Controversies and Misconceptions in Malaria Chemoprophylaxis for Travelers
- Lin H. Chen, MD;
- Mary E. Wilson, MD;
- Patricia Schlagenhauf, PhD
- Author Affiliations: Mount Auburn Hospital, Cambridge (Drs Chen and Wilson) and Harvard Medical School (Drs Chen and Wilson) and Harvard School of Public Health (Dr Wilson), Boston, Mass, and University of Zürich, University of Zürich Center for Travel Medicine, Zürich, Switzerland (Dr Schlagenhauf).
- Corresponding Author: Lin H. Chen, MD, Travel Medicine Center, Division of Infectious Diseases, Mount Auburn Hospital, 330 Mount Auburn St, Cambridge, MA 02238 (lchen{at}hms.harvard.edu).
Abstract
Context Controversies in malaria prevention arise from the absence of data, conflicting data between different studies, conflicting recommendations, deviation of local practice from scientific data, and varying risk thresholds. Misconceptions about the seriousness of malaria, the tolerability of chemoprophylaxis drugs, and the efficacy and safety of repellents contribute to the controversies.
Objectives To compare several national guidelines on malaria chemoprophylaxis to identify variations in recommendations. We reviewed studies on tolerability of mefloquine with particular focus on its neuropsychiatric adverse effects and influence on performance. We also describe why most recommended chemoprophylactic regimens fail to prevent relapses of Plasmodium vivax malaria and review available options.
Evidence Acquisition We searched scientific publications in MEDLINE via PubMED for relevant articles with a cutoff date of December 2006 using the search terms malaria, chemoprophylaxis, travel, mefloquine, neuropsychiatric adverse events, tolerability, vivax malaria, and primaquine. Additional references were obtained from bibliographies of the selected articles. There were no language restrictions.
Evidence Synthesis Gaps and conflicts exist among current guidelines. Health authorities vary in the chemoprophylaxis drugs they recommend, the indications for continuous prophylaxis vs no prophylaxis, and the use of standby emergency treatment. Despite widespread reports on the adverse effects of mefloquine, controlled studies found that serious neuropsychiatric adverse events occur at rates comparable with or lower than other chemoprophylaxis drugs. Moreover, mefloquine does not appear to impair performance while driving, flying, or diving. Vivax malaria causes significant illness in travelers, but current first-line chemoprophylaxis agents do not prevent relapses of vivax malaria. Although not licensed in most countries as primary prophylaxis, primaquine effectively prevents relapses of vivax malaria.
Conclusions Prevention of malaria in travelers requires detailed knowledge of malaria epidemiology and host-vector-parasite interactions. Decisions are complicated by a lack of standardized recommendations, controversies, and misconceptions. Improved international consensus is indicated to minimize conflicting guidelines, clarify controversies, and promote adherence to preventive measures.
- KEYWORDS:
- ANTIMALARIALS
- CHEMOPREVENTION
- MALARIA
- MALARIA, VIVAX
- MEFLOQUINE
- PLASMODIUM VIVAX
- PRIMAQUINE
- PUBLIC HEALTH
- TRAVEL
- WORLD HEALTH
Controversies in malaria prevention may arise due to paucity of data or differences between national guidelines and from travelers' misconceptions perpetuated by rumors, media coverage, and inaccurate advice. Additional sources of controversy include incomplete or inaccessible information, conflicting data, lag between availability of new data and implementation of change, conflict between scientific data and local practice, the desire for standard approaches, and variations in risk thresholds of individuals and policy-making groups.
These controversies present challenges to clinicians who advise travelers. Travelers may acquire inaccurate beliefs regarding ways to prevent malaria; they may disregard recommendations based on national guidelines, and seek unapproved substitutes for repellents or chemoprophylactic drugs or unconventional ways of taking the medications; or they may discontinue chemoprophylaxis due to fears of adverse events. Discussing controversies with travelers may dispel their misconceptions, enhance their understanding of recommendations, and possibly improve their adherence to recommended preventive strategies.
We examine the following global controversies in malaria prophylaxis: (1) lack of consensus in international recommendations; (2) the neuropsychiatric adverse event profile of mefloquine and the tolerability of this drug in persons involved in activities such as flying, diving, and driving; and (3) failure of currently recommended first-line chemoprophylactic regimens to prevent vivax malaria relapses; potential alternate approaches. First-line chemoprophylaxis refers to the preferred medications that are recommended to prevent or suppress malaria, currently including atovaquone-proguanil, chloroquine, doxycycline, and mefloquine. Relapse refers to peripheral parasitemia and malarial symptoms due to activation of the latent liver forms (hypnozoites) of the parasite.
METHODS
We searched the literature in MEDLINE via PubMED with a cutoff date of December 2006 using the search terms malaria, chemoprophylaxis, travel, mefloquine, neuropsychiatric adverse events, tolerability, vivax malaria, primaquine, and obtained additional references from bibliographies of the selected articles. We also reviewed the following journals for relevant reports on malaria in travelers over the past decade: JAMA, New England Journal of Medicine, Lancet, Lancet Infectious Diseases, Clinical Infectious Diseases, American Journal of Tropical Medicine and Hygiene, Journal of Travel Medicine, Transactions of the Royal Society of Tropical Medicine, Morbidity and Mortality Weekly Report, Emerging Infectious Diseases, Bulletin of the World Health Organization, Journal of Infectious Diseases, Annals of Internal Medicine, BMJ, Tropical Medicine and International Health, and Southeast Asian Journal of Tropical Medicine and Public Health. We emphasized the more recent publications, in particular systematic reviews, randomized controlled trials, and travelers' database analyses.
GUIDELINES ISSUES
Recommendations for malaria chemoprophylaxis involve complex decision making and must consider the destination, the host, the activities, and the duration of exposure. Many national health authorities issue recommendations on malaria chemoprophylaxis for commonly encountered situations; however, these broad guidelines miss some itineraries and types of travelers. In addition, conflicting recommendations by authorities in different countries can lead to confusion for travelers and clinicians.
Common controversies include continuous prophylaxis vs no prophylaxis and choice of agent for prophylaxis and for specific risk groups. Most health authorities (with the exception of the Advisory Committee on Malaria Prevention for UK Travelers and Canadian Advisors on Tropical Medicine and Travel, Public Health Agency of Canada) do not address malaria prevention for long-term travelers in detail.1-2 We reviewed this subject recently3 and will not discuss it herein. Most guidelines provide general areas of risk; however, malaria transmission data by specific destination would aid in assessing the potential benefit from chemoprophylaxis. Additionally, health authorities seldom address travelers with frequent, brief visits to malaria-endemic areas. Yet occupational travelers may have a higher incidence of malaria than tourists4 and should receive more focused attention. Most recommendations do not explicitly describe how risk-benefit-cost analyses influence the considerations for chemoprophylaxis.
Differences exist among the chemoprophylaxis regimens that are licensed, recommended, and distributed in each country. Table 1 lists the key medications recommended for malaria chemoprophylaxis in the United States,5-6 Canada,2 United Kingdom,7 France,8 Germany,9 Switzerland,10 Japan,11 and Australia,12 and illustrates differences among the guidelines. Even when the same medications are licensed and available, health authorities may differ in their assessment of risks, leading to different recommendations for the identical traveler and itinerary. Moreover, guidelines are only published periodically. Because risk assessments may change over time, published guidelines may be out of date. This means that clinicians must have reliable access to current data or refer patients to expert consultants.
Table 1. Medications Licensed and Recommended for Malaria Chemoprophylaxis by Various Countries*
Notably, mefloquine is the only approved malaria chemoprophylactic agent in Japan and is not approved for pediatric use, which raises logistical concerns for Japanese children traveling to malarious areas. Thus, the recommended preventive strategy after assessment of competing risks may differ significantly from countries where multiple agents are available. This is reflected in the Japanese guidelines that recommend chemoprophylaxis only for travel to high-risk areas—Papua New Guinea, sub-Saharan Africa, Solomon Island, the Amazon region—and for travel to areas with unreliable or poor medical care. Similarly, the drug proguanil, which is recommended by European authorities (usually in combination with chloroquine) for a number of destinations, is not available in the United States.
Two additional areas highlight the differences among the guidelines: (1) chemoprophylaxis for travelers to Plasmodium vivax–predominant areas or areas with low risk and (2) standby emergency self-treatment (SBET).6
For high-risk regions such as Kenya, the World Health Organization13-14 and all national health authorities consistently recommend chemoprophylaxis.2, 5-12 Recommendations vary more for lower-risk areas, such as India and border areas of Thailand. For these locations, some authorities recommend continuous chemoprophylaxis while others recommend seasonal chemoprophylaxis or SBET.2, 5, 7-12
For travelers to P vivax–predominant areas, such as Mexico, recommendations differ further still and include no chemoprophylaxis, different medications, and different regimens (continuous chemoprophylaxis and SBET).2, 5, 7-12 Of note, the Centers for Disease Prevention and Control recently evaluated malaria in US travelers returning from Mexico and found the incidence to be extremely low and primarily due to P vivax. Therefore, the revised recommendations will reflect the limited malaria risk for most travelers to Mexico and chemoprophylaxis will only be indicated in rare situations (Paul Arquin, MD, Malaria Branch of the CDC, written communication, November 2006).15 Similarly, the recently released UK guidelines also describe risk areas in greater detail and target some popular tourist destinations regarding malaria risk and prevention regimen.7
Standby emergency self-treatment was introduced in 1988 when chloroquine-resistant malaria emerged without reliable alternative chemoprophylaxis, as an option for travelers who needed to self- treat (remote destinations, distant from medical care, or chloroquine-resistant parasite present).16 Controversies surrounding SBET include: when to consider it, which medications to use, and whether SBET can supplant chemoprophylaxis. The misuse of SBET and associated errors added to the debate (tendency of travelers to replace chemoprophylaxis with SBET, unconfirmed diagnosis after initiating SBET, delay or lack of medical evaluation, and mistakes with medication).3, 17-18 Standby emergency self-treatment clearly carries potential dangers of serious morbidity and rare mortality and requires careful selection of patients and detailed instructions. Table 2 compares the current recommendations for SBET by various health authorities and highlights the different indications for SBET as well as medications used.
Table 2. Highlights of Recommendations Regarding Standby Emergency Self-treatment*
MISCONCEPTIONS
Besides differences among guidelines for chemoprophylaxis, travelers may receive inaccurate advice from fellow travelers, local residents, health care clinicians in malarious regions, and tour operators. Some travelers misunderstand malaria to be a trivial illness, especially when they hear stories of repeated malaria attacks and treatment with over-the-counter drugs. Most are unaware of issues with malaria overdiagnosis and widespread counterfeit medications.19-23 Herbal medications and homeopathy have no proven efficacy at present and should not be recommended.24-25 Furthermore, misconceptions regarding personal protective measures add confusion. Some travelers question the safety of repellents in children although reports of toxicity from diethyltoluamide (DEET), the repellent in use since the 1950s, have been rare and associated with inappropriate application.26 The American Academy of Pediatrics and the Centers for Disease Prevention and Control approve and support the use of DEET (up to 30%-50%) in children older than 2 months.27-28 Picaridin, another repellent that has demonstrated protective efficacy comparable with DEET against Anopheles mosquitos,29-32 is currently available in the United States in low concentrations that are suboptimal for malaria protection.
Because of rumors and misinformation, travelers may discontinue drugs once they have reached a destination. The clinician should anticipate this potential scenario and warn travelers about widespread misinformation.
TOLERABILITY OF MEFLOQUINE
Mefloquine is one of the most widely used malaria chemoprophylactic drugs with more than 30 million global users. It has been available in Europe since 1985, in the United States since 1990. Mefloquine adverse event case reports are plentiful and most scientific reports on the tolerability of mefloquine highlight the drug's neuropsychiatric profile. The more recent studies on mefloquine's tolerability have sought to clarify the clinical spectrum of less severe but potentially incapacitating neurological and psychiatric events and to elucidate the risk factors for such events.
This section aims to review the literature focusing on (1) important chemoprophylactic studies that detail the neuropsychiatric adverse event profile of mefloquine and (2) clinical toxicity studies that evaluate the impact of mefloquine use on activities such as driving, flying, and diving.
MAIN AREAS OF CONTROVERSY
Experts disagree over the tolerability of mefloquine prophylaxis vs alternatives, such as doxycycline, atovaquone-proguanil and chloroquine-proguanil, mainly with regard to neuropsychiatric events. Neuropsychiatric disorders include 2 broad categories of symptoms: central and peripheral nervous system disorders (headache, dizziness, vertigo, seizures) and psychiatric disorders (major psychiatric disorders, affective disorders, anxiety, and sleep disturbances). Studies conducted in travelers during the selected period show disparate results due to differing designs, definitions, method, and study populations.33-57
Many studies included in Table 3 are observational or interview-based studies in which potential confounders can distort the association between the risk of developing neuropsychiatric adverse events and the use of the drug. The controlled, double-blind studies comparing mefloquine-associated adverse events with that of the comparator regimens provide more objective data.37, 39-40,45, 52 Some studies use objective, validated psychomotor tests and specialized mood questionnaires, such as the “Profile of Moods States” to quantify moods and feelings.37-39 Whereas, many prospective studies on mefloquine's adverse events may not identify relatively rare severe adverse events partly because of the small number of participants, the database analyses are essential in having a sample size large enough to analyze serious adverse events and in drawing significant conclusions.
Table 3. Chemoprophylactic Studies or Analyses Describing Some Aspect of the Neuropsychiatric Adverse Event Profile of Mefloquine*
Studies from the early 1990s did not identify any significant excess of neuropsychiatric adverse events in mefloquine users. Peace Corps volunteers using mefloquine prophylaxis up to 2½ years experienced strange dreams (25%), insomnia (9%), and dizziness (8.4%), similar to those using chloroquine (corresponding incidence 26%, 6.5%, and 10%); no severe neuropsychiatric reactions were causally associated with mefloquine.54 Results were similar in tourists returning from East Africa (n = 139 164); headache occurred in 6.2% mefloquine users vs 7.6% of chloroquine-proguanil users with no excess of dizziness, depression, and insomnia in mefloquine users.53
A meta-analysis found that rates of withdrawal and overall incidence of adverse events with mefloquine were not significantly higher than those observed with comparator regimens.41 However, mefloquine was more likely to cause insomnia and fatigue (odds ratio, 1.64; 95% confidence interval, 1.18-2.28 and 1.57; 95% confidence interval, 1.01-2.45), respectively).41
A double-blind study of chemoprophylactic regimens showed a significant excess of moderate neuropsychological events with mefloquine compared with doxycycline and atovaquone-proguanil but not when compared with chloroquine-proguanil.37 Regression analysis between medications and sex showed that significantly more women taking mefloquine reported mild to moderate neuropsychological events (including headache and sleep disturbances) than those taking other drugs.37
More recent studies33, 36 have used electronic databases to define mefloquine exposure and outcome. The analysis of the UK–based General Practice Research Database compared the risk for psychiatric disorders during or after the use of mefloquine with the risk of other antimalarial agents; this large study concluded that mefloquine did not increase the first-time diagnosis of depression but may increase the risk of psychosis and anxiety reactions.36
Serious Adverse Events
Serious adverse events constitute apparent threats to life that require or prolonged hospitalization or that result in severe disability. The estimated incidence for mefloquine ranges from 1/607 to 1/20 00048, 53, 56, 58 compared with a rate for chloroquine of 1/1181 to 1/13,600.48, 53 In one retrospective cohort analysis, serious neuropsychiatric adverse events involving hospitalization were noted for 1/607 mefloquine users vs 1/1181 chloroquine-proguanil users.48 This survey of British travelers showed equal rates of any adverse effects (41%) or of stopping or changing medication in mefloquine users and chloroquine-proguanil users; however, neuropsychiatric adverse events were significantly more common in travelers taking mefloquine.48 Furthermore, 0.7% of mefloquine users had disabling adverse effects compared with 0.09% of those using chloroquine-proguanil (P<.001).48 A large cohort study by Steffen et al53 observed serious neuropsychiatric adverse events at a rate of 1/10 600; a total of 5 probably associated hospitalizations were reported: 2 cases of seizures, 2 psychotic episodes, and 1 case of vertigo.53 The rate of such events for chloroquine was 1/13 600 with 3 associated hospitalizations for neuropsychiatric events (1 seizure and 2 psychotic episodes).
The British army's experience with mefloquine prophylaxis found the incidence of severe neuropsychiatric reactions to be 1 or less per 6000.49 A controlled monitoring of adverse events in Canadian travelers found 1 clinically significant neuropsychiatric AE, a moderate to severe anxiety attack, in 1 of the 251 mefloquine users.59 The most recent and comprehensive evaluation of serious events was a US analysis of hospitalizations that found no association between mefloquine prescriptions and any disorder including mental disorders and diseases of the nervous system, including serious adverse events (as measured by hospitalizations).33
Risk Factors Associated With the Incidence of Neuropsychiatric Adverse Events
The mechanism underlying neuropsychiatric adverse events associated with quinoline-antimalarial (chloroquine, mefloquine, quinine) associated with neuropsychiatric adverse events is unknown. Other antimalarial drugs (dihydrofolate reductase inhibitors, sulfonamides, tetracyclines, halofantrine, and atovaquone) do not have this profile of adverse events. Persons with a history of seizures or manic-depressive illness appear to be a major risk group for severe psychiatric reactions and convulsions,55 and all guidelines now recommend that mefloquine be contraindicated for persons with a personal or family history of such disorders and also for individuals with depression. Women are significantly more likely to experience mefloquine-associated adverse events.37, 42, 47-48,51, 55 Studies differed on whether there is an association between low body weight and developing an adverse event while taking a mefloquine prophylaxis.47, 60 Anecdotal reports on the use of a split dose (a half tablet twice weekly) for women with low body weight suggest favorable results. Poorer tolerability in women may also be due to reporting bias, greater compliance with prescription,61 or to sex-related pharmacokinetic factors. A role of mefloquine enantiomers and metabolites has not been confirmed.51 The concomitant use of mefloquine and recreational drugs47 has been suggested, and there may be an interaction between mefloquine and large, but not small, quantities of alcohol.62-63 Recently, it has been hypothesized that the neuropsychiatric adverse effects of mefloquine are associated with polymorphisms in the MDR1/ABCB1 gene that encodes for the efflux pump P-glycoprotein and this is an area that warrants further research.64
Latency of Mild Adverse Events
Many studies have shown that mild, neuropsychiatric adverse events tend to occur early in prophylaxis. Schlagenhauf et al51 found that most minor adverse events occurred early (after the first or second mefloquine dose), and this was also evident in the Australian study47 and other reports that detail latency (Table 3).
Use of Mefloquine While Flying, Driving, or Diving
Because many reports highlighted neuropsychological mefloquine events, concern has emerged that use of mefloquine may impair performance and precision while driving, operating machinery, or being in combat situations. A clinical toxicity study with alcohol challenge has shown that mefloquine, with or without small quantities of alcohol, does not impair driving.63 Although some diving schools prohibit the use of mefloquine, we found no scientific basis to support this ban. Table 4 summarizes findings from studies evaluating the impact of mefloquine intake on various activities.52, 63, 65-67 These controlled studies suggest that although mefloquine is associated with neuropsychiatric events in travelers, there is no performance deficit in persons who tolerate the drug.
Table 4. Performance During Use of Mefloquine*
Summary of Mefloquine Tolerability
The use of the literature to clarify the adverse event profile of mefloquine has limitations and is subject to potential bias. Few trials are designed to investigate the neuropsychiatric adverse event profile of mefloquine. Information on latency, duration and outcome of adverse events is limited. Studies of mefloquine tolerability involving more than 5000 participants have found a low incidence of serious adverse events.36, 41, 53, 56 Studies of minor adverse events have shown that mefloquine's adverse event profile is of the neuropsychiatric-neuropsychological type with an excess of events in women.
Careful prescribing with attention to contraindications is essential, as is clear warning about the potential adverse effects. Before prescribing mefloquine, it is prudent to discuss the pros and cons of alternative chemoprophylactic regimens that are not associated with a potential for severe neuropsychiatric reactions. Because many mefloquine-associated adverse events occur early in dosing, starting mefloquine prophylaxis 2 to 3 weeks before departure may allow for evaluation of tolerability to the regimen. Stopping the drug with early signs of such events should minimize the severity and duration of an adverse event.
DESTINATIONS WITH PREDOMINANT OR SIGNIFICANT P VIVAX
Chemoprophylaxis for Short-term Travelers to P vivax–Predominant Areas
The primary goal of malaria chemoprophylaxis is to prevent deaths from malaria, which are largely caused by Plasmodium falciparum.
Another important goal is to prevent clinical malaria, which can lead to hospitalization with health and economic consequences. The currently recommended first-line drugs for chemoprophylaxis are 80% to 90% effective in preventing clinical episodes of primary malaria infection.68-69
The antimalarial agents commonly used (eg, chloroquine, mefloquine, doxycycline, atovaquone-proguanil) that are active against the blood stage parasites, however, do not prevent relapsing infection caused by Plasmodium vivax and Plasmodium ovale. These Plasmodium species are biologically different and can cause latent infection with hypnozoites in the liver that are not killed by the antimalarials active against the blood stages. Not only can hypnozoites survive despite the presence of a blood stage antimalarial during and after travel, they may emerge to cause symptoms months later. The late appearance of vivax or ovale malaria in a returned traveler who has taken antimalarials as prescribed reflects the different biological characteristics of vivax and ovale malaria. Resistance of vivax malaria to chloroquine has been well documented,70-71 although some reports of resistance may reflect relapses of the surviving liver forms. Use of agents active against the blood stage does not prevent infection but delays the first clinically apparent attack of malaria. Although atovaquone-proguanil may have some activity against the liver stage of P vivax, it does not reliably prevent vivax malaria relapse.72-74
How big is this problem? Vivax malaria is the most geographically widespread of the malarial species and is estimated to cause 70 to 80 million acute episodes per year in endemic areas.75-76 P vivax causes more than 50% of malaria infections outside of Africa and about 10% of those in Africa.75 In parts of Africa, (eg, Ethiopia and other parts of eastern and southern Africa and Madagascar), P vivax may cause up to 20% of malaria cases.75 Among the vivax cases outside of Africa the majority (80%-90%) occur in Asia, the Middle East, and the Western Pacific, and only 10% to 15% in Latin America.75
In travelers, the percentage of infections caused by P vivax varies widely depending on the common destinations for travelers from that geographic area. In the United States, among reported, imported cases of malaria from 2001-2004 for which the species was identified, P vivax caused from 22.9% to 27.8% and P ovale caused from 2.0% to 3.6%.77-78 In European centers, P vivax caused from 9.3% (the Netherlands)79 and 10.4% (Paris)80 to 29.4% (Munich, Germany).81 P vivax accounted for 12.9% of 4801 cases of imported malaria reported to TropNetEurop (European Network on Imported Infectious Disease Surveillance) between January 1999 and September 2003.82 P vivax accounted for 44% to 51% of malaria in Canada (Toronto, Montreal),83-84 and 63% to 74% in Australia (Brisbane, Melbourne),85-87 reflecting the travel of Australians to vivax-dominant areas in Asia. These studies demonstrate that P vivax contributes significantly to the burden of malaria in travelers and that its relative importance varies by travel destination.
The most common countries or regions of origin for vivax malaria cases in the United States in recent years are: Asia (especially, India and Pakistan), Africa (especially, Ethiopia, Ghana, Kenya, and Nigeria), Central America (especially, Honduras, and Guatemala), Oceania (especially, Papua New Guinea), South America, and Mexico.77-78 Despite the large volume of travel from the United States to Latin America, the absolute risk of vivax malaria in those areas is extremely low. Among cases reported to TropNetEurop, 33% of vivax malaria (1999-2003) was acquired in sub-Saharan Africa.82
Although an episode of vivax malaria is less likely to be fatal than infection with P falciparum, vivax malaria can be severe, and rarely, fatal. Despite its name, benign tertian malaria, vivax malaria in its initial clinical presentation can be indistinguishable from falciparum malaria.86, 88 Levels of inflammatory cytokines and tumor necrosis factor are often higher in vivax than in falciparum malaria.89-91 A recent study from India reported 2 deaths among 11 patients with severe vivax malaria (in whom coinfection with P falciparum was excluded by polymerase chain reaction testing), and a woman in her third trimester delivered an infant who died.92 The complications of vivax malaria include acute respiratory distress syndrome, renal failure, jaundice, cerebral complications, bleeding, and splenic rupture.92-99 TropNetEurop found that 60% of 526 patients with confirmed or probable isolated P vivax infection were hospitalized (median 4 days), including 7 with severe disease, although all survived.82
Diagnosis may be problematic. Infections caused by P vivax manifest later than those caused by P falciparum, especially, in persons who have taken prophylactic agents. The time of relapse also depends on the geographic origin of the parasite; those with parasites of tropical origin have a higher probability of relapse and a shorter interval to relapse than those with parasites of temperate origin, eg, Korea.100-102 Relapses may be multiple (especially with tropical strains)74 and can occur more than a year after travel to a malarious area. The late appearance of vivax may delay diagnosis. In the United States, 12% to 15% of imported vivax malaria in 2003-2004 had onset more than 6 months after return.77-78 In Europe, half of patients with vivax became ill more than 60 days after return from an endemic area.82
Returned travelers and their health providers may not perceive the risk for vivax malaria when prophylaxis has been taken as prescribed. Among Israeli travelers with vivax malaria, 80% had taken suppressive prophylaxis.103 In addition, parasitemia in vivax is typically lower than in falciparum, so laboratory personnel reading the malaria slides may not find the parasites. In Belgium, 9 (25%) of 36 of untreated patients with vivax malaria had parasitemia levels of less than 500/μL, a level that may be difficult to detect in laboratories in which technicians have limited experience reading malaria smears.88 The rapid diagnostic tests, currently unavailable in the United States, also are less likely to be positive in vivax malaria.88
Primaquine for Short-Term Travel
Primaquine has 3 potential indications: primary prophylaxis—primary prophylaxis refers to medications that prevent or suppress malaria during and shortly after exposure (rather than medications used for treatment of malaria or eradicating latent parasites in the liver)—presumptive antirelapse therapy (also known as postexposure prophylaxis or terminal prophylaxis), and radical cure-to-treat-established infection with P vivax or P ovale.104 Only the first 2 will be discussed herein. Primaquine is active against all malarial species.74, 104-107 Primaquine has protective efficacy of more than 85% for falciparum malaria and primary infections with P vivax. In healthy nonimmune Colombian soldiers going to a malarious area, primaquine 30 mg daily provided protective efficacy of 94% against P falciparum and 85% against P vivax compared with placebo, although follow-up was only for 3 weeks in base camp.108 Primaquine can eliminate liver hypnozoites and is the only drug currently available with such activity. Although studies show that primaquine is effective as primary prophylaxis of malaria, it is not currently approved by the US Food and Drug Administration (FDA) for this indication mainly due to financial obstacles. The FDA granted license for primaquine in the 1950s for radical cure and the drug has long lost patent protection; the cost to obtain FDA approval for the indication of primary prophylaxis would rest on the investigational new drug holder, an expensive process that no one wishes to bear. When given as presumptive antirelapse therapy,109 it is administered to overlap with the blood-stage active agent; though data demonstrating the efficacy of presumptive antirelapse therapy are lacking.101 Studies done more than 50 years ago suggested that primaquine is more active against hypnozoites when given with chloroquine (or quinine).110
Individuals considered as possible candidates for primaquine must be screened first for glucose-6-phosphate dehydrogenase deficiency. Administration of primaquine to individuals with deficient glucose-6-phoshate dehydrogenase levels can have serious, even lethal, hemolysis. Primaquine should never be given as primary prophylaxis or as presumptive antirelapse therapy to individuals with glucose-6-phospate dehydrogenase deficiency. Although screening needs to be done only once, it involves the expense of testing and delays in decision making.
Some strains of P vivax are relatively resistant to primaquine,111-112 and high failure rates have been reported with the regimen used in the past (15-mg base daily or 26.3-mg primaquine phosphate for 14 days). High rates of failure have occurred in persons with the Chesson strain of P vivax from Papua New Guinea and in persons infected in Southeast Asia. A higher dose of 30-mg base (or 2 tablets of 26.3 mg primaquine phosphate) daily is now recommended.5, 104 The total dose may be more important than the schedule of its delivery.74 Weight-adjusted dosing of primaquine (0.5 mg/kg per day × 14 days) has been recommended to prevent additional relapses in patients with P vivax infection.
Primaquine primary prophylaxis could be considered after screening to establish normal levels of glucose-6-phosphate dehydrogenase for individuals with contraindications to or intolerance of recommended first-line antimalarial agents; multiple, short exposures to malaria endemic areas; or travel to vivax-dominant areas (Figure).113-114 Presumptive antirelapse therapy should be considered for individuals who have had prolonged stays in malarious areas where P vivax, P ovale, or both are present (even if P falciparum is the predominant parasite); specific high-risk itineraries (including participation in a trip in which others in the group have developed P vivax infection). Because primaquine is not currently approved for use as a primary prophylaxis, the clinician should document in the medical record the reasons for its use and note that it is being given off-label.
Figure. Global Distribution of Plasmodium vivax in 2005
Plasmodium vivax has the widest geographical distribution (shaded areas) of all of the plasmodia species. Plasmodia species present in Africa include Plasmodium falciparum (dominant), P vivax, Plasmodium ovale, and Plasmodium malariae; in the Americas, P vivax (dominant) and P falciparum; in the Indian subcontinent, P vivax (dominant) and P falciparum; and in Southeast Asia, P falciparum and P vivax are present with regional variation in dominant species. P malariae is present to a small extent in many P falciparum areas but the distribution is very patchy. P ovale is present in tropical Africa and occasionally in the West Pacific. Data are based on Guerra et al113 and Schlagenhauf-Lawlor et al.114
For travel to areas with low risk of exposure to P vivax, the primary emphasis should be on prompt diagnosis and treatment of relapse of vivax malaria (but also use of blood schizonticide, if significant risk of P falciparum exists). In areas with high risk of exposure to vivax malaria, use of primaquine, either as primary prophylaxis or as postexposure antirelapse therapy, is an option.
CONCLUSIONS
Sources of controversy in malaria prevention include the absence of data, conflicting data from different studies, and conflicting recommendations. Misconceptions about the seriousness of malaria, the tolerability of chemoprophylaxis drugs, and the efficacy and safety of repellents fuel the controversy. These controversies and misconceptions limit compliance with measures to prevent malaria. Improved access to information may reduce confusion (Box 1). Consensus guidelines could reduce the conflicts, and improve compliance with chemoprophylaxis.
Box 1. Most Reliable and Easily Accessible Resources for Clinicians for Malaria Epidemiology
World Health Organization International Travel and Health
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http://whqlibdoc.who.int/publications/2005/9241580364_chap7.pdf
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http://whqlibdoc.who.int/publications/2005/9241580364_country_list.pdf
World Health Organization Global Atlas
Centers for Disease Control and Prevention
Centers for Disease Control and Prevention Regional Malaria Information
Health Protection Agency Guidelines for Malaria Prevention in Travelers from the United Kingdom
International Association of Medical Assistance to Travelers
RETURN TO TEXT
Pretravel advice and the choice of antimalarial drug should be an evidence-based decision that considers the profile of the individual traveler and the risk of malaria. It is crucial to screen medical histories and inform mefloquine users of potential adverse events with advice on how to avoid such events and ways to respond should they occur. Open discussion may decrease the anxiety toward the chemoprophylaxis and improve adherence. Careful prescribing and observance of contraindications is essential.
Finally, an important reason for development of late P vivax is failure of the usual chemoprophylactic agents to clear liver-stage infection. Guidelines should consider the use of primaquine primary chemoprophylaxis for certain travelers. If travelers are given only blood stage active agents for travel to areas where vivax is common, they must be instructed that their pills do not prevent all forms of malaria and they must seek immediate treatment in the event of febrile illness (Box 2).
Box 2. Card for Travelers Who Expect to Be in Areas Endemic for Malaria
Malaria Information for Traveler
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You will be visiting countries with malaria and may be exposed to malaria, which can progress rapidly and kill.
Ways to Reduce Risk
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Stay in accommodations with screens in windows and doors.
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Go indoors from dusk to dawn.
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Use an effective insect repellant, such as one that contains diethyltoluamide (DEET).
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Treat your clothing with insecticide, such as permethrin.
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Sleep under an insecticide-treated bed net.
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Take medication that suppresses malaria as recommended by a travel medicine specialist.
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If you tolerate malaria medication well, continue taking it even if others tell you there is no need.
Symptoms of Malaria
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Symptoms may start as early as 7 to 8 days after exposure but may be delayed for weeks or months (rarely >1 year) after exposure.
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Symptoms include fever, which may be intermittent; body ache; weakness; headache; vomiting; abdominal pain; cough.
Seek Medical Attention
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If you have any of the symptoms, seek medical evaluation as soon as possible, even if fever is not constant.
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Inform the clinicians that evaluate your fever that you may have been exposed to malaria.
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Check blood tests, including malaria smears, every 12 to 24 hours until at least 3 sets of smear results are negative for malaria.
RETURN TO TEXT
Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chen, Wilson, Schlagenhauf.
Acquisition of data: Chen, Schlagenhauf.
Analysis and interpretation of data: Chen, Wilson, Schlagenhauf.
Drafting of the manuscript: Chen, Wilson, Schlagenhauf.
Critical revision of the manuscript for important intellectual content: Chen, Wilson, Schlagenhauf.
Administrative, technical, or material support: Chen, Schlagenhauf.
Study supervision: Schlagenhauf.
Financial Disclosures: Dr Chen reports that she has received honoraria for serving on the editorial board of Travel Medicine Advisor, AHC Media LLC. Dr Schlagenhauf reports that she has received research funding honoraria for speaking at conferences from F. Hoffmann La Roche and GlaxoSmithKline and consultancy fees from F. Hoffmann La Roche. Dr Wilson reports no conflicts of interest.
Funding/Support: We report no funding organization or sponsor in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Acknowledgment: We thank the following colleagues for their input regarding their health authority guidelines: David R. Hill, MD, DTM&H, National Travel Health Network and Centre, and London School of Hygiene and Tropical Medicine, London, England; Karin Leder, MD, MPH, DTMH, Monash University, Melbourne, Australia; Anne McCarthy, MD, MSc, FRCPC, DTMH, Ottawa Hospital, and University of Ottawa, Ottawa, Canada; Tetsuya Nakamura, MD, University of Tokyo, Tokyo, Japan; and Philippe Parola, MD, PhD, University Hospital of Marseille, Marseille, France. We also thank Wei-Fan Chen, MD, for translating the Japanese guidelines and Mr Hanspeter Jauss for assistance with the P vivax map. Drs Hill, Leder, McCarthy, Nakamura, Parola, and Chen received no compensation for their contributions.
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