Bledsoe, Gregory H. MD, MPH
Each year in the United States, approximately 1,400 cases of malaria are reported to the Centers for Disease Control and Prevention (CDC) despite the fact that malaria is not a reportable disease and data are considered underrepresentative of the problem. In 2001, half of these cases were caused by Plasmodium falciparum, a usually severe form of malaria and the cause of most of the 10 reported deaths.1 Because of the nonspecific nature of most symptoms of malaria and the unfamiliarity of most US physicians with the disease, many cases are initially misdiagnosed, and valuable treatment time is lost.2 The purpose of this report is to provide basic information about malaria to primary care clinicians who could possibly have the opportunity to intercept this disease on its initial presentation.
All but eradicated in the United States and most of the industrial world, malaria is still a scourge in many developing nations, causing approximately 2 million deaths annually, mostly in children under the age of 5 years.3 Though the worldwide prevalence of malaria, approximately 400 to 500 million, is 10 times that of human immunodeficiency virus (HIV), malaria receives a fraction of the publicity, and many in the lay public consider it a disease from a distant time.
Recent data from the CDC indicate that although a relatively rare phenomenon in the United States, primary care clinicians still encounter patients with malaria and need to know how to recognize and treat this entity. The fact that most US clinicians have never seen a case of malaria and do not know its typical presentation, plus the fact that malaria chemotherapy can be a confusing conundrum for the nonspecialist, makes the likelihood of mismanagement of this disease quite high.
Most of the approximately 1,400 cases of malaria that occur in the United States each year occur in travelers and military personnel returning from malaria-endemic regions. The incidence of imported malaria cases seems to be on the rise,4 most significantly in the civilian population. In 2001, 891 civilians from the United States were diagnosed with malaria, the highest incidence of malaria in US civilians in 30 years.1
Though considered to have been eradicated from the continental United States since 1970,5 local outbreaks do still occasionally occur. Eleven local outbreaks containing a total of 20 cases have occurred in the United States since 1992, the most recent of which was the local transmission of Plasmodium vivax in Palm Beach County, Florida, in 2003.5,6 Other locations of recent local outbreaks include such geographically diverse regions as New York,7 Virginia,8 and California,9 indicating that clinicians anywhere could be presented with patients infected with this parasite.
Parasitic Life Cycle
To accurately prevent, diagnose, and treat malaria infections, a proper understanding of the parasitic life cycle is necessary. The complexity of the malaria life cycle not only creates difficulty in the prevention and diagnosis of the disease but also leads to confusion when dealing with malaria terminology and chemotherapy.
Malaria is actually caused by four different species of the Plasmodium parasite: P falciparum, P vivax, P ovale, and P malariae. Infection with each of these has its own specific traits and areas of distribution, but all four lead to such similar clinical presentations that differentiating them during the initial diagnostic period is difficult if not impossible.
Of the four, P falciparum is the most deadly and the greatest threat to travelers abroad. P falciparum causes what has been described as “cerebral malaria” and can quickly overcome a healthy patient. P vivax and P ovale are infrequently fatal in healthy adults but cause much morbidity in endemic areas. Plasmodium vivax and P ovale are also notable for their ability to exist as dormant forms in the liver hepatocyte, which can cause a relapse of the infection months to years after exposure. All four can be transmitted through blood transfusions if the blood is not carefully screened, and cases of transplacental and needle-stick transmission have also been reported.10
The basic life cycle of the parasite begins when male and female gametocyctes are ingested by a female Anopheles mosquito during feeding on an infected human (Fig. 1). The gametocytes form a sexual union and burrow into the stomach lining of the mosquito, where they undergo sexual reproduction producing thousands of sporozoites. These sporozoites travel to the salivary glands of the mosquito vector, where they can be transmitted to another human being during a blood meal.
Within minutes of being injected into the bloodstream of the victim, the sporozoites travel to the liver, where asexual reproduction begins.11 This reproduction creates a latent phase lasting between 8 to 30 days. Plasmodium vivax and P ovale can form dormant hypnozoites that can remain in the liver cells for many years unless properly treated with chemotherapy (Primaquine) targeting the dormant stage. Eventually, merozoite forms are released from the liver back into the bloodstream, where they infect erythrocytes and begin another asexual cycle that leads to the lysing of the red blood cells after 48 or 72 hours. This synchronous lysing is what causes the clinical scenario of cyclical fevers in mature infections. An unknown trigger causes some of these merozoites to differentiate into gametocyctes that are taken up by another mosquito to acquire the infection. Without gametocytes, the patient is infected but not infectious.
One of the difficulties in evaluating patients with possible malarial infection is the lack of specific signs or symptoms to aid in the diagnosis.12 The typical patient with malaria has paroxysmal chills, fevers, and sweats with headaches, myalgias, and possible gastrointestinal symptoms. The cyclical fevers only occur in mature infections, and the lack of cyclical febrile episodes does not rule out a diagnosis of malaria. Laboratory evidence consistent with malarial infections includes such nonspecific findings as thrombocytopenia, a white cell count with a left shift, and anemia.2
This nonspecific clinical picture further emphasizes the importance of a high level of clinical suspicion and the need for a thorough history when evaluating patients with fevers. Though chemoprophylaxis with proper medications has been shown to be approximately 98% effective in preventing a malarial infection,13,14 patients who have recently traveled to malaria-endemic regions and report compliance with their chemoprophylactic medications are still at risk. According to the 2001 CDC data, 20% of the 891 US civilians diagnosed with malaria reported compliance with their prophylactic medication regimens.1 This apparent contradiction can be explained by patients not properly understanding the medicine regimen, taking an improper medication for chemoprophylaxis, or developing onset of symptoms from a dormant species of Plasmodium after having finished their chemoprophylaxis.
The diagnosis of malaria has traditionally been made by the evaluation of thick and thin blood smears from the patient. The blood samples are stained with 3% Giemsa stain and then evaluated by a microscopist trained to recognize the malaria parasite in erythrocytes. Clinicians evaluating patients for malaria in countries where malaria infections are infrequent should note that maintaining the skills necessary to correctly identify the parasite in blood smears has been reportedly difficult when cases are rare15 and can be affected by the level of parasitemia. Multiple microscopic fields should be examined before the diagnosis of malaria is ruled out, and even then up to three sets of thick and thin smears obtained 8 to 12 hours apart have been recommended in patients with a high clinical likelihood of malaria.4 In addition to whether the patient is infected with malaria, a diagnostic smear can determine which species are responsible for the infection and the level of parasitemia in the blood. Patients with greater than 3% parasitemia or patients infected with falciparum malaria should be hospitalized.10 Patients treated in an ambulatory setting should have close follow-up and repeated smears to ensure response to drug therapy, however.
Newer means of detecting the malaria parasite include antigen detection through a variety of rapid diagnostic tests and the identification of parasitic genetic material through polymerase chain reaction tests. None of these tests has yet to gain Food and Drug Administration approval in the United States, however. Clinicians should be mindful that malaria is to be considered a medical emergency and that patients in whom a high clinical suspicion exists for malarial infection should have treatment begun immediately.
Medication Clinical Groupings
Malaria chemotherapy can be a tremendous challenge to the clinician unaccustomed to seeing patients in his clinical practice with the disease. It is helpful to begin by placing the common malaria medications into clinical groupings based on their mechanism of attacking the malaria parasite (Fig. 2). Malaria medications can be easily divided into three broad groupings, or classes. The first class targets the parasite at its asexual reproductive stage in the red blood cell. Drugs in class I do not prevent the initial inoculation of the patient with the parasite, but they should prevent clinical disease by attacking the infection within the red blood cells.
Classes II and III consist of a single drug per group. Class II contains Primaquine, a drug that targets both the initial liver stage of all four species, as well as the hypnozoite form of vivax and ovale and the erythrocytic stage of vivax, but cannot be given to patients with the glucose 6-phosphate dehydrogenase (G-6-PD) deficiency. Class III contains a relatively new malaria medication, Malarone. Malarone is a combination of atovaquone and proguanil and can attack the parasite during both its initial liver stage and during its asexual reproductive stage in the red blood cell. The ability of class II and class III drugs (Malarone and Primaquine) to fight the parasite in both the liver and erythrocytic stages is an important distinction that allows patients to discontinue their prophylactic regimens only 1 week after exiting a malaria-endemic region, as compared with the normally recommended 4 weeks of prophylaxis with the other medications.
Medical Prophylaxis for Travelers
Because there is no vaccine for malaria, travelers to endemic regions must rely on chemoprophylaxis as a mainstay of malaria prevention. It is important for clinicians prescribing chemoprophylaxis to understand proper drug regimens because inadequate medical advice has been linked to high rates of malaria infection in returning travelers.16 When considering pharmacological prophylaxis for malaria, it is helpful to know that prophylaxis can be broken down into two main types: “causal prophylaxis” and “suppressive prophylaxis,”14 with a third type of prophylaxis termed “terminal prophylaxis” referring to treating a patient with Primaquine after they have returned from an endemic P ovale or P vivax region to prevent late relapses from hypnozoite forms.4 Causal prophylaxis fights the initial liver stages of the parasite, preventing the spread of the infection to the erythrocytes. Malarone is the only medication commonly used for causal prophylaxis, although Primaquine has recently been approved as a secondary drug for causal prophylaxis in regions with high rates of chloroquine-resistant Plasmodium falciparum.10 Both Malarone and Primaquine require only 1 week of continued use after the patient returns from a malaria region—class I agents require an additional month of prophylaxis to ensure adequate protection. Suppressive prophylaxis does nothing to prevent the liver stages of the disease but fights the parasite during the erythrocytic stage and can be accomplished by a number of medications, as illustrated in Figure 2. The most recent recommendation by the American Public Health Association is for Primaquine to be given as terminal prophylaxis only after prolonged exposure in areas endemic with P ovale or P vivax.17
The only geographic locations where P falciparum is still sensitive to chloroquine are Central America including Mexico, the Caribbean, and a few countries in the Middle East. If one travels to parts of the world where chloroquine resistance is not present, then chloroquine can be used as a prophylactic medication.18 Chloroquine is most often prescribed in the United States in its salt form, an enteric-coated tablet called Aralen; the generic chloroquine phosphate is dosed differently in its base form. However, when in chloroquine-resistant malaria areas, the traveler should be taking one of the three recommended prophylactic regimens—mefloquine (Lariam) once a week, doxycycline once a day, or Malarone once a day—or, as a secondary choice, Primaquine once a day.10,19 Studies comparing doxycycline, mefloquine, and Malarone have demonstrated similar clinical efficacy in preventing malaria infections14, and data from Primaquine trials appear to demonstrate similar efficacy.20 It should be noted that doxycycline is the drug of choice for chemoprophylaxis when traveling to rural Thailand, especially near the borders of Cambodia and Burma, due to high rates of mefloquine-resistant malaria.10 Pregnant women and children are at increased risk for development of malaria, and although there are medications such as chloroquine and mefloquine that can be given to pregnant patients, in general it is not recommended for pregnant individuals to electively travel in malaria endemic regions.19 Children can be given chemoprophylactic medications based on their age and weight (Table 1), and parents should be educated about the dosing regimens of these drugs.
Patients should be made aware of the major side effects of any prescribed drugs. Photosensitivity is the most common side effect in patients taking doxycycline, and this medication can also cause discoloration of the teeth if given to children under the age of 8 years. Vivid dreams, mood swings, and rare cases of psychosis have been attributed to mefloquine, and for these reasons, patients with a history of seizures and psychiatric diagnoses should have other drugs prescribed. Much has been written about mefloquine in the popular media, and, although the risk of significant neuropsychiatric effects from the medication are exceeding low, many patients are afraid to take the drug and will not use it even if it is prescribed. This noncompliance with mefloquine prescription has contributed to an increase in imported malaria cases in the United Kingdom,21 and, for this reason, patients who are reluctant to take mefloquine should have another drug prescribed. If a patient must be switched from either doxycycline or mefloquine to Malarone during chemoprophylaxis, the patient should be kept on the Malarone “for 4 weeks after the switch or 1 week after returning, whichever is longer.”22
Though not routinely used by most travelers, Primaquine has been recommended as a means of terminal prophylaxis for those persons who have stayed from months to years in a P vivax or P ovale endemic region, since these two species of malaria can form dormant hypnozoites. Primaquine is the only drug available for the eradication of these hypnozoites. The most significant side effect of Primaquine is hemolysis in patients with glucose 6-phosphate dehydrogenase (G-6-PD) deficiency, a response first witnessed by an incarcerated laboratory technician named Charles Ickes (Reference Note 1, 2003) who was working in the Army Malaria Research Project while serving an armed robbery sentence at Stateville Penitentiary in Illinois.23,24
The drug combination chloroquine/proguanil is often used by European travelers as a chemoprophylaxic agent. Its effectiveness falls far short of the 98% malaria prevention rate of mefloquine, doxycycline, and Malarone, and an approximate efficacy of 70% for chloroquine/proguanil is often quoted.25,26 Chloroquine/proguanil is not available in the United States, and travelers to malaria-endemic regions—especially Africa, where chloroquine resistance is high—are encouraged not to switch to this drug from the other recommended regimens despite possible peer pressure from other travelers.27
Treatment of Malaria
Because no chemoprophylactic regimen is completely effective, even patients who have been compliant with their medications should be considered for infection. Treatment regimens are based on the region of travel and clinical presentation of the patient. Correct diagnosis of potential patients with malaria should be initiated, but treatment must not be withheld while awaiting diagnostic verification. In cases of falciparum infection in nonimmune hosts, the possibility of fatality increases directly with parasite number so time from infection to proper treatment is critical.
Patients returning from regions containing chloroquine-sensitive P falciparum who present with clinically mild disease and a parasitemia less than 3% can be begun on Aralen (choloroquine salt). However, if there is a possibility of being infected with choloroquine-resistant malaria, a treatment protocol of mefloquine plus doxycycline orally (or mefloquine alone)10 should be administered (Table 2). Children under the age of 8 years and pregnant patients cannot be given doxycycline, so clindamycin is recommended in these patients.4,10 The combination of quinine and clindamycin has been demonstrated to be a good therapy for patients infected with resistant falciparum.28
Patients with signs or symptoms of more clinically severe infections—defined by the CDC as patients having “one or more of the following clinical criteria: impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions” (http://www.cdc.gov/malaria/diagnosis_treatment/clinicians2.htm#general)—patients with parasitemia greater than 3%,10 or patients not tolerating oral medications should be admitted for intravenous therapy. Although quinine is used throughout most of the world for severe cases of malaria, quinidine is the only parenteral medication approved in the United States and should be combined with doxycycline for severe malarial infections. Patients placed on intravenous quinidine should have constant cardiac monitoring because the drug can cause widening of the QRS complex, widening of the QT interval, and hypotension. The infusion can be slowed or even periodically stopped in patients who have development of these cardiac effects. Quinidine can also increase release of insulin, so glucose levels should be regularly monitored in these patients.10 Patients with severe malaria necessitate intensive medical care to treat any dehydration, respiratory distress, and acidosis because they can decompensate quickly even when on proper antibiotic therapy.
The CDC stopped providing parenteral quinine in 1991,27 and, with the decreased use of quinidine as an antiarrhythmic agent, cases of poor outcomes including deaths have been reported due to a lack of available quinidine in hospital formularies.29,30 Clinicians with questions regarding the management of malarial infections can still call the CDC Malaria Hotline, however, during business hours at (770) 488–7788. After hours, the CDC Malaria Branch clinician can be contacted by calling (770) 488–7100.
Malarone can also be used for treatment of malaria and is at times indicated for presumptive self-treatment if the patient is far removed from laboratory services.22 However, this method of treatment is not advised if the patient is already taking Malarone for chemoprophylaxis, in which case four tablets of mefloquine (1,000 mg) could also serve as presumptive treatment. Malarone is dosed in these cases as four tablets (equivalent to 1,000 mg atovaquone and 400 mg proquanil) each day for 3 days. The patient should be advised that presumptive self-treatment is only a temporizing treatment and that they need to proceed to the nearest health facility immediately for further evaluation.
Patients diagnosed with either ovale or vivax infections should also be given Primaquine to eradicate the hypnozoite forms of these species. Patients should be tested for the G-6-PD deficiency before the administering of this drug. A 14-day treatment with Primaquine should begin after the symptomatic infection has been treated with an appropriate regimen.
Other drugs to note are Artesunate, Fansidar (sulfadoxine/pyrimethamine), and chloroquine/proguanil, because they sometimes will be taken by travelers who have symptoms while still overseas. Artesunate is a new anti-malarial agent originally developed in China and has been used extensively in other countries for the treatment of symptomatic malaria. Though not approved for treatment in the United States, research involving Artesunate is ongoing. Results thus far indicate Artesunate is excellent therapy for malaria infection when used in conjunction with other agents, especially in regions with high rates of multi–drug-resistant P falciparum, such as the Thai-Burmese border.4,31 Fansidar is a sulfa drug used in parts of Africa to treat pregnant women and children. Resistance to this drug is growing throughout the African continent and is already prominent in Southeast Asia and parts of South America.4 Fansidar is not part of the current malaria treatment protocols in the United States.
Mosquito Bite Prevention
Because no chemoprophylaxis is 100% effective in preventing malaria, mosquito bite prevention remains an important component of any strategy to reduce mosquito-borne disease transmission, not only of malaria but also other diseases such as West Nile and Dengue Fever32. Travelers to endemic areas should be encouraged to use proven methods to decrease mosquito bites. Individuals should wear long-sleeved clothing,27 especially when traveling through rural regions, and inspect their sleeping quarters for mosquitoes before going to sleep at night due to the nocturnal biting tendencies of the Anopheles mosquito. Popular devices such as ultrasonic wristbands have not been shown to keep away insects.33,34 However, current recommendations include the wearing of light-colored clothing because mosquitoes are attracted to darker colors.17
Chemical repellants that contain N,N-diethyl-m-toluamide (DEET) can be applied to skin and can dramatically reduce the number of mosquito bites.34,35 At least one study indicated that DEET applied only to the ankles and feet can reduce mosquito bites because Anopheles mosquitoes target the lower extremities.36 Permethrin-containing compounds can be applied to clothes, bed-nets, tents, and other equipment37–39 and serves to kill mosquitoes that contact it. When used together, DEET on all exposed skin and permethrin on the clothes appears to act synergistically to further increase bite protection compared with the use of one chemical or the other.40,41 Bed-nets treated with permethrin have been shown to be efficacious in preventing disease transmission,42–44 and all bed-nets should be inspected for holes before use.
Malaria is an important disease worldwide and has an increasing incidence among civilian travelers from the United States. North American clinicians need to be aware of this entity and use a high level of clinical suspicion to catch infections in their earliest stages. Travelers going to malaria-endemic regions need to be counseled about chemoprophylaxis and the importance of medication compliance, and physicians should be aware of different resistance patterns and species of parasites in the various geographic regions.
The author thanks Theresa Shapiro, MD, PhD, and R. Bradley Sack, MD, PhD, for their kindness in reviewing the manuscript and making editorial recommendations. Furthermore, the classification diagram in Figure 2 is the product of Dr. Shapiro and was used with permission.
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1. Talalay P, Beutler E. The role of Charles Ickes in the Army Malaria Research Project (personal communication). 2003:Baltimore, Maryland.
malaria; chemotherapy; mosquito; human immunodeficiency virus
© 2005 Southern Medical Association