G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries

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Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk.

Methods and Findings

Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene’s X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4–8.8) across MECs, and 5.3% (4.4–6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd.

Conclusions

G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit.

Background

Malaria is a parasitic infection that is transmitted to people through the bites of infected mosquitoes. Of the four parasites that cause malaria, Plasmodium falciparum is the most deadly and P. vivax is the commonest and most widely distributed. Malaria parasites have a complex life cycle. Infected mosquitoes inject “sporozoites” into people, a form of the parasite that replicates inside human liver cells. After a few days, the liver cells release “merozoites,” which invade red blood cells where they replicate rapidly before bursting out and infecting other red blood cells. This increase in the parasitic burden causes malaria’s characteristic fever and can cause organ damage and death. Infected red blood cells also release “gametocytes,” which infect mosquitoes when they take a blood meal. In the mosquito, gametocytes multiply and develop into sporozoites, thus completing the parasite’s life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Treatment with effective antimalarial drugs also decreases malaria transmission.

Why Was This Study Done?

The Global Malaria Action Plan aims to reduce malaria deaths to zero by 2015 and to eradicate malaria in the long-term through its progressive elimination in malaria-endemic countries (countries where malaria is always present). Primaquine is a key drug for malaria elimination. It is the only treatment effective against the gametocytes that transmit malaria between people and mosquitoes and against P. vivax “hypnozoites,” which hibernate in the liver and cause malaria relapses. Unfortunately, primaquine induces mild to severe destruction of red blood cells (hemolysis) in people who have a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency (G6PDd) is common in some ethnic groups but the global distribution of individuals at risk of primaquine-induced hemolysis is unknown and there is no practical field test for G6PDd. Consequently, it is hard to design and implement primaquine treatment practices that balance the benefits of malaria transmission reduction and relapse prevention against the risk of hemolysis. Here, the researchers use a geostatistical model to map the prevalence (frequency in a population) of G6PDd in malaria-endemic countries and to estimate how many people are affected in these countries. They also develop a national index of relative hemolytic risk.

What Did the Researchers Do and Find?

The researchers fed data from community surveys of the prevalence of phenotypic G6PDd (reduced enzyme activity) for 1,734 sites (including 1,289 sites in malaria-endemic countries) into a geostatistical model originally developed to map global malaria endemicity. The model predicted that G6PDd is widespread across malaria-endemic regions, with the lowest prevalences in the Americas and the highest in tropical Africa and the Arabian Peninsula, but that most G6PDd individuals live in Asian countries. The predicted prevalence of G6PDd varied considerably over relatively short distances in many areas but, averaged across malaria-endemic countries it was 8%, which corresponds to about 350 million affected individuals; averaged across countries that are currently planning for malaria elimination, the prevalence was 5.3% (nearly 100 million affected individuals). Finally, the researchers used data on the geographical occurrence of G6PD variants classified according to their enzyme activity levels as mild or severe to derive an index of hemolytic risk from G6PDd for each malaria-endemic country. The greatest risk was in the Arabian Peninsula and west Asia where the predicted prevalence of G6PDd and the occurrence of severe G6PD variants were both high.

What Do These Findings Mean?

These findings suggest that G6PDd is widespread and spatially heterogeneous across most of the malaria-endemic countries where primaquine would be valuable for malaria control and elimination. The accuracy of these findings is limited, however, by the assumptions made in the geostatistical model, by the accuracy of the data fed into the model, and by the lack of data for some malaria-endemic countries. Moreover, there is considerable uncertainty associated with the proposed index of hemolysis risk because it is based on phenotypic G6PDd enzyme activity classifications, which is presumed, but not widely demonstrated, to be a surrogate marker for hemolysis. Nevertheless, these findings pave the way for further data collection and for the refinement of G6PDd maps that, in the absence of non-toxic alternatives to primaquine, will guide the design of safe primaquine regimens for the elimination of malaria.

Citation: Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, et al. (2012) G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map. PLoS Med 9(11): e1001339. doi:10.1371/journal.pmed.1001339

Academic Editor: Lorenz von Seidlein, Menzies School of Health Research, Australia

Received: February 22, 2012; Accepted: October 4, 2012; Published: November 13, 2012

Funding: This work was supported by a Wellcome Trust Biomedical Resources Grant (#085406), which funded REH, FBP, OAN, and MMH; SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#095066) that also supports PWG and KEB; APP was funded by a Biomedical Resources Grant from the Wellcome Trust (#091835). MD is funded by the Oxford University-Li Ka Shing Foundation Global Health Programme. This work forms part of the output of the Malaria Atlas Project (MAP), principally funded by the Wellcome Trust, UK. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: G6PDd, glucose-6-phosphate dehydrogenase deficiency; GRUMP, Global Rural-Urban Mapping Project; IQR, interquartile range; MEC, malaria endemic country; PPD, posterior predictive distribution; UN, United Nations; WHO, World Health Organization

Full Article: G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map (PDF)

Copyyight © 2012 Rosalind E. Howes, Frédéric B. Piel, Anand P. Patil, Oscar A. Nyangiri, Peter W. Gething, Mewahyu Dewi, Mariana M. Hogg, Katherine E. Battle, Carmencita D. Padilla, J. Kevin Baird, Simon I. Hay

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.

Malaria or Kidney Infection?

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QUESTION

Two months ago my daughter was in Uganda working and when came back to the States she was hospitalized for 4 days with Malaria symptoms. Her tests came back negative they really didn’t act like they knew how to treat this. They kept telling her they didn’t know how to diagnosis Malaria. So they treated her for it. She now after 2 months is once again hospitalized with the same symptoms. They are telling her they think it is a kidney infection. Can malaria be misdiagnosed as a kidney infection. She once again has all the symptoms as malaria?

ANSWER

What tests did the doctors do to try to diagnose malaria in your daughter when she first got back to the States? Usually, malaria is diagnosed by a blood test, whereby a trained technician will look at the patient’s blood under a microscope. The technician looks for signs of the malaria parasite in the patient’s blood, and if seen, can determine the intensity of the infection as well as the species of malaria. This is important information for accurate treatment. Alternatively, rapid diagnostic tests, which utilize a droplet of blood in a device which looks similar to a pregnancy test, and can very quickly determine whether someone is infected with malaria. It is important to know that malaria cannot be diagnosed by looking at standard blood parameters. If you don’t think your doctors know what is afflicting your daughter, you should take her to a clinic which specializes in tropical or travel medicine. There, they will certainly know how to effectively diagnose your daughter.

Given that your daughter experienced a resurgence of symptoms two months after returning, if she did have malaria, then there are two kinds which she might have: Plasmodium ovale and Plasmodium vivax. The other types of malaria, including the most deadly kind, P. falciparum, are not able to come back and relapse once they are treated. However, in order to prevent future relapses, your daughter may also have to be treated with another form of medication called primaquine. I will emphasize again, however, that it is crucial to gain an accurate diagnosis before taking any form of treatment for malaria.

Recurrence of Malaria

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QUESTION

If a person treated for malaria after being infected from a malaria endemic country of West Africa and cured then he travel back to his country which does not known for malaria endemic region of the world. Question is: Is there any chance of re-occurrence even he is not being exposed to malaria spreading mosquito for some time may be year?
Is it true Malaria parasites stays in liver as hibernation for a long period and attack after many months or year?
If so what treatment can prevent it?

Please advise.

ANSWER

There are several different types of malaria which are found in West Africa, and the most common and deadly form, Plasmodium falciparum, is not able to hibernate in the liver. However, two other types of malaria are able to lay dormant in the liver – these two kinds are called Plasmodium vivax and P. ovale. Both are not nearly as common as P. falciparum in West Africa, though P. ovale has been reported at prevalences of over 10% in some areas, which is double its usual prevalence elsewhere in the world. Weeks, months or even years after an initial infection with P. vivax or P. ovale, the patient may experience what is known as a relapse, which is when the dormant liver forms become active again and re-invade the blood stream, causing a renewal of malaria symptoms. These relapses can be treated with normal anti-malarial drugs (even chloroquine, in many cases), but a different drug is required to kill the dormant liver forms and prevent future relapse. This drug is called primaquine, and may not be suitable for people with certain types of G6DP deficiencies, so you should talk to your doctor about having a test for this condition before taking primaquine.

Positive RDT After Malaria Treatment

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QUESTION

I have Pv malaria repeated 2 times in two month then doctor give arthemether, lumefantrine tablet for three days twice in a day and primaquine tablet for 14 days..after this treatment malaria show positive on rapid test by a faint line….what is this?

ANSWER

It sounds like your doctor has treated you appropriately. What the line on the rapid test means depends a bit on the type of test it was. Some of these rapid tests look for parts of the malaria parasite which the body recognizes as causing disease (called antigens)—sometimes, these antigens can persist a bit in the body even after the malaria infection has been cured. Therefore, that could explain a slight positive result in a  rapid test soon after treatment. It will be important to follow this up with a second rapid test, maybe in a week, just to make sure you do not have an active infection. You should also be aware that Plasmodium vivax can remain dormant in the liver (primaquine is used to kill these dormant forms), and if primaquine treatment does not work, you will still be ay risk of relapse but you will not have any malaria parasites in the blood, and thus even a rapid test will be negative.

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.

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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How is Malaria Treated

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QUESTION

how is malaria treated?

ANSWER

Malaria can be a severe, potentially fatal disease (especially when caused by Plasmodium falciparum) and treatment should be initiated as soon as possible.

Patients who have severe P. falciparum malaria or who cannot take oral medications should be given the treatment by continuous intravenous infusion.

Most drugs used in treatment are active against the parasite forms in the blood (the form that causes disease) and include:

  • chloroquine
  • atovaquone-proguanil (Malarone®)
  • artemether-lumefantrine (Coartem®)
  • mefloquine (Lariam®)
  • quinine
  • quinidine
  • doxycycline (used in combination with quinine)
  • clindamycin (used in combination with quinine)
  • artesunate (not licensed for use in the United States, but available through the CDC malaria hotline)

In addition, primaquine is active against the dormant parasite liver forms (hypnozoites) and prevents relapses. Primaquine should not be taken by pregnant women or by people who are deficient in G6PD (glucose-6-phosphate dehydrogenase). Patients should not take primaquine until a screening test has excluded G6PD deficiency.

How to treat a patient with malaria depends on:

  • The type (species) of the infecting parasite
  • The area where the infection was acquired and its drug-resistance status
  • The clinical status of the patient
  • Any accompanying illness or condition
  • Pregnancy
  • Drug allergies, or other medications taken by the patient

If you have or suspect you have malaria, you should contact your doctor immediately.

Dormant Malaria

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QUESTION

I was bitten by mosquitoes many years ago and I was wondering can the symptoms lie dormant for as long as 40 years? The reason I am asking is that every summer I am ill with several of these symptoms. I do not have a good immune system.

ANSWER

There are a couple of types of malaria, namely Plasmodium vivax and Plasmodium ovale, which can lie dormant for many years, and often cause relapses at regular intervals.

Next time you suffer from these symptoms, you should go to your doctor and have a blood test to check for malaria; while you are experiencing symptoms, if you have malaria, the parasites will be visible in your blood.

Once positively diagnosed, your doctor can provide you with treatment. If you do have malaria, you will need one medication to clear the infection from your blood (which kind depends on where you were when you got those mosquito bites; malaria has become resistant to certain types of medication in some areas), plus another type of medication to kill the dormant forms which are responsible for the yearly relapses. This latter medication is called primaquine, and is not recommended for people with G6DP deficiency, so you should be tested for this prior to taking the medication.

Having said all of that, it is very important to get the blood test if you suspect you have malaria, because the symptoms of malaria are very general (fever, chills, nausea, aches) and can be mistaken for many other illnesses. If your blood test is negative for malaria, then you should talk to your doctor about other possible infections.

Malaria Fever

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QUESTION

My Father aged 65 years was diagnosed with 2 types of malaria almost a week back. he has been given medicines but temperature is fluctuating and not coming down. all other organs are functionining properly except platelet count which is little less.

Now he has been suggested new medicines for a duration of 14 days.
How fast can he recover from this malaria and when will the fever come down?

ANSWER

When patients are given the appropriate treatment against malaria, the fever is usually reduced very quickly and the patient will start to recover after a few days. The right kind of treatment depends on the severity of the infection and the type (or, in your father’s case, types) of malaria the patient is infected with.

If your father was infected with P. falciparum alongside another type of malaria (probably P. vivax, P. malariae or P. ovale), then he should have first received an artemisinin-based combination therapy (ACT) drug first. These drugs combine artemisinin or a derivative (such as artemether, artesunate or dihydroartemisinin) with another anti-malarial, such as lumefantrine. Common brand names of these ACTs include Coartem, Alu and Duo-Cotecxin.

There are no reported cases of resistance to these combination therapies at present, so if your father continued to feel sick after completing this treatment, he should be re-tested for malaria; it is possible that the malaria parasites were killed, and his continuing fever was an after effect either of the medication or just an indication that the body was recovering from the infection.

If he was re-tested and found positive, then other second-line drugs can be prescribed. However, it is important to note that malaria is resistant to chloroquine in many areas, and so this drug is not suitable for treatment in these places. Similarly, resistance is widespread to sulfadoxine-pyrimethamines, such as Fansidar, and in south-east Asia, P. falciparum is also resistant to mefloquine (Lariam) in some cases. As such, your father’s doctor should be careful to prescribe him an appropriate treatment for the area in which he is living.

In addition, if your father was found to be co-infected with either P. vivax or P. ovale, then there is a chance of later relapse into malaria again, weeks or even months after the initial infection has been treated. This is because the parasites in these types of malaria can form dormant stages in the liver, where they escape being killed by the normal forms of treatment. In this case, your father should ask about the possibility of being treated with primaquine; the course is normally 14 days, so it may be that this is what his doctors have currently given him. If so, this will kill the dormant liver stages and prevent relapse. Prior to taking primaquine, patients should be tested for G6DP deficiency, as patients with this condition may become dangerously anaemic when they take primaquine.

Am I more susceptible to malaria?

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QUESTION

I contracted common malaria, vivax?, when i was 20 yrs old from long visit to Papua NewGuinea, 1970. Returned to USA and was treated with chloro, primaquine drugs and really no problems since treatment.

Now going to Thailand for week, Chiang Mai and region. If bitten by local malarial mosq. am i more likely to recur? And should I certainly choose prophylaxis? thnx

ANSWER

If you were treated successfully with chloroquine and primaquine then there is no reason for your malaria to reoccur. Since it has been a long time since you had malaria, you probably also don’t have any antibodies against the parasite in your system anymore; this just means you don’t have any extra immunity against P. vivax (which you might have done if you had returned to a malaria area, and particularly one with the same strain of P. vivax as that which infected you, within a few months or years of being infected the first time), but it doesn’t mean you will be any more susceptible than someone who never had malaria.

In terms of where you are going, the city of Chiang Mai itself is not considered to have malaria transmission, but the areas surrounding it are, particularly as you get closer to the Burmese border. As such, if you will be travelling in rural and/or forested areas, you might want to consider taking prophylactic medication (and other preventative measures, like sleeping under a long-lasting insecticide treated bednet).

Thailand unfortunately has seen the emergence of resistance to a couple widely used prophylactic measures, namely chloroquine and mefloquine (sold as Lariam), so these are not appropriate preventative medicine in this region. Instead, you should consider taking doxycycline or atovaquone-proguanil (sold as Malarone).