Overview

Malaria is one of the most important infectious diseases; annually, it affects more than 250 million people and is a leading cause of illness and death in the developing world. This infection poses a particularly serious threat to North American travelers who lack immunity to it. American military troops are at an increased risk when entering countries with lax public health policy or with no facilities to examine and treat cases of malaria. This course will provide a basic understanding of malaria for healthcare professionals who care for traveling patients and military troops. Current treatment and prevention options will be explored in depth.

Education Category: Infection Control / Internal Medicine
Release Date: 10/01/2013
Expiration Date: 09/30/2016

Audience

This course is designed for healthcare professionals involved in the care of persons traveling to or from areas where malaria transmission is common.

Accreditations & Approvals

NetCE is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NetCE is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NetCE is accredited by the International Association for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

NetCE designates this enduring material for a maximum of 3 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 3 ANCC contact hour(s). NetCE designates this continuing education activity for 1 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 3.6 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 3 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE is authorized by IACET to offer 0.3 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through December 12, 2017); California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; Florida, Provider #50-2405; Iowa, Provider #295; Kentucky, Provider #7-0054 through 12/31/2017.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

Malaria poses a particularly serious threat to U.S. travelers who lack immunity to it, and delayed diagnosis is a leading cause of death among malaria patients in the United States. The purpose of this course is to provide healthcare professionals with the information necessary to accurately identify, treat, and educate patients regarding the risks of malaria in order to protect those who may be exposed to the disease.

Learning Objectives

Upon completion of this course, you should be able to:

  1. Describe the history and natural life cycle of malaria.
  2. Identify how and where the transmission of malaria occurs.
  3. Differentiate between uncomplicated and severe (complicated) malaria and identify the symptoms of each.
  4. Compare the methods used to diagnose malaria and review the importance of prompt diagnosis.
  5. Recommend the appropriate treatment for malaria of various origins.
  6. Identify the preventive measures against malaria that have been recommended, including presumptive self-treatment, and discuss considerations for non-English proficient patients.

Faculty

Richard A. Ade, RN, MPH, earned his Bachelor degree in occupational and environmental nursing from St. Joseph's College in 1980 and his Master's degree in Public Health from the City University of Los Angeles in 1993. He has more than 30 years experience in military nursing, focusing on radiology, military science, and public health issues.

Faculty Disclosure

Contributing faculty, Richard A. Ade, RN, MPH, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Table of Contents

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#94361: Malaria and the International Traveler

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INTRODUCTION

The symptoms of malaria were first described around 2700 B.C.E. in ancient Chinese medical writings [1]. Thousands of years later, malaria continues to be one of the most significant infectious diseases. Approximately 3.2 billion people live in areas of malaria transmission, and an estimated 200 to 300 million cases of malaria are reported each year. Malaria is a leading cause of illness and death in the developing world, killing an estimated 660,000 people each year [2]. Young children and pregnant women are the groups most affected [2,37]. Although the transmission of malaria was successfully interrupted in the United States during the late 1940s, it continues to pose a challenging health threat to individuals who travel to and emigrate from malarious areas [5,54].

LIFE CYCLE OF MALARIA

Malaria is a mosquito-borne disease caused by a parasite from the genus Plasmodium. Although there are more than 100 species of Plasmodium, only five are known to infect humans. These include P. falciparum, P. vivax, P. malariae, P. ovale, and the more recently discovered P. knowlesi (a simian malaria parasite), which has previously been misdiagnosed in humans as P. malariae [6,7,8,9]. P. falciparum and P. vivax cause the most infections worldwide. P. falciparum is the agent of severe, potentially fatal malaria due to its unique ability to invade and multiply inside erythrocytes. If treated promptly and effectively, however, it is almost always curable. P. vivax is the most geographically widespread of the species. Although it produces symptoms that are less severe, relapses of infection caused by P. vivax may occur up to 3 years after the initial infection. P. malariae produces long-lasting infections that have the ability to persist asymptomatically for years. Occurrences of infection from P. ovale are rare and generally limited to West Africa [3,10,11]. Little is known about the morphology of P. knowlesi parasites, but they do appear to have unique characteristics that can be identified through the use of light microscopy [12]. P. knowlesi appears to cause less severe clinical disease than P. falciparum; however, it may cause more severe and potentially fatal infections than P. vivax or P. malariae [6]. The severity of infection caused by P. knowlesi is the result of its rapid (i.e., 24-hour), targeted erythrocytic cycle. P. knowlesi is widespread throughout Malaysia, accounting for approximately 70% of human malaria infections in this area. Cases of infection with P. knowlesi have also been reported in Thailand, China, Singapore, and the Philippines [12].

These malaria-causing parasites are carried and transmitted by the female Anopheles mosquito. As the mosquito takes a human blood meal, it injects the parasites as sporozoites (the invasive form of the parasites) [13]. The sporozoites travel to the liver, where they invade liver cells, grow, divide, and produce successive generations of parasites called merozoites. The merozoites exit the liver cells and continue the cycle by invading other red blood cells, replicating asexually, and releasing newly formed merozoites into the host bloodstream. Some of these infected cells leave the cycle of asexual replication and develop into male or female gametocytes, which continue circulating in the host bloodstream. When the gametocytes are ingested by the mosquito during a blood meal, another cycle of growth and multiplication in the mosquito is begun (Figure 1) [3,10]. The success of this cycle depends on factors such as temperature, humidity, mosquito longevity, and individual host factors [3,14].

THE LIFE CYCLE OF MALARIA

TRANSMISSION

As discussed, malaria is transmitted to humans by the female Anopheles mosquito. Only 30 to 40 of the known Anopheles species are vectors and spread malaria. The A. gambiae, which exists exclusively in Africa, is one of the most efficient vectors and also one of the most difficult to control [3]. Malaria transmission may also occur through exposure to contaminated blood products or from mother to fetus; however, these instances are rare [10,15].

Malaria is transmitted in areas that allow the Anopheles mosquito to survive and multiply. This occurs mainly in tropical and subtropical areas where the temperature, humidity, and rainfall create an environment that allows malaria parasites to complete their growth cycle in the mosquitoes. Temperature is particularly critical to completion of the life cycle. For example, even within the areas where transmission is most common (i.e., tropical and subtropical regions), it does not occur at high altitudes, during cooler seasons in some areas, and in most desert areas. Transmission is most common in sub-Saharan Africa, with the highest case rates occurring among travelers returning from West Africa [15]. Although malaria has been eliminated in western Europe and the United States, the presence of the Anopheles mosquito in these regions poses a constant risk of reintroduction of the disease, especially in regions with temperate climates [2,53].

The Centers for Disease Control and Prevention (CDC) began malaria surveillance in 1957. Since then, 63 outbreaks of locally acquired malaria have occurred. The last outbreak, which consisted of eight cases, occurred in the United States in 2003 and was linked to a strain of the P. vivax parasite. Testing by the CDC indicated that the parasite originated in the Americas [17].

SYMPTOMS AND DIAGNOSIS

Following the infective mosquito bite, an incubation period of between 7 and 30 days usually passes before the first symptoms of disease appear. Shorter incubation periods are associated with P. falciparum; longer periods are characteristic of P. malariae. A string of recurrent attacks is typical and generally includes chills, fever, and sweating. In addition to these symptoms, headache, general malaise, fatigue, muscular pains, nausea, vomiting, and diarrhea are also common [3,10,18].

Although infrequently observed, a classical attack of "uncomplicated" malaria lasts from 6 to 10 hours and recurs either every second or third day, depending on the infectious Plasmodium species. Additional physical findings may include weakness, an enlarged spleen or liver, mild jaundice, and an increased respiratory rate. Laboratory results may indicate mild anemia, thrombocytopenia, elevated bilirubin, aminotransferases, and albuminuria and the presence of urinary casts [3,18].

Malaria infections with P. falciparum are categorized as severe when complicated by serious organ failure or abnormalities in the patient's blood or metabolism. Severe malaria occurs most frequently in persons either with no immunity or decreased immunity to the disease. The presence of one or more of the following clinical criteria indicates severe malaria [4]:

  • Seizures or other neurologic abnormalities

  • Impaired consciousness or coma

  • Abnormal behavior

  • Severe normocytic anemia

  • Pulmonary edema

  • Acute respiratory distress syndrome

  • Circulatory shock

  • Disseminated intravascular coagulation

  • Spontaneous bleeding

  • Acidosis

  • Hypoglycemia

  • Hemoglobinuria

  • Jaundice

  • Acute kidney failure

  • Repeated generalized convulsions

  • Parasitemia greater than 5%

Severe illness is a medical emergency requiring urgent, aggressive treatment [3].

Prompt diagnosis of malaria is important to ensure timely treatment and prevent the spread of infection. Malaria may be suspected based on the patient's symptoms, travel history, and physical findings at examination. Patients with suspected infection should be urgently and thoroughly evaluated. Delayed diagnosis is a leading cause of death among malaria patients in the United States [3]. It is important, however, that treatment not begin until the diagnosis has been confirmed with specific diagnostic tests (e.g., microscopy or rapid diagnostic tests) that help identify the type of infectious parasite and determine the severity of the infection. Identification of these factors will help the clinician determine the appropriate course of treatment [18,19].

The gold standard of microscopic diagnosis involves examination of thick and thin blood smears. (Thick smears are more sensitive but more difficult to read.) The smears are stained, usually with the Giemsa stain, which gives the parasites a distinctive appearance. A negative blood smear usually indicates no presence of infection. However, because nonimmune individuals may be symptomatic at very low parasite densities that are initially undetectable, the CDC has recommended that smears be repeated every 12 to 24 hours for 48 to 72 hours [4,19,20].

Alternative methods for laboratory diagnosis include immunologic tests to detect antigens derived from malaria parasites [18,21]. These rapid diagnostic tests (RDTs) provide results within minutes and may be used where reliable microscopic diagnosis is not available. In 2007, the U.S. Food and Drug Administration (FDA) approved the first RDT for use in the United States. The CDC has recommended that all RDT results be confirmed with microscopy [19,22]. Although RDTs are becoming increasingly more common, they have not been widely adopted because of cost, accuracy, and performance issues [2,22]. Polymerase chain reaction (PCR) may be used to detect parasite nucleic acids. Although it is a more sensitive and accurate diagnostic tool than microscopy, PCR is not a useful tool for diagnosing the acutely ill patient, primarily because of the time required to obtain results [4,19].

Diagnosis of malaria may be difficult, and misdiagnosis is a common problem, particularly in areas where malaria is not endemic, like the United States. In areas where malaria is endemic, diagnosis may be difficult because intense transmission allows some individuals to develop immunity that protects them against illness but not infection. Healthcare providers should obtain a travel history from every febrile patient and should routinely suspect malaria in a patient who has recently traveled to an area with known malaria transmission [4,5,15,19].

Malaria is a reportable disease in the United States and is included in the National Notifiable Diseases Surveillance System [23]. The CDC has recommended that healthcare providers report all cases of laboratory-confirmed malaria to their local or state health departments. These reports are then transmitted to the CDC for surveillance, prevention, and reporting purposes. Information about how to report a case of malaria, as well as reporting forms, are available from the CDC [24].

TREATMENT

As previously stated, treatment of malaria should not be initiated until the diagnosis has been confirmed by laboratory analysis. After the diagnosis has been confirmed, treatment should begin immediately and be guided by the infecting Plasmodium species, the drug susceptibility of the infecting parasites, the geographical location (if known) of infection, and the patient's clinical status [4,10].

Determination of the infecting species is important because P. falciparum infections may progress rapidly and lead to severe illness or death. They therefore require urgent initiation of the appropriate therapy. P. vivax and P. ovale infections require specific, additional treatment because they produce dormant liver-stage parasites that are capable of causing relapses. P. falciparum and P. vivax species have demonstrated drug resistance patterns that vary by geographic region. Identification of the infecting species as well as knowledge of the geographic area where the infection was acquired can provide information about the drug resistance pattern of the infecting parasite and enable the clinician to choose an appropriate drug regimen and course of treatment [4]. Knowledge of drug resistance patterns is vital to the development and discovery of new antimalarial drugs [25].

The CDC has indicated that oral antimalarial drugs are an effective treatment choice for patients diagnosed with uncomplicated malaria. More severe disease requires aggressive treatment with parenteral antimalarials [4].

TREATMENT OF UNCOMPLICATED MALARIA

Table 1 contains a summary of treatment recommendations for uncomplicated malaria. In instances when either the diagnosis or the infecting species cannot be confirmed, treatment against P. falciparum should begin immediately and should include continuous monitoring of the patient's clinical status. Blood smears should be made to confirm an adequate response to treatment of infections with P. falciparum or suspected chloroquine-resistant P. vivax [4].

TREATMENT RECOMMENDATIONS FOR UNCOMPLICATED MALARIA

Plasmodium speciesDrugDosingComments
P. falciparum or
"species not identified" in areas without chloroquine-resistant strains
Chloroquine
Initial oral dose: 600 mg base (1000 mg salt), followed with 300 mg base (500 mg salt) at 6, 24, and 48 hours
Maximum dose: 1500 mg base (2500 mg salt)
Use adult dosing in pregnancy.
Adjust pediatric dosing by patient weight; do not exceed recommended adult dosing.
Consider atovaquone-proguanil (preferred) or mefloquine if quinine is unavailable.
Quinine and atovaquone-proguanil are recommended for use in children 8 years of age and younger.
Hydroxychloroquine (2nd-line alternative)Initial oral dose: 620 mg base (800 mg salt), given immediately, followed with 310 mg base (400 mg salt) at 6, 24, and 48 hours
Maximum dose: 1550 mg base (2000 mg salt)
P. falciparum or
"species not identified" in areas with chloroquine-resistant strains
Atovaquone/proguanil1 g/400 mg as a single dose, once daily for 3 daysThese are fixed dose combination medicines that may be used for nonpregnant adult and pediatric patients. Both have been found to be very effective.
Artemether/lumefantrine
Patients 25 to <35 kg: Three tablets at hour 0 and hour 8 on the first day, then 3 tablets twice daily on days 2 and 3
Patients≥35 kg: Four tablets at hour 0 and hour 8 on the first day, then 4 tablets twice daily on days 2 and 3
Quinine sulfate plus doxycycline, tetracycline, or clindamycin648 mg every 8 hours for 3 to 7 daysQuinine sulfate plus either doxycycline or tetracycline generally preferred. Treatment duration depends on area of acquisition. Quinine sulfate/clindamycin is recommended during pregnancy. Quinine dosing duration depends on area of acquisition; clindamycin dosing should continue for 7 days regardless of area of acquisition.
Mefloquine5 tablets (1250 mg) as a single dose dailyAssociated with severe neuropsychiatric reactions; recommended only when other options cannot be used. If clinical improvement is not seen within 48 to 72 hours, an alternative therapy should be used for retreatment.
P. malariaeChloroquineSame as for P. falciparumThere is little evidence of chloroquine resistance in P. malariae. May be used during pregnancy.
Hydroxychloroquine (2nd-line alternative)Same as for P. falciparum
P. vivax acquired in all areas except Papua New Guinea or IndonesiaChloroquineSame as for P. falciparumIf patient is nonresponsive, change treatment to one of the three options listed for treatment of P. vivaxmalaria acquired in Papua New Guinea and notify state health department and CDC.
Hydroxychloroquine (2nd-line alternative)Same as for P. falciparum
P. vivax acquired in Papua New Guinea or IndonesiaQuinine sulfate plus doxycycline or tetracycline648 mg every 8 hours for 3 to 7 daysHigh possibility of chloroquine-resistant strains. Options are equally recommended. During pregnancy, treat with quinine for 7 days, regardless of area of acquisition. Risk/benefit of adding doxycycline or tetracycline (pregnancy category D) to quinine should be carefully evaluated. Risk/benefit of using atovaquone-proguanil or mefloquine (both pregnancy category C) should be carefully evaluated.
Atovaquone/proguanil1 g/400 mg as a single dose, once daily for 3 consecutive days
Mefloquine5 tablets (1250 mg) as a single dose daily
P. ovaleChloroquineSame as for P. falciparumMay be used during pregnancy
Hydroxychloroquine (2nd-line alternative)Same as for P. falciparum
P. knowlesiAtovaquone/proguanil250 mg/100 mg, 4 times per day for 3 daysThere is little evidence comparing various medications for the treatment of this relatively new strain.

Relapses may occur in patients in whom either P. vivax or P. ovale are the infectious agent because, as noted, these agents have dormant liver-stage parasites capable of reactivating. Relapses may occur months to years after the initial infection and may or may not have associated symptoms. Treatment with primaquine phosphate is available to reduce the chance of relapses. The CDC has recommended a 14-day course of treatment, when appropriate. It is important to note that primaquine may cause hemolytic anemia in persons with glucose-6-phosphate-dehydrogenase (G6PD) deficiency; therefore, patients (including pediatric patients) should be screened for G6PD deficiency prior to commencement of treatment. Primaquine is contraindicated during pregnancy [3,4,26].

Treatment without the benefit of laboratory confirmation ("presumptive" treatment) should be initiated only in extreme circumstances, such as strong clinical suspicion of infection, indications of severe disease, or the inability to obtain prompt confirmation via laboratory investigations [4]. The CDC has additionally recommended presumptive treatment of P. falciparum malaria in persons emigrating from endemic areas prior to their entry into the United States. This strategy is designed to decrease the risk of complications or death in a population that might lack access to health care. It is also designed to prevent existing infections from progressing to severe disease and reduce the risk of reintroduction of malaria into the United States [27].

TREATMENT DURING PREGNANCY

Malaria infection during pregnancy has been associated with high risks to both mother and fetus, including miscarriage, premature delivery, low birth weight, congenital infection, and maternal and perinatal morbidity and mortality. The reasons for these risks are poorly understood but may include a reduced maternal immune response that ineffectively clears the malaria infection. This is compounded by the ability of the malaria parasites to sequester and replicate in the placenta. Pregnant women are three times more likely than nonpregnant women to develop severe malaria [4]. Healthcare providers should counsel nonpregnant women of childbearing age to use contraception and avoid pregnancy during, and for up to 3 months following, treatment for malaria [4,26].

TREATMENT OF SEVERE MALARIA

Of the 1,500 cases of malaria diagnosed in the United States each year, approximately 10% are cases of severe malaria that carry an increased risk of death [28]. Because most deaths from severe malaria occur within the first 24 to 48 hours, patients with manifestations of severe malaria (including pregnant women) should be treated aggressively with parenteral antimalarial therapy as soon as possible after the diagnosis has been made [4,26]. Oral antimalarial drugs (i.e., quinine, chloroquine, or mefloquine) are not recommended for the initial treatment of severe malaria [3,4]. The treatment recommendations for patients with severe malaria are summarized in Table 2.

TREATMENT RECOMMENDATIONS FOR SEVERE MALARIAa

DrugDosingComments
Quinidine gluconate
IV loading dose: 6.25 mg base/kg (10 mg salt/kg) over 1 to 2 hours. Follow with continuous IV infusion 0.0125 mg base/kg/min (0.02 mg salt/kg/min).
Alternate regimen:
IV loading dose: 15 mg base/kg (24 mg salt/kg) over 4 hours. Eight hours after loading dose, follow with 7.5 mg base/kg (12 mg/kg salt) over 4 hours, every 8 hours.
At least 24 hours of infusion are recommended.
When parasite density is <1% and patient is able to take oral medication, complete treatment course with oral quinine per recommendations for uncomplicated malaria.
Reduce maintenance dose by one-third to one-half on the third treatment day in patients with no clinical improvement or in patients with renal failure that persists.
Doxycycline
IV: 100 mg every 12 hours
Oral: 100 mg every 12 hours for 7 days
TetracyclineOral: 250 mg every 6 hours for 7 days
Clindamycin
IV: 5 mg base/kg IV every 8 hours
Oral: 20 mg base/kg/day divided 3 times/day for 7 days
a The regimen for the treatment of severe malaria in the United States consists of quinidine plus either doxycycline, tetracycline, or clindamycin.

Parenteral quinidine gluconate is cardiotoxic and may cause ventricular arrhythmia, hypotension, hypoglycemia, and prolongation of the QTc interval. The CDC has recommended that this drug be administered in an intensive care setting with continuous cardiac and frequent blood pressure monitoring. Consultation with a cardiologist and a physician experienced with the treatment of severe malaria with quinidine also has been recommended [3,4].

The CDC has recommended that exchange transfusion (e.g., the removal of infected red blood cells) be strongly considered for persons with a parasite density of more than 10%. It also should be considered if the patient has complications, such as cerebral malaria, acute respiratory distress, or renal complications. The beneficial effects of exchange transfusion should, however, be carefully weighed against the risks (e.g., febrile or allergic reactions). Parasite density should be monitored at 12-hour intervals until the level is less than 1% [4].

Quinidine gluconate, an antiarrhythmic drug with antimalarial action, has traditionally been the only parenterally administered antimalarial drug available in the United States. However, with the advent of newer antiarrhythmics, quinidine has become less available in U.S. hospitals. Where quinidine is either not an option or is contraindicated for a particular patient, parenteral artesunate (from the class of medications known as artemisinins) is available as an investigational new drug (IND) through the CDC. The World Health Organization (WHO) has preferentially recommended artesunate (rather than quinidine) for the treatment of severe malaria [28]. The IND classification has made the drug available to U.S. hospitals for patients hospitalized and in need of intravenous treatment due to [4,28]:

  • Severe malaria disease

  • High levels of malaria parasites in the blood

  • Inability to take oral medications

  • Lack of timely access to intravenous quinidine

  • Quinidine intolerance or contraindications

  • Quinidine failure

Reports of the emergence of parasites that are resistant to artemisinin derivatives are considered a threat to the global effort to control and eliminate malaria, and WHO has taken steps to confirm and contain such strains [2].

PREVENTION

Between 1997 and 2006, more than 10,000 cases of malaria among U.S. residents were reported to the CDC. The vast majority of these cases (86.8%) were acquired as a result of travel outside the United States [35]. In 2010 alone, 1,691 cases were reported in the United States, the largest number since 1980, with nearly all cases (99.8%) resulting from international travel [15]. Travelers to sub-Saharan Africa are at greatest risk of acquiring a fatal malarial infection [15,31,32]. Although malaria poses a serious threat to travelers, it is preventable in most cases [2,33].

Malaria prevention consists of a combination of infection prevention (including personal protection) and chemoprophylaxis among persons at risk. It also includes assessing the risk factors for individual travelers and identifying appropriate preventive measures based upon that assessment. Travelers to malaria-endemic areas who have previously acquired malaria should be reminded that it may be acquired more than once [30,33].

There is no gold standard for assessing a traveler's risk of contracting malaria, so it is important that pre-travel guidance be obtained from a healthcare professional experienced in travel medicine. The level of risk and the individual traveler's profile will guide decision making in determining appropriate preventative measures [30,34].

RISK ASSESSMENT

Factors to consider and include in a traveler's profile include knowledge about the traveler's destination, the season during which travel will occur, how and for how long the individual will travel, and the traveler's basic personal history. It is important to know the traveler's destination because the risk of acquiring malaria is not uniformly distributed throughout all countries; it may be confined to small areas in some countries. The season of travel is also important because temperature and rainfall may affect malaria transmission. The traveler's anticipated accommodations and activities should also be included in the risk assessment. Indoor accommodations, for example, may be less risky to the traveler than outdoor (e.g., camping) accommodations. Additionally, if the traveler expects to participate in outdoor evening activities, this will increase the risk of exposure to the infecting mosquito. The CDC has found that the greatest risk is among first- and second-generation immigrants who live in non-malaria-endemic countries and then return to their countries of origin to visit family and friends. Because many of these individuals incorrectly consider themselves to be immune, they forego pre-travel preventive measures [30,33,34].

The WHO has compiled a convenient ABCD memory aid for travelers [29]:

  • Be aware of the risk, the incubation period, and the main symptoms.

  • Avoid being bitten by mosquitoes, especially between dusk and dawn.

  • Take antimalarial drugs (chemoprophylaxis) to suppress infection where appropriate.

  • Immediately seek diagnosis and treatment if a fever develops one week or more after entering an area where there is a malaria risk and up to 3 months after departure.

PERSONAL PROTECTIVE MEASURES

The CDC and the Infectious Diseases Society of America have recommended that individuals traveling outside the United States be aware of and employ the following personal protective measures [30,33]:

  • Avoid travel to known malaria-endemic areas, when possible.

  • Be aware of peak exposures times and places, usually outdoors at dawn and dusk.

  • Wear clothing that minimizes skin exposure.

  • Use bed nets and ensure that they completely cover the sleeping area. Nets pretreated with insecticides or repellents may be purchased prior to travel. Nets may also be treated after purchase.

  • Use insecticides (with caution and as directed). N,N-diethylmetatoluamide (DEET) is an ingredient in many commercially available products and is the most effective repellent.

CHEMOPROPHYLAXIS

According to the WHO, an estimated 30,000 travelers become ill with malaria each year despite the fact that malaria in travelers is usually preventable [55]. A CDC surveillance summary of cases of malaria in patients with onset of illness in 2009 found that a majority of these patients had not adhered to a region-appropriate regimen of chemoprophylaxis [15].

In addition to the personal protective measures previously discussed, malaria prophylaxis is an important prevention component [15]. All travelers to malaria-endemic areas should take an antimalarial drug. Drug recommendations depend upon the country of travel. Up-to-date recommendations may be found on the CDC Traveler's Health website at http://www.cdc.gov/travel.

Travelers should be reminded that no antimalarial drug regimen is 100% protective and that it should always be combined with the personal protective measures, as discussed. The CDC has compiled a list of drugs for consideration in those instances when more than one drug has been recommended for a specific area (Table 3). Travelers should also be cautioned to be alert for counterfeit antimalarial drugs, which may contain either none or less than the required amount of the active ingredient(s). Some of these counterfeits have reportedly led to deaths [36]. Precautions that all travelers should employ when buying antimalarial drugs include [36]:

  • Buying them in their home country before travel begins

  • Carrying the manufacturer's name and the drug names (generic and brand) with them in case an additional supply is needed

  • Inspecting the drug's packaging carefully and ensuring that it is intact

  • Being suspicious of drugs that have a peculiar odor, taste, or color. Additional information about counterfeit drugs may be found on the FDA website.

CHOOSING A MALARIA PROPHYLAXIS REGIMEN FOR TRAVELERS

DrugBenefitsRisks/Contraindications
Atovaquone/
proguanil
May be started 1 to 2 days before traveling to a malaria-endemic area
Must only be continued for 7 days after traveling, rather than 4 weeks
Very well tolerated medicine
Pediatric tablets are available and may be more convenient
Contraindicated in women who are pregnant or breastfeeding a child who weighs less than 5 kg
Contraindicated in patients with severe renal impairment
Tends to be more expensive than some of the other options
Some patients would rather not take a daily medication
Chloroquine
Taken only weekly
Some patients (e.g., those with chronic rheumatologic conditions) may already be taking hydroxychloroquine
Can be used in all trimesters of pregnancy
Cannot be used in areas with chloroquine or mefloquine resistance
May exacerbate psoriasis
Must continue taking medication for 4 weeks after travel
Must be started 1 to 2 weeks prior to travel
Doxycycline
May be started 1 to 2 days before traveling to a malaria-endemic area
Tends to be the least expensive antimalarial
Patients may already be taking doxycycline chronically for prevention of acne
Doxycycline can also prevent some additional travel-related infections (e.g., Rickettsia and leptospirosis), particularly if patients plan to hike, camp, or swim in fresh water
Contraindicated for pregnant women and children younger than 8 years of age
Some patients would rather not take a daily medication
Must continue taking medication for 4 weeks after travel
Long-term antibiotic use can increase the risk of fungal overgrowth
Increased risk of sun sensitivity and gastrointestinal side effects
Mefloquine
Taken only weekly
Can be used in the second and third trimester of pregnancy and in the first trimester if there is no other option (e.g., postpone travel)
Contraindicated for travel to areas with mefloquine resistance and in patients with seizure disorders and certain psychiatric conditions
Not recommended for patients with cardiac conduction abnormalities
Must be started at least 2 weeks prior to travel and continued for 4 weeks after return
Primaquine
The most effective medication for preventing P. vivax
May be started 1 to 2 days before traveling to a malaria-endemic area
Must only be continued for 7 days after traveling, rather than 4 weeks
Contraindicated in patients with glucose-6-phosphatase dehydrogenase (G6PD) deficiency or whose G6PD deficiency status is unknown
Contraindicated in pregnant women and women who are breastfeeding, unless the infant has also been tested for G6PD deficiency
Increased risk for gastrointestinal side effects

PRESUMPTIVE SELF-TREATMENT

Malaria may be effectively treated early in the course of the disease; however, delay of appropriate treatment may have serious, even fatal, consequences. Travelers who choose not to take an antimalarial drug, who are on a less than effective regimen (e.g., chloroquine in a chloroquine-resistant risk area), whose medical history dictates a suboptimal drug, or who may be traveling to very remote areas may be prescribed a presumptive self-treatment course (Table 4). Travelers should be advised to take the treatment promptly if fever, chills, or other influenza-like illness occurs. This is particularly important if the traveler is unable to access professional medical care within 24 hours. Travelers should also be advised to seek medical care as soon as possible after self-treatment [15,35].

Presumptive Self-Treatment with Atovaquone/Proguanil

PatientDoseComments
Adult4 tablets (1000 mg atovaquone and 400 mg proguanil each) orally as a single daily dose for 3 consecutive days
Not currently recommended for pregnant women and women breastfeeding infants weighing less than 5 kg
Contraindicated in persons with severe renal impairment
Child 5–8 kg2 pediatric tablets (62.5 mg atovaquone and 25 mg proguanil each)Not currently recommended for children <5 kg
Child 9–10 kg3 pediatric tablets
Child 11–20 kg1 adult tablet
Child 21–30 kg2 adult tablets
Child 31–40 kg3 adult tablets
Child ≥41 kg4 adult tablets
Self-treatment should be initiated if professional medical care is not available within 24 hours. Medical care should be sought immediately after treatment.

INFECTION AND DISEASE PREVENTION

Infection may be prevented when the offending mosquitoes are prevented from biting humans. The three most common methods of prevention include insecticide-treated bed nets, intermittent preventive treatment of malaria in pregnant women, and indoor residual spraying [37].

Insecticide-Treated Bed Nets

Insecticide-treated bed nets have been shown to effectively reduce illness, disease, and death caused by malaria. They can reduce overall child mortality by as much as 20% and have additionally been shown to reduce the intensity of transmission [38,39]. Because mosquitoes are able to feed through nontreated nets and those with even the tiniest holes or tears, the application of insecticides to bed nets improves protection significantly by repelling mosquitoes. Additionally, in communities where insecticide-treated nets are widely used, an overall reduction in the mosquito population has been found to occur.

Long-lasting insecticide-treated nets have also been developed. They offer significant maintenance and use advantages over the older nets, which had to be retreated frequently. The long-lasting insecticide-treated nets offer protection for up to 3 years. The WHO has recommended several long-lasting insecticide-treated nets, which are undergoing performance and durability testing by the CDC [37,40]:

  • DawaPlus 2.0 (Tana Netting)

  • DuraNet (Clarke Products)

  • Interceptor Net (BASF)

  • LifeNet (Bayer CropScience)

  • MAGNet (V.K.A. Polymers Private Limited)

  • NetProtect (Bestnet) (also marketed as ICONLife [Syngenta])

  • Olyset Net (Sumitomo Chemical)

  • Plyset Plus (Sumitomo Chemical)

  • PermaNet 2.0 (Vestergaard-Frandsen)

  • PermaNet 2.5 (Vestergaard-Frandsen)

  • PermaNet 3.0 (Vestergaard-Frandsen)

  • Royal Sentry (Disease Control Technologies)

  • Yorkool LN (Yorkool International)

Infection and Disease Prevention During Pregnancy

As previously discussed, malaria can have severe, even fatal consequences for a pregnant woman and her fetus. Women who are having their first or second pregnancy and women who are HIV-positive are at an increased risk. The effects of malaria infection on the pregnant woman and her fetus have been found to vary according to the area of transmission. These effects range from maternal anemia, acute respiratory distress, and low-birth-weight infants (generally in areas of high transmission) to severe disease, premature delivery, and even fetal loss (generally in areas of low transmission) [41]. Intermittent preventive treatment involves administration of a full course of an antimalarial at specified intervals (generally 2 doses for pregnant women), regardless of the confirmed presence of infection. Intermittent preventive treatment has been recommended for pregnant women in areas of high transmission [37]. The antimalarial sulfadoxine-pyrimethamine has been found to reduce the burden of malaria in this population [38,42,43].

Indoor Residual Spraying

Indoor residual spraying involves the application of long-acting chemicals to the walls and other surfaces of a house. The goals of indoor residual spraying are to reduce both the population density and the life span of infecting mosquitoes. Indoor residual spraying was part of a global eradication effort conducted from 1955 to 1969, which was successful in Europe, the Soviet Republic, parts of Asia, and the Caribbean. The effort did not include the African continent [44].

VACCINE DEVELOPMENT

Although no effective malaria vaccine is available for the prevention of malarial disease as of 2013, several are in development. In 2004, a Phase II trial with a pre-erythrocytic vaccine (RTS,S/AS02A) demonstrated a 30% reduction in total clinical episodes of malaria and a 58% reduction in severe clinical episodes in young children in the short term in Mozambique, suggesting that the development of an effective vaccine against malaria may be feasible [45,46]. Subsequent studies concluded that the vaccine was safe, efficacious, and well-tolerated among the study participants (i.e., infants and young children) [47,48,49,50].

A phase III efficacy trial with a pre-erythrocytic vaccine (RTS,S/AS01) was launched in Africa in 2009. The results showed a 56% reduction in total clinical malaria and a 47% reduction in severe malaria [56,57].

The Malaria Vaccine Initiative supports the development of a malaria vaccine by testing multiple vaccine candidates simultaneously. Projects focus primarily on P. falciparum because of its destructiveness; however, focus is increasing on P. vivax, which is less severe but more widespread than P. falciparum [51]. In addition to the attention being given to discovering a vaccine for malaria, researchers are beginning to focus on intervention techniques that will interrupt the malarial life cycle and, thus, the spread of malaria [16].

CONSIDERATIONS FOR NON-ENGLISH PROFICIENT PATIENTS

Because patient education is such a vital aspect of preventing the spread of malaria, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter.

CONCLUSION

Malaria is one of the most significant infectious diseases in the world. It affects between 200 and 300 million people each year worldwide and is a leading cause of illness and death in the developing world. Malaria imposes significant costs to individuals and governments. Such costs can add substantially to the economic burden of malaria on endemic countries and impede their economic growth [2,18].

Malaria poses a particularly serious threat to U.S. travelers who lack immunity. Although the transmission of malaria was successfully interrupted in the United States during the late 1940s, it continues to pose a challenging health threat to individuals who travel to and emigrate from malarious areas. Because malaria cases are rare in the United States, misdiagnosis is a common problem [4,5]. Malaria may be suspected based on the patient's symptoms, travel history, and physical findings at examination. Patients with suspected infection should be urgently and thoroughly evaluated. Delayed diagnosis is a leading cause of death among malaria patients in the United States [3].

Patients suspected of having malaria infection should be urgently evaluated, and the diagnosis should be confirmed by laboratory investigations before treatment begins. Presumptive treatment, without the benefit of laboratory confirmation, should be reserved for extreme circumstances [5].

RESOURCES

CDC Malaria Hotline
770-488-7788 or 855-856-4713 (Monday through Friday, 9 a.m. to 5 p.m., Eastern)
770-488-7100 (for emergency consultation after hours)
CDC Travelers' Health
This site contains general traveler's health precautions and malaria-specific information. The current CDC Health Information for International Travel (the Yellow Book) may also be viewed.
http://www.cdc.gov/travel
The Global Partnership for a Malaria-Free World
http://www.rollbackmalaria.org
The RBM Partnership
Secretariat hosted at WHO
20, Avenue Appia
1211 Geneva 27
Switzerland
CDC Malaria
Guidelines for Treatment of Malaria in the United States
http://www.cdc.gov/malaria/diagnosis_treatment/treatment.html
Malaria Vaccine Initiative
This site contains information about the research into and development of a vaccine for malaria.
http://www.malariavaccine.org/about-overview.php
U.S. Food and Drug Administration: Counterfeit Medicine
The site contains information for consumers about counterfeit medicine.
http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/CounterfeitMedicine

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Evidence-Based Practice Recommendations Citation

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