On
Plasmodium
vivax
Malaria
in
Southeast
Asia
Ryleigh Repass
NGT
21 November, 2013
Plasmodium vivax Malaria in Southeast Asia
Introduction: Malaria
The parasites that cause malaria are spread by mosquitoes and infect humans and some animals.
A parasitic protozoan of the genus Plasmodium causes malaria. There are five species of plasmodia that
can infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Of these, P.
falciparum and P. vivax are the most commonly found.
P. vivax malaria is rare amongst those of African descent due to the common lack of Duffy
glycoprotein expression on the surface of red blood cells, which prevents invasion of P. vivax
merozoites (Mueller et al. 2009). Therefore, P. vivax is not as commonly found in Africa as P.
falciparum. P. vivax, however, is the most common form of malarial infection in south Asia, Southeast
Asia, and the Americas. In fact, 26 of the 34 malaria eliminating countries have a malaria burden solely
or mainly due to P. vivax (Cotter et al. 2013).
Transmission and Symptoms of P. vivax:
Plasmodium vivax is spread by the female Anopheles mosquito. Transmission occurs when an
infected female mosquito bites a human vector, spreading the sporozoites into the bloodstream. From
there, the sporozoites migrate to the liver within minutes, invade hepatocytes, and develop into an
actively dividing schizont or a dormant hyponozoite (see Figure 1). There is absolutely no understanding
of the biological decision to replicate or remain dormant. An important part of P. vivax that makes it so
dangerous and distinguishable from other strains is the fact that it can be transmitted from human to
mosquito and back to humans before showing signs of infection (Douglas et al. 2010).
The symptoms of P. vivax have only recently been discovered. Previously, P. vivax was thought
to be a benign disease with little to no significant symptoms. Mueller et al. (2009) studied hospital
admissions in endemic areas and found that P. vivax is not a benign form of malaria and causes similar
symptoms as P. falciparum. These symptoms might include cerebral maloria, hepatic dysfunction with
severe jaundice, acute lung injury, acute respiratory distress syndrome, pulmonary oedema, shock, renal
failure, splenic rupture, severe thrombocytopena hemorrhage, and severe anemia. It is extremely
important to note the lack of ability to distinguish between P. falciparum and P. vivax when diagnosing
a patient. If a patient is misdiagnosed as having P. falciparum malaria, the reservoirs of P. vivax could
proliferate and cause a relapse after medication. Also, this inability to distinguish between the two skews
the statistical analysis of malaria. If fewer rates of P. vivax are reported than actually exist, there is a
eview
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lesser chance that P. vivax will ever gain importance in the scientific world. Therefore, P. vivax has a
small chance of ever being acknowledged as a very serious threat and will continue to be understudied.
P. vivax, however, has been gaining popularity as more research connecting P. vivax to other
health problems comes to light. Specifically, a study by Williams et al. (1997) on the relationship
between P. vivax and malnutrition in young children supported the possibility that P. vivax may produce
considerable global mortality. The research was on 1511 children younger than ten in Espiritu Santo,
Vanuata. There were three categories of malnutrition: underweight, wasting, and stunting. The results
showed that the incidences of P. vivax malaria were significantly higher in underweight and wasted
children than in non-underweight and non-wasted children. Furthermore, the only significant differences
between the groups of children chosen were the area in which they lived South (hyperendemic area)
and East (mesoendemic area). The children in the South were found to have higher rates of underweight,
wasting and stunting than those in the East. The data collected in the study support the hypothesis that P.
vivax is a leading cause of malnutrition in young children. Therefore, it is extremely important that vivax
malaria is recognized as a danger to development in children throughout the world.
Sporozoites inoculated
by mosquito
Oocyst ruptures
Salivary gland
Sporozoites
Midgut
epithelium
Gametocytes
ingested
by mosquito
Sporozoites
s
izont
e sch
Tissu
Merosome
Hypnozoite
Trophozoite
Merosome
rupture
Ring
Merozoites in
blood stream
Reticulocytes
Gametes
Male and female gametocytes
Schizont
Schizont
rupture
Immature gametocytes
Figure:
Life cycle of the human malaria parasite Plasmodium vivax
Source?
Once infective sporozoites are inoculated into the skin by female anopheles mosquitoes, they reach the bloodstream and enter hepatocytes initiating the
exoerythrocytic stage. Within the liver, P vivax can either dierentiate into tissue schizonts, which after thousands of mitotic replications in individual hepatocytes
release merozoites into the bloodstream, or dierentiate into a dormant stage called a hypnozoite that, upon activation after months or years, causes clinical relapse.1
The merosome featured here has, so far, only been described in malaria in rodents2 but is predicted to be present in late stage liver infections with P vivax and other
During the erythrocytic stages, P vivax merozoites predominantly, if not exclusively, invade reticulocytes,2 and these cells become enlarged and more
species.
deformable.3 This cyclical developmental process takes about 48 h. In addition, P vivax produces specific proteins to create caveolavesicle complexes that appear as
profuse speckling in Giemsa-stained blood smears, known as Schfnners dots.4 Moreover, some P vivax parasites can dierentiate into mature gametocytes before a
clinical infection and illness develops, thus having the advantage of continued transmission to the insect vector before the appearance of clinical symptoms and
5
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Difficulty Treating P. vivax and Eradication:
According to Cotter et al. (2013), between the years of 2000 and 2010 gross domestic product
per head in the 34 malaria-eliminating countries increased by 3-5% most likely due to lowered rates of
malaria. During this time period, there was in an increase in funding, effective vector control,
strengthening of health systems, improved case management with more effective treatment regimes, and
improved case reporting and surveillance. However, as overall malaria rates went down, proportions of
all cases caused by P. vivax rose. This information highlights the fact that P. vivax is not necessarily
eradicated with the current treatment regimens.
Vivax malaria is different from P. falciparum in that it has a dormant liver stage that can relapse
even after treatment. In a study, vivax malaria was shown to relapse in 20-80% of treated patients even
in low transmission areas (Price et al. 2007). The lack of ability for medicine to eliminate malaria from
the system makes P. vivax next to impossible to eradicate from a community. Furthermore, early
gametocyte development in the infection of the host causes the infected individuals blood to be a
reservoir that can successfully transmit infection to a mosquito (Mueller et al. 2009). Due to this
reservoir as well as inability to eradicate latent cells, P. vivax continues to be a serious problem.
Another aspect of P. vivax that makes it so difficult to eradicate
is the inability to grow it in a lab setting. Vivax malaria invades the
Figure
1
reticulocytes, which only make up a small percentage of red blood cells,
making it almost impossible to culture in vitro and perform experiments on (Baird et al. 2007).
The first step in eradicating P. vivax is funding research into better understanding the biology of
the parasitic disease. Meuller et al. (2009) stresses the importance of understanding the biological
determinant that dictates the active or dormant development pathways. In figuring this out, scientists
could take the next step to block the dormant development in order to erase the possibility of dormancy
in the liver. With that said, medication used to eliminate the dormant cells is understudied. Initial
treatment of malaria with chloraquine eradicates the blood-stage cells but not the liver-stage dormant
cells. However, there is a current treatment for vivax malaria infection primaquine. The biology of
primaquine is not well understood. Baird et al. (2003) states that it has the ability to kill both latent and
developing asexual stages in the liver and sterilize the gametocytes of P. vivax.
The primaquine drug was first administered in 1950 to the American troops in the Korean War.
Since then, no research has been conducted on the effectiveness of primaquine until recently. The
original dose of primaquine was 15 mg a day for 14 days. However, Baird et al. (2003) found that the 15
mg dose is no longer effective, most likely due to resistance. Baird et al. (2004) state that a dose of 22.5
mg daily for 14 days or a total of 315 mg for as long as 8 weeks is effective in eradicating latent malaria.
On
Plasmodium
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Furthermore, as long as an adequate dosage is administered, the schedule in which it is administered
does not matter (Baird et al. 2004). This finding allows for a more flexible schedule and hopefully a
better compliance.
Treatment of vivax malaria:
A study by Adak et al. (1998) tested the effects of chloroquine without any primaquine on P.
vivax.This study was conducted in Delhi, India on inhabitants belonging mainly to low socioeconomic
strata. They began by testing the patients at the Malaria Research Centre for P. vivax and only included
those that were positive and did not have previous symptoms of malaria in the study. They administered
900 mg of chloroquine base (600 mg on first day and 300 mg on second day) to all patients. All patients
were categorized into three groups: primary case (no history of malaria), nonrelapse case (no clinical
symptoms or parasitologic evidence of P. vivax after primary infection) and relapse case (renewed
clinical symptoms and positive for P. vivax). They found that P. vivax infections were predominant
between April to early December. In a five-year period, 44.3% of patients studied relapsed. Overall, the
duration of P. vivax infection is at least 3 years and the five-year pooled data showed a nonrelapse in
70.96% of the patients. They conclude that the National Malaria Eradication Program needs to
reconsider their recommended administration of primaquine for the radical cure of P. vivax. This
conclusion brings forth many questions. To begin with, if chloroquine is so effective, then why was
primaquine even administered? Was the method of research and data collection in this study unreliable?
How effective is chloroquine if administered with primaquine? If the relapse rate of P. vivax is zero
when chloroquine is administered with primaquine, then wouldnt it make sense to use primaquine? The
study by Adak et al. (1998) is a good start to understanding the importance of antimalarial drugs but
should have gone one step further by testing the relapse rate if chloroquine is taken with primaquine.
Dao et al. (2007) tested the efficacy of combining artesunate and primaquine in fighting vivax
malaria. The artesunate plus primaquine treatment is shorter than the chloraquine (3 days) plus
primaquine (14 days) treatment. A main issue with many drugs is the patient compliance to the lengthy
treatment. Thus, Dao et al. (2007) not only hoped to see a better compliance with the short regimen but
also a higher efficacy rate in curing malaria. They administered artesunate (200 mg) at 0, 12, 24, and 36
hours after admission to the study followed by three primaquine tablets twice a day for seven days. They
followed up on the 28 patients 28 days after treatment. Initial treatment in all patients led to a rapid
reduction in parasite density and also immediately reduced fever. The 28-day follow up showed that
only one of the 28 patients had a recurrence of vivax malaria. The regimen was well tolerated and was
highly effective in eliminating blood-stages of P. vivax malaria. Unfortunately, the testing period was
short and was unable to test the effectiveness in eliminating the hypnozoites in the liver. This study,
On
Plasmodium
vivax
Malaria
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however, is significant in that it proposes an alternative to the lengthy chloroquine treatment and further
research to support these findings should be completed.
Conclusion:
LITERATURE CITED
Adak, T., Sharma, V., Orlov, V., 1998 Studies on the Plasmodium Vivax Relapse Pattern in Delhi,
India The American Journal of Tropical Medicine and Hygeine 59(1): 175-79.
Baird, J., Hoffman, S., 2004 Primaquine therapy for malaria Clinical infectious diseases 39(9): 133645.
Baird, J., Rieckmann, K., 2003 Can primaquine therapy for vivax malaria be improved? Trends in
parasitology 19(3): 115-20.
Baird, J., Schwartz, E., Hoffman, S., 2007 Prevention and treatment of vivax malaria Current
infectious disease reports 9(1): 39-46.
Cotter, C., Sturrock, H., Hsiang, M., Liu, J., Phillips, A., Hwang, J., Gueye, C., Fullman, N., Gosling,
R., Feachem, R., 2013 The Changing Epidemiology of Malaria Elimination: New Strategies for
New Challenges The Lancet Infectious Diseases 382 (9895): 900-11.
Dao, N., Cuong, B., Ngoa, N., Duy, D., Dai, B., Thanh, N., Edstein, M., 2007 Vivax malaria:
preliminary observations following a shorter course of treatment with artesunate plus
primaquine. Transactions of the Royal Society of Tropical Medicine and Hygiene 101(6): 534
-39.
Douglas, N., Anstey, N., Angus, B., Nosten, F., Price, R., 2010 Artemisinin combination therapy for
vivax malaria The Lancet infectious diseases 10(6): 405-16.
Gordon, H., Dieuaide, F., Marble, A., Christianson, H., Dahl, L., 1947 Treatment of Plasmodium vivax
malaria of foreign origin: a comparison of various drugs Archives of Internal Medicine 79(4):
365.
Hill, D., Baird, J., Parise, M., Lewis, L., Ryan, E., Magill, A., 2006 Primaquine: report from CDC
expert meeting on malaria chemoprophylaxis I The American Journal of Tropical Medicine and
Hygiene 75(3): 402-415.
Mueller, I., Galinski, M., Baird, J., Carlton, J., Kochar, D., Alonso, P., Del Portillo, H., 2009 "Key Gaps
in the Knowledge of Plasmodium Vivax, a Neglected Human Malaria Parasite" The Lancet
Infectious Diseases 9(9): 555-66.
Price, R., Tjitra, E., Guerra, C., Yeung, S., White, N., Anstey, N., 2007 "Vivax Malaria: Neglected and
Not Benign" American Journal of Tropical Medicine and Hygiene 77 (6): 79-87.
Wells, T., Burrows, J., Baird, J., 2010 Targeting the hypnozoite reservoir of Plasmodium vivax: the
hidden obstacle to malaria elimination Trends in parasitology 26(3): 145-51.
Williams, T., Maitland, K., Phelps, L., Bennett, S., Peto, T., Viji, J., Timothy, R., Clegg, J.,
Weatherall, J., Bowden, D., 1997 "Plasmodium vivax: A Cause of Malnutrition in Young
Children" Q J Med 90: 751-53.
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Plasmodium
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Southeast
Asia
Ignore this part (notes for myself) !
Therefore, relapse is common in P. vivax infected humans because quinine cannot rid the body entirely
of latent hypnozoites (Baird et al. 2003).
http://www.webmd.com/drugs/drug-12232-primaquine+oral.aspx
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a607037.html
http://wwwnc.cdc.gov/travel/destinations/traveler/none/argentina
http://www.map.ox.ac.uk/explore/countries/
P. vivax is different from P. falciparum in that it forms hypnozoites which can lie dormant in the
liver. The hypnozoites can lie dormant anywhere between 16 days and a few years (Baird et al. 2004).
An interesting and significant result of primaquine is that it rapidly and completely stops the
development of P. vivax in mosquitoes, which makes it impossible to transmit (Baird et al. 2004).
