Plasmodium falciparum in Cambodia: Difference between revisions

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Cambodia has an area of 69,898 square miles and about 60% this is comprised of forests and plains (5). Coupled with the Monsoon-dominated weather making Cambodia’s climate very moist and with its shady and wooded landscape, it makes Cambodia the perfect home for mosquitoes to survive and breed. Most of the population in Cambodia lives in these dense and moist forests where mosquitoes can transmit malaria to humans. Forest regions bordering Thailand and rubber plantations found in the East and Northwest are where malaria is likely to be found. About 15% of Cambodians are at elevated risks of malaria infection, of these forest inhabitants, migrant and border workers, pregnant women, and infants and children are the most susceptible to the disease (5). [[Image:Fake_artesunate_300w.jpg‎‎#filelinks|thumb|right|alt=Counterfeits drugs in Cambodia|]]
Cambodia has an area of 69,898 square miles and about 60% this is comprised of forests and plains (5). Coupled with the Monsoon-dominated weather making Cambodia’s climate very moist and with its shady and wooded landscape, it makes Cambodia the perfect home for mosquitoes to survive and breed. Most of the population in Cambodia lives in these dense and moist forests where mosquitoes can transmit malaria to humans. Forest regions bordering Thailand and rubber plantations found in the East and Northwest are where malaria is likely to be found. About 15% of Cambodians are at elevated risks of malaria infection, of these forest inhabitants, migrant and border workers, pregnant women, and infants and children are the most susceptible to the disease (5). [[Image:Fake_artesunate_300w.jpg‎‎#filelinks|thumb|right|alt=Counterfeits drugs in Cambodia|]]


Poor health infrastructure and poor communication systems are also major contributing factors to the malaria epidemic in Cambodia. In high transmission areas such as forests, the facilities such as hospitals are lacking, and transportation systems are deficient or nonexistent. Poor road conditions, lack of suitable vehicles and a lack of telephone facilities lead to treatment delays for the infected in remote areas. Many of the affected areas are inaccessible.  
Poor health infrastructure and poor communication systems are also major contributing factors to the malaria epidemic in Cambodia. In high transmission areas such as forests, the facilities such as hospitals are lacking, and transportation systems are deficient or nonexistent. Poor road conditions, lack of suitable vehicles and a lack of telephone facilities lead to treatment delays for the infected in remote areas. Many of the affected areas are inaccessible (18).


In addition, the inadequate health care adds to the problem of malaria in Cambodia. There are often shortages of diagnostic kits and appropriate drugs, as well as a lack of qualified private practitioners. Many unqualified doctors and pharmacies do not follow the national treatment guidelines. There are also large numbers of fake drugs available in the market due to lack of strict regulation and quality control practices. The counterfeits may contain no active ingredients or contain ingredients different from the package label. In 1999, fake antimalarial drugs were responsible for at least 30 peoples death in Cambodia (18).
In addition, the inadequate health care adds to the problem of malaria in Cambodia. There are often shortages of diagnostic kits and appropriate drugs, as well as a lack of qualified private practitioners. Many unqualified doctors and pharmacies do not follow the national treatment guidelines. There are also large numbers of fake drugs available in the market due to lack of strict regulation and quality control practices. The counterfeits may contain no active ingredients or contain ingredients different from the package label. In 1999, fake antimalarial drugs were responsible for at least 30 peoples death in Cambodia (19).


==What is being done to address this problem==
==What is being done to address this problem==

Revision as of 02:21, 28 August 2009

Introduction to Malaria

Malaria is fatal disease that infects about 515 million people worldwide and kills nearly a million people annually (1). It is widespread mostly in tropical and subtropical countries whrere conditions allow the Anopheles mosquitoes to thrive. Also, very often malaria is found in poor-economic countries, where people are unable to afford the preventive vaccinations or any medical treatments.

There are four types of human malaria which are Plasmodium(P) falciparum, Plasmodium vivax, Plasmodium malariae and Plassmodium oval. Among these four, P. falciparum and P. vivax, are the most common ones, and P. falciparum is the one that causes the most number of deaths.

Malaria infected individuals have symptoms such as fever, abdominal pain, chills, headaches, nausea, diarrhea, vomiting which can appear after couple of days or weeks after the infection. Also, very often malaria can lead to severe anemia, seizures, kidney failure, confusion and death if not treated on time (5).

Symptoms of Malaria

An interesting study shows that in Southeast Asia malaria was first transmitted to humans by chimpanzees and not by mosquitoes (6). The parasite in monkeys is Plasmodium Knowlesi , not Plazmodium falciparum, and is found in monkeys only. There have also been found some similarities between the human and monkey parasites which suggested that those two strains might have evolved from a common ancestor million of years ago. As a result of these findings, researchers are now wondering if P. Knowlesi is the fifth human malaria.

Also, studies have shown that increasing global temperature and climate changes may also lead to malaria’s rise. Increasing temperature, humidity and rains may all favor the spread of malaria transmitting mosquitoes to the areas where previously they did not exist (4).

As a result of its devastating effects on the human population, many organizations (Gates Foundation) and countries (Global Fund) have banded together to find preventative measures and treatments for this global epidemic.

Description of Malaria

In Cambodia, the specific species (Anopheles dirus, A. minimus, and A. sundaicus) transmit the malaria-causing parasites (Plasmodium falciparum and P. vivax) to the host during feeding with the bite, transmitting the parasite through their saliva (2).

The parasite initially enters the liver, where it multiplies and then infects the red blood cells. Here parasites still continue to multiply until eventually the red blood cells burst and the parasite appears in the plasma. Now, the parasites are free in the plasma and will infect any mosquito that bites and feeds on the host’s blood. Once the parasites enter the mosquito, they are also found in its saliva and are ready to be transferred to another individual and repeats the cycle after biting another host.

The number of infected people observed in Cambodia each year exceeds more than a million out of which about 10-15% die (5). Victims of malaria are mostly children, infants, and pregnant women because of their weaker immune system (3). Forest inhabitants, border workers and migrants are also in high risk in getting the disease because of their increased exposure to mosquito vectors. Due to global warming, the increasing temperatures, humidity, and rains may all favor the spread of malaria as mosquito habitats spread (4).

Description of the Plasmodium falciparum

Plasmodium falciparum is species of the genus Plasmodium, which of the Eukaryote domain and Plasmodiidae family. Plasmodium are much more complex than simple bacteria because of a “genetic complexity five times greater” (1). Their complex genome allows them more flexibility in various environments where simple bacteria can’t survive. Aside from having a complex genome, Plasmodium possesses various invasive stages for targeting specific host.

Infection

Plasmodium possesses various forms, the most prominent being sporozoite, merozoite, and ookinete. These various forms of a plasmodium are directly tied to the cycle of infection. Sporozoite enters the human body via the saliva of mosquitoes during a blood meal. Sporozoites infect the hepatocytes (liver cell) within 30 minutes. From the hepatocyte, the parasite reproduces asexually into merozoites until they are released from the liver and enter the bloodstream. Merozoites then invade the erythrocytes (red blood cells) within 10 minutes. The merozoites continue proliferation in infected erythrocytes and also infect other uninfected erythrozytes. In an erythrocyte, merozoite can also differentiate to become gametocyte where they can be carried off by female mosquitoes after a blood meal. The gametocytes travel to the mosquitoes’ guts where they differentiate into male and female cells for fertilization. A zygote or ookinete is ultimately formed. The ookinete develops into sporozoites and venture into the saliva of the mosquitoes where they can further infect other human (NEED CORRECT REF #).

Symptoms of Malaria

This cycle ties human and mosquitoes directly in the transmission and infection of malaria. In this relation, anopheline mosquitoes act as a vector and aid in spreading the infection. However, not all mosquitoes can be vectors. Only 68 out of 460 Anopheles can be vectors. Moreover, only female mosquitoes can take up gametocytes and transmit sporozoites as they are the only mosquitoes that bite.

Reasons for Symptoms

Symptoms of malaria are caused by the effects of merozoites interfering with the red blood cells' ability to carry oxygen. In infected erythrocytes, the cells are found to be deformed and stiff. Hemoglobins also function as food and nutrients for the merozoites. Infected red blood cells are more prone to rosetting and sequestration. Rosetting is when red blood cells attached to other red blood cell. With malaria, this occurs at a higher rate to allow for further infection of other red blood cells. Sequestration is the attachment of infected blood cells to the endothelial layer by rolling. Rolling is when the infected red blood cell rolls as a result fluid dynamics between receptors binding to the endothelium and force being exerted on the cells by the flowing fluids. As the cell rolls, receptors are able to bind to the endothelium. This results in the cell slowing down to a stop. The site of sequestration also prompts more infected cells to attach resulting in a buildup. Sequestration hinders oxygen delivery to organs and tissues. The effects of sequestration can lead to coma symptoms in severe cases of malaria. The combined effect of rosetting, sequestration, and consumption of hemoglobin by merozoites play a strong role in hindrance of oxygen delivery. This leads to the flu like symptoms of malaria (NEED CORRECT REF #).

Prevention/Treatment

Malaria preventive measures can be approached in various ways. Simple preventative measures can be vector control or protection from mosquitoes bites via mosquito nets or the use of bug sprays containing DEET. Anti-malaria drugs can be combined with vector control or bite prevention to lower the risk of infection. Unlike typical diseases, vaccination is not a viable solution due to the disease's complexity.

Hey, let me know; does this qualify as prevention? (NEED CORRECT REF #) "Cambodia recommends prophylaxis for all areas. Other medicines are mefloquine (Lariam, doxycycline, and atovaquone (Malarone), Mefloquine should be taken once a week, and this should be started two weeks prior to arriving in Cambodia. Mefloquine may cause mild neuropsychiatric symptoms, such as nausea, vomiting, dizziness, insomnia, and nightmares. Other severe reactions occur: “depression, anxiety, psychosis, hallucinations, and seizures.” However, in the cities near Thai border, mefloquine is not recommended because there is mefloquine-resistant malaria in the forested areas. Atovaquone/proguanil (Malarone) should be taken once a day with food, from two weeks before arrival and also seven days after departure. Atovauqone can cause mild symptoms like “abdominal pain, nausea, vomiting, headache, diarrhea, or dizziness.”

Why is this disease a problem in Cambodia?

Cambodia is one of a few countries in Southeast Asia that have been struck by the malaria epidemic. It is home to the world’s most drug-resistant strain of malaria and continues to fear that it’s growing more resistance to antimalarial drugs. Plasmodium falciparum, one of the most common and deadliest strands of malaria has been a major problem in Cambodia due to numerous factors.

Cambodia has an area of 69,898 square miles and about 60% this is comprised of forests and plains (5). Coupled with the Monsoon-dominated weather making Cambodia’s climate very moist and with its shady and wooded landscape, it makes Cambodia the perfect home for mosquitoes to survive and breed. Most of the population in Cambodia lives in these dense and moist forests where mosquitoes can transmit malaria to humans. Forest regions bordering Thailand and rubber plantations found in the East and Northwest are where malaria is likely to be found. About 15% of Cambodians are at elevated risks of malaria infection, of these forest inhabitants, migrant and border workers, pregnant women, and infants and children are the most susceptible to the disease (5).

Counterfeits drugs in Cambodia

Poor health infrastructure and poor communication systems are also major contributing factors to the malaria epidemic in Cambodia. In high transmission areas such as forests, the facilities such as hospitals are lacking, and transportation systems are deficient or nonexistent. Poor road conditions, lack of suitable vehicles and a lack of telephone facilities lead to treatment delays for the infected in remote areas. Many of the affected areas are inaccessible (18).

In addition, the inadequate health care adds to the problem of malaria in Cambodia. There are often shortages of diagnostic kits and appropriate drugs, as well as a lack of qualified private practitioners. Many unqualified doctors and pharmacies do not follow the national treatment guidelines. There are also large numbers of fake drugs available in the market due to lack of strict regulation and quality control practices. The counterfeits may contain no active ingredients or contain ingredients different from the package label. In 1999, fake antimalarial drugs were responsible for at least 30 peoples death in Cambodia (19).

What is being done to address this problem

The government of Cambodia believes that the increase of infections was because of the early rains. So the government distributed mosquito net, which prevents mosquitos from causing malaria by injecting parasites into the bloodstream. (1) Also, the government provided Rapid Diagnostic Tests (RDT), and Blister packaging. Rapid Diagnostic Tests assists, also known as dipstick, the diagnosis of malaria by detecting the parasites in bloodstream. This improves the quality of management for malaria infections. Blister packaging contains one dose of sulphadoxine/pyrimethamine (HAS BEEN RENDERED INEFFECTIVE FOR P. FALC) and three doses of artesunate. This provides high quality and effective treatments for malaria. This package is sold cheaper than other drug combinations.

Cambodia government recommends prophylaxis (REALLY? WASN'T IT AN ARTESUNATE AND MEFLOQUINE COMBO?) for all areas. Other medicines are mefloquine (Lariam, doxycycline, and atovaquone (Malarone), Mefloquine should be taken once a week, and this should be started two weeks prior to arriving in Cambodia. Mefloquine may cause mild neuropsychiatric symptoms, such as nausea, vomiting, dizziness, insomnia, and nightmares. Other severe reactions occur: “depression, anxiety, psychosis, hallucinations, and seizures.” However, in the cities near Thai border, mefloquine is not recommended because there is mefloquine-resistant malaria in the forested areas. Atovaquone/proguanil (Malarone) should be taken once a day with food, from two weeks before arrival and also seven days after departure. Atovauqone can cause mild symptoms like “abdominal pain, nausea, vomiting, headache, diarrhea, or dizziness.” Doxycycline is effective but not useful in the tropics because it exaggerates. (2)

However, drug-resistant malaria has emerged in Cambodia. In Western Cambodia, there are Artemisinin resistant malaria, which is the first-line treatment for malaria. The best solution now is to prevent the “spread of resistant parasites when they emerge.” (HOW?) Moreover, over the past few years, many counterfeit antimalarial drugs have been distributed in Cambodia. The counterfeit antimalarial drugs cause mutation of resistant strains of the parasites that cause malaria, which makes the real drug to lose its effectiveness. However, Malaria Workers (VMW) distribute the proper medication and dipstick test, which confirms P. Falsiparum. Their efforts huge changes in Cambodia; it slows down the drug resistance, and it also prevents the spread of malaria. MOT (Malaria Outreach Teams) reaches out to remote areas and provide diagnosis and treatment services at public and private facilities. This is extremely helpful for children who are in rural area because they have weak immune system.

The National Malaria Control Program (CNM), has strategies to improve the health status of the people in Cambodia. CNM's goal is to strengthen the institutional capacity of the national malaria control program and improve the management of malaria and preventive measures to protect the population groups at risk. (3) Another program, the Health Education Department of Cambodia, works to reduce morbidity and mortality rates of illness. In this program, they inform malarial prevention techniques and urge them to "initiate behavioral change regarding illness and prevention techniques within the community.” (4) Due to the awareness efforts, the number of malarial infections and deaths have decreased in recent years because of education and mosquito net distribution. The rate has “decreased from 2.81 percent to 1.68 percent for every 100,000 people” in 2008. (5)

1. <http://www.ox.ac.uk/media/news_stories/2009/090731.html> 2. <http://www.mdtravelhealth.com/destinations/asia/cambodia.php> 3. <http://cnm.gov.kh/?Programs> - Hide quoted text - 4. <http://cnm.gov.kh/?Health_Education> 5. <http://www.irinnews.org/report.aspx?ReportId=77967>

What else could be done to address this problem

A fairly efficient method currently used to ensure that the individuals who need the drug treatments receive and correctly use them are Village Malaria Workers (VMW) and Malaria Outreach Teams (MOT). These groups greatly increase treatment accessibility by diffusing into areas including rural and difficult to reach endemic areas. They perform an effective survey of the local population with RDTs which are relatively inexpensive, mobile, and quick in relation to past tests done in laboratories. They provide high grade A+M (artemisinin-mefloquine drugs) virtually free to those infected and check on their progress and whether they have completed the full course of anti-malarials(14). And those who believe they have become infected then have convenient access to diagnosis and treatment.

There is quite a large monetary cost associated with the start up and upkeep of these groups. The VMW are funded and run by “National Malaria Control Programme” and receive additional funding from the “Global Fund for AIDS, Tuberculosis and Malaria”, and the MOT is funded by "Médecins Sans Frontières" (MSF) (15). More investment is needed to extenuate the reach of these groups, along with increased global awareness, and possibly the use of dedicated volunteers; the positive effects of these groups can be even greater and more widespread.

A method necessary for prevention includes an awareness campaign in which communities are educated on identifying symptoms of malaria and where to go and what to expect during treatment as well as how to identify genuine and counterfeit blister packaging of A+M. They must also be provided with insecticide treated nets (ITN), to reduce mosquito contact, at no or very low costs to encourage their use among the large numbers of people who live in poverty. The aforementioned groups can then check to see whether people are utilizing the nets. Campaigning and ITNs will be costly and global awareness along with funding are imperative.

Since Plasmodium falciparum is multi-drug resistant, certain drugs like chloroquine and pyrimethamine-sulfadoxine are ineffective as treatment. First-line drug treatment in Cambodia is currently artemisinin combined with the use of another suitable anti-malarial, known as an artemisinin combination therapy (ACT). The secondary drug most prevalently used is mefloquine. ACT is important because artemisinin monotherapy (using artemisinin alone) will very likely cause a widespread artemisinin-resistant Plasmodium falciparum, which would be devastating. More research must be allotted towards finding another other suitable drugs for treatment in the event that there is a widespread artemisinin resistance. ACTs are effective as treatment because they decrease malaria transmission by preventing the development of P. falciparum gametocytes (16).

Another problem is the tendency for individuals living in rural endemic areas to seek treatment from informal health providers who would often times sell them artemisinin monotherapies, sub-standard artemisinin-mefloquine (A+M), or even fake drugs. Along with these low-grade drugs, individuals were not checked to see if they had finished the full course of the drug treatment (16). In many other instances, individuals were given anti-malarials with the sign of a mere fever without any biological confirmation of malaria itself (16). These are large contributing factors to the drug resistances that Plasmodium falciparum has developed towards other previously effective anti-malarials. Blister packages are now used to ensure the user of high-grade A+M because it would be evident if the drug and packaging were tampered with. This system packages drugs recognized internationally by “Good Manufacturing Practice” (GMP) and are run by the “National Malaria Centre” (CNM) and supported by the “World Health Organization” (WHO) (15). But these blister packages have been victim to counterfeiting, causing a new array of problems.

Unfortunately, counterfeit blister packaging containing less than sufficient amounts of artemisinin are often being sold by informal health providers. This is a problem because the drug is not capable of wiping out P. falciparum, thus enabling the possibility of an artemisinin-resistant P. falciparum mutant, which would, again, be catastrophic (14). Genuine A+M blister packaging contains a specific hologram and other key features that consumers should learn to identify, which needs to be taught because the differences between counterfeit and authentic blister packaging are very subtle. But fake blister packages may contain holograms as well, and special attention to details is necessary to identify a counterfeit. As counterfeit awareness has been increasing, sometimes, the counterfeits now being produced are so well duplicated that the average consumers may not even be able to differentiate between the real and the fakes. Chemical testing, i.e. LC-MS and Raman spectroscopy, may even be necessary in order to determine its authenticity (17). Luckily, receiving free genuine A+M from VMW's and MOT's can assist in alleviating widespread distribution of counterfeits.

References

[Sample reference] Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.

Lusine's Refs. 1. “Genome of Parasite that Causes Relapsing Malaria Decoded.” 2009. ScienceDaily. 9 Oct. 2008.

2. Pierce, Susan K., Miller, Louis H. World Malaria Day 2009: What Malaria Knows about the Immune System that Immunologists Still Do Not. 2009. The Journal of Immunology. 5 March, 2009.

3. “Drug-Resistant Malaria Has Emerged in Cambodia.” 2009. Science Daily. 13 Aug. 2009.

4. “Is Global Warming Likely to Cause an Increase Incidence of Malaria?” 2009. Libyan Journal of Medicine. 13 Feb. 2009.

5. "Fewer Malaria Cases in Cambodia.” 2009. Population Reference Bureau. Dec. 2002.

6. "Epidemiological Profile of Cambodia" World Malaria Report 2008. Geneva : World Health Organization , ©2008. p.51-54.

Chuong's Refs. 7. http://www.impact-malaria.com

8. Molecular aspect of malaria.

Ben's Refs.

9. "Drug-resistant malaria has emerged in Cambodia." University of Oxford. 31 July 2009. Web. 31 July 2009. <Drug-resistant malaria has emerged in Cambodia>.

10. "Mdtravelhealth." Http://www.mdtravelhealth.com/destinations/asia/cambodia.php. Mdtravelhealth. Web.

11. "THE NATIONAL MALARIA CONTROL PROGRAM." The National Center for Parasitology, Entomology and Malaria Control, Cambodia. CAMBODIA National Malaria Center (CNM), 2008. Web. <http://cnm.gov.kh/?Programs>.

12."THE NATIONAL MALARIA CONTROL PROGRAM." The National Center for Parasitology, Entomology and Malaria Control, Cambodia. CAMBODIA National Malaria Center (CNM), 2008. Web. <http://cnm.gov.kh/?Health_Education>.

13."CAMBODIA: Malaria on the decline due to concerted awareness efforts." IRIN. PHNOM PENH, 29 Apr. 2008. Web. 29 Apr. 2008. <http://www.irinnews.org/report.aspx?ReportId=77967>.

Kat's Refs.

14. Yeung, Shunmay, Wim Van Damme, Doung Socheat, Nicholas J. White, and Anne Mills. "Access to artemisinin combination therapy for malaria in remote areas of Cambodia." Malaria Journal 96th ser. 7.1 (2008). Malaria Journal. Web. 26 Aug. 2009. <http://malariajournal.com/content/7/1/96>.

15. Yeung, Shunmay, Wim Van Damme, Doung Socheat, Nicholas J. White, and Anne Mills. "Cost of increasing access to artemisinin combination therapy: the Cambodian experience." Malaria Journal 84th ser. 7.1 (2008). BioMed Central Ltd. Web. 26 Aug. 2009. <http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2413253>.

16. Guerin, Philippe J., Piero Olliaro, Francois Nosten, Pierre Druilhe, Ramanan Laxminarayan, Fred Binka, Wen L. Kilama, Nathan Ford, and Nicholas J. White. "Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development." The Lancet Infections Diseases 2.9 (2002): 564-73. The Lancet. Web. 26 Aug. 2009. <http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(02)00372-9/fulltext>.

17. Alterhall, Krystyn, Paul N. Newton, Micheal D. Green, Marleen De Veij, Peter Vandenabeele, David Pizzanelli, Mayfong Mayxay, Arjen Dondorp, and Facundo M. Fernandez. "Characterization of Counterfeit Artesunate Antimalarial Tablets from South East Asia." The American Journal of Tropical Medicin and Hygiene 75.5 (2006): 804-11. The American Journal of Tropical Medicine and Hygiene. Web. 26 Aug. 2009. <http://www.ajtmh.org/cgi/content/full/75/5/804>.

Betsy's refs

18. “Malaria Situation in Cambodia, in 2003.” National Malaria Center for Parasitology, Entomology & Malaria Control. Web. 20 August 2009. <www.actmalaria.net/downloads/pdf/info/2004/Cambodia.pdf>.

19. “Counterfeit and Substandard Antimalarial Drugs.” Centers for Disease Control and Prevention, 26 July 2006. Web. 24 Aug. 2009. < http://www.cdc.gov/malaria/travel/counterfeit_drugs.htm>.

Edited by [Betsy Chiem, Lusine Minasyan, Chuong Do, Katherine Leu, Albert Luong and Ben Cho], students of Rachel Larsen