquito’s fitness under laboratory conditions.

“The immune system of the Anopheles mosquito is capable of killing a large proportion—but not all—of the disease-causing parasites that are ingested when the mosquito feeds on an infected human,” said George Dimopoulos, PhD, senior author of the study and associate professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. “We’ve genetically engineered this immune system to create mosquitoes that are better at blocking the transmission of the human malaria parasite Plasmodium falciparum. ”

For the study, Dimopoulos and his team genetically engineered Anopheles mosquitoes to produce higher than normal levels of an immune system protein Rel2 when they feed on blood. Rel2 acts against the malaria parasite in the mosquito by launching an immune attack involving a variety of anti-parasitic molecules. Through this approach, instead of introducing a new gene into the mosquito DNA, the researchers used one of the insect’s own genes to strengthen its parasite-fighting capabilities. According to the researchers, this type of genetically modified mosquito could be further developed and used to convert malaria-transmitting to Plasmodium-resistant mosquito populations. One possible obstacle for this approach is the fitness of the genetically modified malaria resistant mosquitoes, since they would have to compete with the natural malaria-transmitting mosquitoes. The researchers showed with their study that the Rel2 genetically modified mosquito strain lived as long, and laid as many eggs, as the non-modified wild type mosquitoes, thereby suggesting that their fitness had not become significantly impaired.

“Malaria is one of world’s most serious public health problems. Mosquitoes and the malaria parasite are becoming more resistant to insecticides and drugs, and new control methods are urgently needed. We’ve taken a giant step towards the development of new mosquito strains that could be released to limit malaria transmission, but further studies are needed to render this approach safe and fail-proof,” said Dimopoulos.
Worldwide, malaria afflicts more than 225 million people. Each year, the disease kills approximately 800,000, many of whom are children living in Africa.

Authors of “Engineered Anopheles immunity to Plasmodium infection” are Yuemei Dong, Suchismita Das, Chris Cirimotich, Jayme A. Souza-Neto, Kyle J. McLean and George Dimopoulos.

The Johns Hopkins Malaria Research Institute is a state-of-the-art research facility at the Johns Hopkins Bloomberg School of Public Health. It focuses on a broad program of basic science research to treat and control malaria, develop a vaccine and find new drug targets to prevent and cure this deadly disease.

The researchers’ findings were published December 22, 2011 in the online journal PLoS Pathogens. Funding was provided by the National Institutes of Health and the Johns Hopkins Malaria Research Institute.

 

Source: Johns Hopkins Bloomberg School of Public Health

Researchers Introduce Technology to Manufacture Artemisinin in Tobacco Plants

by

Combating malaria is one of the eight Millennium Development Goals described in the United Nations Millennium Declaration signed by all UN members at the year 2000. A key intervention to control malaria is prompt and effective treatment with artemisinin-based combination therapies. Artemisinin is a natural compound from Artemisia annua (sweet wormwood) plants, but low-cost artemisinin-based drugs are lacking because of the high cost of obtaining the natural or chemically synthesized drug. Despite extensive efforts invested in the last decade in metabolic engineering of the drug in both microbial and heterologous plant systems, production of artemisinin itself was never achieved.

Recently, Yissum Research Development Company of the Hebrew University of Jerusalem Ltd., the technology transfer arm of the University of Jerusalem, introduces a novel method allowing artemisinin production in a heterologous (that is, other than A. annua) plant system, such as tobacco. The method was developed by Professor Alexander Vainstein from the Robert H. Smith Faculty of Agriculture, Food and Environment at the Hebrew University, and sponsored by a fellowship of Mr. Isaac Kaye. It was published under the title “Generation of the Potent Anti-Malarial Drug Artemisinin in Tobacco” in the latest issue of the prestigious publication Nature Biotechnology.

Professor Vainstein and his graduate student Mr. Moran Farhi have developed genetically engineered tobacco plants carrying genes encoding the entire biochemical pathway necessary for producing artemisinin. In light of tobacco’s high biomass and rapid growth, this invention will enable a cheap production of large quantities of the drug, paving the way for the development of a sustainable plant-based platform for the commercial production of an anti-malarial drug. The invention is patented by Yissum, which is now seeking a partner for its further development.

Yaacov Michlin, CEO of Yissum said, “Professor Vainstein’s technology provides, for the first time, the opportunity for manufacturing affordable artemisinin by using tobacco plants. We hope that this invention will eventually help control this prevalent disease, for the benefit of many millions of people around the globe, and in particular in the developing world.”

Malaria is caused by a parasite called Plasmodium, which is transmitted via mosquitoes. Symptoms of malaria include fever, headache, and vomiting, and usually appear between 10 and 15 days after the mosquito bite. If not treated, malaria can quickly become life-threatening by disrupting the blood supply to vital organs.

More than 3 billion people are at risk of malaria. Every year, this leads to about 250 million malaria cases and nearly one million deaths. People living in the poorest countries are the most vulnerable.

Malaria is especially a serious problem in Africa, where 20% of childhood deaths are due to the effects of the disease and every 30 seconds a child dies from malaria.

Source: Business Wire

Researchers Cure Mice of Bloodstream Malaria Infection

by

Researchers have discovered how malaria manipulates the immune system to allow the parasite to persist in the bloodstream. By rescuing this immune system pathway, the research team was able to cure mice of bloodstream malaria infections.

The findings could point the way to a new approach for treating malaria that does not rely on vaccination and is not susceptible to the parasite’s notorious ability to develop drug resistance.

“Malaria is chronic, prolonged infection and the host immune defense has a tough time clearing it and sometimes it never clears it,” says Noah Butler, Ph.D., UI postdoctoral research scholar at the University of Iowa,  and lead study author. “We’ve determined that this prolonged infection actually drives dysfunction of the immune cells that are supposed to be fighting the infection, which in essence allows further persistence of the parasite infection.”

More specifically, the study showed that the malaria parasite stimulate these key immune cells (known as CD4+ T cells) so that they continuously express molecules called inhibitory receptors. Under normal circumstances, these molecules help to “apply the brakes” to the immune response and prevent over-activation that can be harmful. However, by keeping the mechanism turned on, the malaria parasite damps down the immune response significantly, reducing the T cells’ ability to fight the parasite and allowing it to persist.

Importantly, the team also showed that blocking the action of the inhibitory receptor molecules resulted in immediate and complete clearance of the malaria parasite.

“When we blocked the function of these molecules, we took the brakes off the host’s immune response and everything got better — the overall immune response was dramatically improved and there was immediate control and accelerated clearance of the parasite,” says John Harty, Ph.D., professor of microbiology and pathology at the UI Carver College of Medicine and senior study author. “These findings suggest an alternative approach for the treatment of existing malaria infection.”

200 million malaria cases

More than half the world’s population is at risk of malaria, a mosquito-borne parasite that causes anemia and high fever and which can persist for weeks or months. There are more than 200 million cases of malaria each year and an estimated 800,000 children die from malaria annually.

Harty notes that the current study was done in mice and it is not yet known if the same approach will work in humans. However, two factors suggest the strategy may have potential. First, drugs that block inhibitory receptor molecules are available and currently being tested as cancer therapies. And second, the UI team found that malaria infection in humans does lead to increased expression of inhibitory receptors on CD4+ T cells suggesting that these molecules could represent a viable target for human therapies.

The human findings were the product of an important collaboration between the UI team and malaria researchers working in the sub-Saharan country of Mali. The Mali team based at the University of Bamako works in a sophisticated lab set up by the National Institutes of Health. In Mali’s dry season there are no mosquitoes, so there’s no malaria; in the wet season, the mosquitoes come out and malaria appears.

“Workers in the NIH lab obtained blood samples from malaria-free children at the end of the dry season, and then when some of the children returned to the clinic with malaria at the beginning of the next wet season they were treated immediately and the workers also took a second blood sample,” Harty explains. “This allowed us to analyze the blood for expression of this inhibitory molecule before and after infection and we found that the molecule went up after infection.”

Malaria further compromises immune system

A second collaboration, born closer to home, allowed Harty’s team to prove that it is the CD4+ T cells that are disrupted by the malaria infection.

Using a new technique that was developed in the lab of UI microbiologist Steve Varga, Ph.D., the researchers were able to track the behavior of the responding T cells during malaria infection. They found that chronic malaria infection led to sustained expression of the inhibitory receptor molecules on the surfaces of this type of T cell and also showed that the T cells’ ability to fight the parasite was significantly reduced.

The study also found that as the parasite persists the inhibitory receptor molecules remain upregulated and the immune system became more and more compromised.

“The T-cells are so over-stimulated that they eventually lose their function or even die — this is known as T-cell exhaustion,” Butler explains.

The concept that prolonged persistence of an “insult” to the immune system, such as cancer or chronic viral infections like HIV, disrupts and exhausts the immune response is well established. However, this study is the first time it has been shown for malaria. The study finding suggests that rescuing CD4+ T cells from exhaustion could be an effective strategy to control and clear bloodstream malaria infections.

The study was undertaken by University of Iowa researchers and colleagues, and was published Dec. 11, 2011 in the Advance Online Publication of the journal Nature Immunology.  In addition to Harty and Butler, UI researchers Lecia Pewe, Lorraine Tygrett, and Thomas Waldschmidt, Ph.D., also were involved in the study. The team also included Jacqueline Moebius and Peter Crompton from the National Institute of Allergy and Infectious Diseases in Rockville, Md., and Boubacar Traore and Ogobara Doumbo from the Malaria Research and Training Center, University of Bamako in Mali.

The study was funded in part by grants from the NIH and the UI Department of Microbiology.

Source: University of Iowa Health Care Media Relations, 200 Hawkins Drive, Room W319 GH, Iowa City, Iowa 52242-1009

Starving Malaria Parasites

by

Researchers have developed an antimalarial agent that is effective at clearing infections caused by the malaria parasite most lethal to humans—by literally starving the parasites to death. The study by researchers at Albert Einstein College of Medicine of Yeshiva University, carried out on a small number of non-human primates, could bolster efforts to develop more potent therapies against one of the world’s leading killers.

Malaria is a mosquito-borne disease caused by single-celled parasites belonging to the Plasmodium genus. The U.S. Centers for Disease Control and Prevention estimated that in 2008 (the latest year for which figures are available) between 190 million and 311 million cases of malaria occurred worldwide and between 708,000 and 1.003 million people died, most of them young children in sub-Saharan Africa. Plasmodium falciparum, the malaria species most likely to cause severe infections and death, is very common in many countries in Africa south of the Sahara desert.

The Einstein researchers exploited what is arguably P. falciparum’s Achilles’ heel: it can’t synthesize purines, vital building blocks for making DNA. Instead, the parasite must make purines indirectly, by using an enzyme called purine nucleoside phosphorylase (PNP) to make a purine precursor called hypoxanthine. By inhibiting PNP, the drug BCX4945 kills the parasites by starving them of the purines they need to survive.

After BCX4945 showed potency against laboratory cultures of P. falciparum, owl monkeys were chosen as the non-human primate model for further testing of the drug. Three animals were infected with a strain of P. falciparum that is consistently lethal without antimalarial therapy. Orally administering BCX4945 twice a day for seven days cleared the infections from all the animals between the fourth and seventh day of treatment. The monkeys remained parasite-negative for up to nine days post-treatment. Parasitic infection eventually returned in all three monkeys after treatment ended, although a lower rate of parasitic growth was observed. No signs of toxicity were observed during the study period (30 days after the first dose).

BCX4945 belongs to a class of drugs known as transition state analogs that Dr. Schramm has been developing since 1994. Transition states form in every chemical change and whenever an enzyme does its job of converting one chemical (the substrate) into another (the product). The fleeting transition-state molecule is neither substrate nor product, but something in between—a ghostly intermediate to which the enzyme clings for just one billionth of a millionth of a second.

After figuring out the brief-lived transition-state structure for a particular enzyme, Dr. Schramm is able to design transition-state analogs to knock that enzyme out of action. The analogs closely resemble the actual transition-state structure but with one big difference: they powerfully inhibit the enzyme by binding to it and not letting go.

The transition-state analog BCX4945 was chosen for this study because of its high affinity for both P. falciparum PNP and human PNP (which the parasite obtains from the red blood cells it infects). Since PNP is abundant in mammalian red blood cells and those cells are constantly replaced, BCX4945 is toxic only to the parasite and not its mammalian hosts. (Two of Dr. Schramm’s other PNP inhibitors—one for T-cell cancers, the other for gout—are being evaluated in clinical trials.)

“Inhibiting PNP differs from all other current approaches for treating malaria,” said Dr. Schramm. “For that reason, BCX4945 fits well with the current World Health Organization protocols for malaria treatment, which call for using combination-therapy approaches against the disease.”

The study, published in the November 11, 2011 issue of PLoS ONE, was led by senior author Vern Schramm, Ph.D., professor and Ruth Merns Chair in Biochemistryat Einstein.

The paper is titled “Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model.”

Other Einstein researchers involved in the study were Steven Almo, Ph.D., lead author Maria Cassera, Ph.D. (now at Virginia Polytechnic Institute and State University), Keith Hazleton, M.D./Ph.D. candidate, Emilio Merino (now at Virginia Polytechnic Institute and State University), Meng-Chiao Ho, Ph.D., (now at Academia Sinica), Andrew Murkin, Ph.D., (now at SUNY Buffalo), and Jemy Gutierrez, Ph.D., (now at Pfizer). This research was supported primarily by the National Institute of Allergy and Infectious Disease, part of the National Institutes of Health, and early aspects of the study were funded by Medicines for Malaria.

Source: Albert Einstein College of Medicine of Yeshiva University

Contrasting Patterns of Malaria Drug Resistance Found Between Humans and Mosquitoes

by

A recent study has detected contrasting patterns of drug resistance in malaria-causing parasites taken from both humans and mosquitoes in rural Zambia.

Parasites found in human blood samples showed a high prevalence for pyrimethamine-resistance, which was consistent with the class of drugs widely used to treat malaria in the region. However, parasites taken from mosquitoes themselves had very low prevalence of pyrimethamine-resistance and a high prevalence of cycloguanil-resistant mutants indicating resistance to a newer class of antimalaria drug not widely used in Zambia.

The study was conducted by researchers at the Johns Hopkins Malaria Research Institute and their Zambian colleagues and the findings were published November 7, 2011 in the online edition of the journal PNAS.

Surveillance for drug-resistant parasites in human blood is a major effort in malaria control. Malaria in humans is caused by the parasite Plasmodium falciparum, which is spread from person to person through the feeding of the Anopheles mosquito. Over time, through repeated exposure to medications, the parasites can become less susceptible to drugs used to treat malaria infection, limiting their effectiveness.

“This contrast in resistance factors was a big surprise to us,” said Peter Agre, MD, an author of the study and director of the Johns Hopkins Malaria Institute. “The contrast raises many questions, but we suspect that the malaria parasite can bear highly host-specific drug-resistant polymorphisms, most likely reflecting very different selection preferences between humans and mosquitos.”

For the study, Sungano Mharakurwa, PhD, lead author and senior research associate with the Johns Hopkins Malaria Research Institute in Macha, Zambia, conducted a DNA analysis of P. falciparum found in human blood samples to those found in mosquitoes collected inside homes in rural Zambia. In samples taken from human blood, pyrimethamine-resistant mutations were greater than 90 percent and between 30 percent to 80 percent for other polymorphisms. Mutations of cycloguanil-resistance were 13 percent.

For parasites found in the mosquito midgut, cycloguanil-resistant mutants were at 90 percent while pyrimethamine-resistant mutants were detected between 2 percent and 12 percent.

“Our study indicates that mosquitoes exert an independent selection on drug resistant parasites—a finding that has not previously been noticed. If confirmed in other malaria endemic regions, it suggests an explanation for why drug resistance may appear so rapidly,” said Mharakurwa.

Worldwide, malaria afflicts more than 225 million people. Each year, the disease kills approximately 800,000, many of whom are children living in Africa.

Authors of “Malaria antifolate resistance with contrasting Plasmodium falciparum dihydrofolate reductase (DHFR) polymorphisms in humans and Anopheles mosquitoes” are Sungano Mharakurwa, Taida Kumwenda, Mtawa A. P. Mkulama, Mulenga Musapa, Sandra Chishimba, Clive J. Shiff, David J. Sullivan, Philip E. Thuma, Kun Liu and Peter Agre.

The Johns Hopkins Malaria Research Institute is a state-of-the-art research facility at the Johns Hopkins Bloomberg School of Public Health. It focuses on a broad program of basic science research to treat and control malaria, develop a vaccine and find new drug targets to prevent and cure this deadly disease.

Funding was provided by the Johns Hopkins Malaria Research Institute, the Bill & Melinda Gates Foundation and the National Institutes of Health.

Source: Johns Hopkins University

Central Venous Catheter Use in Severe Malaria: Time to Reconsider the World Health Organization Guidelines?

by

To optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH2O. However there are few data from clinical trials to support this recommendation.

Methods
Twenty-eight adult Indian and Bangladeshi patients admitted to the intensive care unit with severe falciparum malaria were enrolled in the study. All patients had a CVC inserted and had regular CVP measurements recorded. The CVP measurements were compared with markers of disease severity, clinical endpoints and volumetric measures derived from transpulmonary thermodilution.

Results
There was no correlation between the admission CVP and patient outcome (p = 0.67) or disease severity (p = 0.33). There was no correlation between the baseline CVP and the concomitant extravascular lung water (p = 0.62), global end diastolic volume (p = 0.88) or cardiac index (p = 0.44). There was no correlation between the baseline CVP and the likelihood of a patient being fluid responsive (p = 0.37). On the occasions when the CVP was in the WHO target range patients were usually hypovolaemic and often had pulmonary oedema by volumetric measures. Seven of 28 patients suffered a complication of the CVC insertion, although none were fatal.

Conclusion
The WHO recommendation for the routine insertion of a CVC, and the maintenance of a CVP of 0-5 cmH2O in adults with severe malaria, should be reconsidered.

Authors: Josh Hanson1,2*, Sophia WK Lam1,2, Sanjib Mohanty3, Shamshul Alam4, Md Mahtab U Hasan5, Sue J Lee2, Marcus J Schultz6, Prakaykaew Charunwatthana2, Sophie Cohen7, Ashraf Kabir8, Saroj Mishra3, Nicholas PJ Day2,9, Nicholas J White2,9 and Arjen M Dondorp2,9

* Corresponding author: Josh Hanson drjoshhanson@gmail.com

Author Affiliations

1 Department of Medicine, Cairns Base Hospital, Queensland, Australia
2 Mahidol Oxford Research Unit, Mahidol University, Bangkok, Thailand
3 Department of Medicine, Ispat General Hospital, Rourkela, India
4 Department of Intensive Care Medicine, Chittagong Medical College Hospital, Chittagong, Bangladesh
5 Department of Medicine, Chittagong Medical College Hospital, Chittagong, Bangladesh
6 Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
7 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
8 Department of Anaesthetics, Cox’s Bazar Medical College, Cox’s Bazar, Bangladesh
9 Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

Citation: Malaria Journal 2011, 10:342 doi:10.1186/1475-2875-10-342

Full Article: Central Venous Catheter Use in Severe Malaria: Time to Reconsider the World Health Organization Guidelines? (PDF)

Copyright © by the authors, 2011. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.