Treatment of Malaria in the United States a Systematic Review

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CLINICAL REVIEW CLINICIAN’S CORNER

Treatment of Malaria in the United States A Systematic Review

Kevin S. Griffith, MD, MPH Context Many US clinicians and laboratory personnel are unfamiliar with the diag- Linda S. Lewis, DVM, MPVM nosis and treatment of malaria. Sonja Mali, MPH Objectives To examine the evidence base for management of uncomplicated and severe malaria and to provide clinicians with practical recommendations for the diag- Monica E. Parise, MD nosis and treatment of malaria in the United States. VEN THOUGH ENDEMIC MALARIA Evidence Acquisition Systematic MEDLINE search from 1966 to 2006 using the has been eliminated from the search term malaria (with the subheadings congenital, diagnosis, drug therapy, epi- United States, it remains a lead- demiology, and therapy). Additional references were obtained from searching the bib- ing infectious disease world- liographies of pertinent articles and by reviewing articles suggested by experts in the wide.E As a consequence, every year in treatment of malaria in North America. the United States an average 1200 cases Evidence Synthesis Important measures to reduce morbidity and mortality from of malaria are reported, almost all im- malaria in the United States include the following: obtaining a travel history, consid- ported, resulting in up to 13 deaths per ering malaria in the differential diagnosis of fever based on the travel history, and year.1 The unfamiliarity of US clini- prompt and accurate diagnosis and treatment. Chloroquine remains the treatment cians and laboratory personnel with ma- of choice for Plasmodium falciparum acquired in areas without chloroquine- resistant strains. In areas with chloroquine resistance, a combination of atovaquone laria and drug resistance patterns has and proguanil or quinine plus tetracycline or doxycycline or clindamycin are the best contributed to delays in diagnosis and treatment options. Chloroquine remains the treatment of choice for all other treatment, at times with adverse out- malaria species, with the exception of P vivax acquired in Indonesia or Papua New comes.2 Guinea, in which case atovaquone-proguanil is best, with mefloquine or quinine To address this problem, we pro- plus tetracycline or doxycycline as alternatives. Quinidine is currently the recom- vide clinicians with practical recommended treatment for severe malaria in the United States because the artemisinins mendations for the diagnosis and treat- are not yet available. Severe malaria occurs when a patient with asexual malaria ment of malaria in the United States, parasitemia, and no other confirmed cause of symptoms, has 1 or more designated clinical or laboratory findings. The only adjunctive measure recommended in severe based on published evidence; the Cen- malaria is exchange transfusion. ters for Disease Control and Preven- tion (CDC) experience in assisting US Conclusions Malaria remains a diagnostic and treatment challenge for US clinicians clinicians; and the available drugs and as increasing numbers of persons travel to and emigrate from malarious areas. A strong evidence base exists to help clinicians rapidly initiate appropriate therapy and mini- diagnostic modalities used in this mize the major mortality and morbidity burdens caused by this disease. country. JAMA. 2007;297:2264-2277 www.jama.com METHODS evance to this article, hand searched America. Recommendations are based We performed a systematic MEDLINE bibliographies of pertinent articles, and on randomized controlled trials, ob- search from 1966 to 2006 using the reviewed articles suggested by experts servational studies, and consensus ex- search term malaria (with the subhead- in the treatment of malaria in North pert opinion. ings congenital, diagnosis, drug therapy, epidemiology, and therapy). This search Author Affiliations: Malaria Branch, Division of Parasitic National Center for Zoonotic, Vector-Borne and Enteric Diseases, National Center for Zoonotic, Vector-Borne and Diseases, Centers for Disease Control and Prevention. was conducted on August 1, 2006, and Enteric Diseases, Coordinating Center for Infectious Dis- Corresponding Author: Monica E. Parise, MD, Para- resulted in 5588 potentially relevant ar- eases, Centers for Disease Control and Prevention, At- sitic Diseases Branch, Division of Parasitic Diseases, Na- ticles. We reviewed titles and/or ab- lanta, Ga (Drs Griffith and Parise and Ms Mali); and Butte tional Center for Zoonotic, Vector-Borne and Enteric County Department of Public Health, Oroville, Calif (Dr Diseases, Centers for Disease Control and Preven- stracts of all articles to determine rel- Lewis). Dr Griffith is now with the Bacterial Diseases Branch, tion, 4770 Buford Hwy NE MS F22, Atlanta, GA 30341 DivisionofVector-BorneInfectiousDiseases,NationalCen- ([email protected]). ter for Zoonotic, Vector-Borne and Enteric Diseases, Co- Clinical Review Section Editor: Michael S. Lauer, MD. CME available online at ordinating Center for Infectious Diseases, Centers for Dis- We encourage authors to submit papers for consid- www.jama.com ease Control and Prevention. Dr Parise is now with the eration as a Clinical Review. Please contact Michael Parasitic Diseases Branch, Division of Parasitic Diseases, S. Lauer, MD, at [email protected].

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BIOLOGICAL AND Plasmodium ovale may reactivate weeks Plasmodium ovale occurs mostly in West EPIDEMIOLOGIC or months after the initial infection, pro- Africa and is occasionally encountered CONSIDERATIONS ducing relapses. in Southeast Asia and Papua New In the Plasmodium life cycle (FIGURE 1), Of the 4 Plasmodium species that in- Guinea. Plasmodium malariae occurs at the asexual blood stages (rings, tropho- fect humans, Plasmodium falciparum is low frequency in a patchy distribution zoites, schizonts) are responsible for the the one with potential to rapidly progress worldwide. Plasmodium falciparum ac- symptoms of malaria, and thus are the to severe illness or death. It predomi- counts for slightly more than 50% and main target of chemotherapy. The nates in sub-Saharan Africa, Hispani- P vivax approximately 25% of reported sexual blood stages (gametocytes) do ola, and Papua New Guinea. Among the cases in the United States.1,2 not cause any known pathology and other species, P vivax is the most com- Chloroquine-resistant strains of P fal- thus are not a primary target of treat- mon3 and predominates in South Asia, ciparum occur in all endemic areas ex- ment. Dormant liver stage parasites Eastern Europe and Northern Asia, and cept Central America west of the Panama (hypnozoites) of Plasmodium vivax and Central and most of South America.4 Canal, Mexico, Hispaniola, and parts of

Figure 1. Plasmodium Life Cycle

Mosquito Stages Human Liver Stages Human Blood Stages

Exo-Erythrocytic Schizont Mosquito Injects Sporozoites

Erythrocyte Immature Ruptured Merozoites Trophozoite Exo-Erythrocytic Sporozoites Infected (Ring Stage) Schizont Migrate to Hepatocyte Salivary Glands Ruptured Schizont Ruptured Oocyst ASEXUAL STAGES

Hypnozoite Hypnozoites (Dormant Stage; Can Reactivate, P vivax, P ovale) Causing Relapses Oocyst in Midgut Mature Trophozoite Schizont

Ookinete (Motile Zygote) Amplification of Infection

Zygote SEXUAL STAGE

Gametes Gametocytes

Mosquito Ingests Gametocytes

The morphology of Plasmodium life cycle stages varies between species. Those shown in the illustration are Plasmodium falciparum, except for the hypnozoite, which occurs only in Plasmodium vivax and Plasmodium ovale. In P falciparum, the mature asexual stages (eg, schizonts) are sequestered in the microvasculature of vital organs due to cytoadherence of infected erythrocytes to the capillary endothelium and are rarely seen circulating in the peripheral blood. (Blood film photomicrograph insets: Giemsa stain; source: Division of Parasitic Diseases/Centers for Disease Control and Prevention).

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the disease. The typical incubation pe- Diagnostic confirmation is ob- Box. Manifestations riod usually varies between 9 and 18 days tained by microscopic demonstration of Severe Malaria* for P falciparum, P vivax, and P ovale12; of malaria parasites on Giemsa- Prostration it is longer (18-40 days) for P malariae stained thick and thin blood films, and may be as short as 7 days for P fal- which should be examined as soon as Impaired consciousness/coma ciparum.13 However, symptoms may oc- possible but within 12 hours of the pre- Respiratory distress (acidotic cur weeks or even months after expo- sentation of any patient with sus- breathing) sure as a result of inadequate prophylaxis pected malaria. Institutions unfamil- Multiple convulsions or treatment, immune response, or re- iar with malaria diagnosis should not Circulatory shock lapses. Some temperate strains of P vivax, delay microscopic diagnosis (eg, by Pulmonary edema such as the North Indian and North Ko- sending the films out to a laboratory Acute respiratory distress syndrome rean strains, can exhibit delayed pri- that cannot provide same-day re- Abnormal bleeding mary attacks, occurring 12 to 18 months sults), but should promptly refer the pa- after an infected mosquito bite.14 Of cases tient to a more experienced institu- Jaundice reported in the United States from 1995 tion or consult with more experienced Severe anemia to 2004, 98% (n=3626) of patients with personnel at other institutions, their Acute renal failure P falciparum malaria experienced their state department of health, or submit Disseminated intravascular first symptoms within the first 3 months digital images captured from stained coagulation of arrival in the United States, and 57% films directly to the CDC’s telediagno- Acidosis (n=1743) and 96% (n=2906) of pa- sis service ([email protected], or through Hemoglobinuria tients with non-falciparum malaria had the CDC Malaria Hotline or CDC Emer- symptom onset within the first 3 and 12 gency Operations Center [Malaria Hot- Parasitemia Ͼ5% months, respectively. During this same line 770-488-7788 Monday-Friday, 8 *Sources: WHO Management of Severe Ma- time period, 85% of patients with im- AM to 4:30 PM. Off-hours, weekends, laria (2000)21 and WHO Guidelines for the ported P falciparum malaria acquired and federal holidays, CDC clinicians Treatment of Malaria (2006).22 their infection in Africa. can be reached by calling the CDC Absence of a travel history does not Emergency Operations Center at 770- rule out malaria. Patients may provide 488-7100 and asking for the malaria cli- China and the Middle East, and multi- an inaccurate history or may have been nician on-call to be paged]). drug-resistant strains occur in South- infected in the United States through The parasite density (ie, percentage east Asia, South America, and sub- other rarely occurring mechanisms such of infected erythrocytes on a thin film) Saharan Africa. Due to increasing as transfusion, congenital transmis- should be quantified as 1 measure of the resistance of P falciparum to the drug sion, or local mosquito-borne trans- severity of the disease and its response combination of sulfadoxine and pyri- mission.1 to treatment, which should be closely methamine, the CDC no longer recom- The initial presentation of malaria monitored. If the initial film is nega- mends sulfadoxine-pyrimethamine for is nonspecific and similar to that of tive and the patient is suspected of hav- treatment of malaria in the United States many other febrile illnesses. Fever is ing malaria, blood films should be re- or as standby treatment for US travel- the most commonly reported symp- peated at 12- to 24-hour intervals for ers. A high prevalence of chloroquine- tom, being present in 78% to 100% of 48 to 72 hours. If the diagnosis is clini- resistant P vivax (CRPV) is found in case patients,2,15-18 but fever periodic- cally suspected and proficient labora- Papua New Guinea and Indonesia. Baird ity is often not seen.15,19,20 Patients tory diagnosis is impossible, empirical and Hoffman have written an excellent may experience a wide spectrum of treatment for P falciparum malaria, as review on CRPV (which details well its other symptoms including chills, discussed below, should be initiated, geographic distribution).5 There is evi- headache, malaise, nausea, vomiting, pending referral of the patient and/or dence for rates up to 25% in a few sites diarrhea, abdominal pain, myalgias, specimen. It is important that a differ- in Burma,6 Malaysia,7 Vietnam,8 India,9 back pain, weakness, dizziness, confu- ential identification of Babesia sp and Turkey.10,11 sion, cough, and/or coma. Spleno- (which may be morphologically simi- megaly is a frequent physical finding lar to P falciparum) be made during mi- RECOGNITION (24%-40% of case patients).15,16,18 croscopic examination. Although non- AND DIAGNOSIS Severe malaria is characterized by 1 or specific, thrombocytopenia, a low white Consideration of malaria based on travel more of the signs or symptoms shown blood cell count, and signs of hemoly- history is the key to diagnosis. Any pain the BOX. Severe malaria is almost in- sis, such as an elevated bilirubin level, tient who has been in an endemic area variably caused by P falciparum, with found during general laboratory test- in the year preceding the onset of ma- rare reports of severe malaria caused by ing are possible clues to the presence larial symptoms should be evaluated for P vivax.2,23-30 of malaria.

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In addition to microscopy, polymer- teriorate rapidly and progress to cline in one trial that directly com- ase chain reaction and rapid immuno- death within 1 to 2 days,32 and many pared the 2 regimens.52 chromatographic diagnostic tests31 are centers do not have the expertise to ad- Quinine has a rapid onset of action alternate diagnostic tools that are not equately triage (eg, to accurately quan- and, in combination with either tetracy- routinely available. Rapid immuno- tify the parasite density), the CDC ad- cline, doxycycline, or clindamycin, has chromatographic diagnostic tests are vises that patients infected with P been shown to be a very efficacious treat- not yet licensed for use in the United falciparum or an unidentified Plasmo- ment option for P falciparum infections States. Serological tests document past dium species should be initially admit- acquired in regions with chloroquine- exposure and are thus of limited use in ted to ensure that the medication is tol- resistant strains.52-73 For P falciparum in- acute case management. erated and the patient is improving fections acquired in Southeast Asia, a clinically and parasitologically. Blood 7-day course of both quinine and the ac- CLINICAL SITUATIONS AND films should be repeated to ensure clear- companying antibiotic is recom- RECOMMENDED TREATMENT ance of P falciparum parasitemia. Pa- mended54,59,60,63,64,69,70,73; for infections ac- General tients who are not responding clini- quired outside Southeast Asia, a 3-day To manage malaria successfully, treat- cally (with defervescence within 72 course of quinine and a 7-day course of ing physicians should seek the answer hours) need follow-up malaria blood the accompanying antibiotic is recom- to the following 5 questions: (1) What films and may also require a search for mended.52,53,66 The quinine and antibi- is the species? (2) What is the density other causes of fever. Of note, game- otic should be started at the same time of parasitemia? (3) What is the drug- tocytes may be less susceptible to many or should at least overlap by 2 days. Al- resistant pattern where the infection antimalarial drugs than are asexual though published treatment trials mainly was acquired? (4) Are there signs of se- parasites, and their persistence in the used quinine in combination with tet- vere malaria? and (5) Can the patient blood in the absence of asexual para- racycline, doxycycline has excellent an- tolerate oral medication? sites does not indicate drug resis- timalarial efficacy in chemoprophy- Patients with malaria should be tance. laxis trials and is considered an equally treated immediately because P falcipa- efficacious substitute.74-85 Tetracycline or rum infections can rapidly progress to Uncomplicated Falciparum Malaria doxycycline is generally preferred to clin- severe illness or death in as little as 1 For P falciparum malaria acquired in a damycin as the accompanying antibi- to 2 days.32 Immunity wanes in the limited number of areas (FIGURE 2),4 otic because of more extensive efficacy absence of continued antigen expo- chloroquine (with hydroxychloro- data and field experience. The quinine sure and thus semi-immune persons quine as a second-line alternative) re- and clindamycin regimen also has been who have left an endemic area for an mains the treatment of choice (Table). shown to be efficacious against P falci- extended period of time and then Chloroquine-resistant P falciparum parum infections acquired in areas with return are susceptible to severe disease strains are found in all other malari- chloroquine resistance† and is useful in and death. If the species cannot be ous areas, where 3 treatment options treatment of pregnant women and identified, the patient should be are currently recommended: (1) oral children younger than 8 years in whom treated as if infected with P falciparum quinine plus either tetracycline, doxy- tetracyclines and doxycycline are until the infecting species can be iden- cycline, or clindamycin; (2) atova- contraindicated. tified. The patient’s travel history pro- quone-proguanil; or (3) mefloquine. Quinine is commercially available in vides useful clues for selecting an The first 2 options are preferred due to the United States only as an oral medi- effective antimalarial drug, in terms of a higher rate of moderate to severe neu- cation. Cinchonism (a complex of symp- risk of drug resistance. Because base ropsychiatric reactions seen when mef- toms including nausea, vomiting, head- and salt conversions for antimalarial loquine is used at treatment doses35-50 ache, tinnitus, deafness, dizziness, and drugs are a source of confusion and compared with persons taking the drug visual disturbances) is common with qui- can result in treatment errors,33 where for prophylaxis. The incidence rate for nine or quinidine (the isomer of qui- pertinent, the base equivalency is fol- moderate or severe neuropsychiatric ad- nine) use. For example, tinnitus was re- lowed by the salt equivalency in verse reactions at mefloquine treat- ported in 13% to 94% of patients taking parentheses (TABLE). ment doses has been estimated to be 1 quinine in clinical trials,52,60,65,68,69,88 and There has been some controversy in 215 to 1 in 1754 treatments.39,50 None the syndrome of cinchonism was re- about the need for initial hospital ad- of the reported neuropsychiatric ad- ported in 94% of patients in another mission for all patients with P falcipa- verse reactions were lethal and most re- trial.63 Quinine binding to plasma pro- rum malaria, and some authors have solved spontaneously.* Atovaquone- teins, principally to ␣-1-glycoprotein, is tried to define triage criteria for which proguanil was better tolerated than the increased in malaria.89,90 This explains patients need to be admitted vs those combination of quinine and tetracy- why plasma quinine levels that have been who can be followed as outpatients.34 However, since these patients can de- *References 35, 37, 39, 41, 42, 46, 47, 50, 51. †References 55, 58, 61, 62, 65-69, 72, 86, 87.

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Table. Antimalarial Drugs Available in the United States Recommended for Use in the Treatment of Malaria Potential Adverse Drug Indication Adult Dosage Pediatric Dosage* Effects Comments Atovaquone- Plasmodium Adult tablet = 250 mg Pediatric tablet = 62.5 mg Abdominal pain, Not indicated for use in pregnant proguanil falciparum from atovaquone/100 mg atovaquone/25 mg nausea, vomiting, women due to limited data (oral) chloroquine- proguanil proguanil) diarrhea, Contraindicated if hypersensitivity to resistant areas 4 Adult tablets orally per 5-8 kg: 2 pediatric tablets headache, rash, atovaquone or proguanil; severe day ϫ 3d orally per day ϫ 3d mild reversible renal impairment (creatinine Ͼ8-10 kg: 3 pediatric tablets elevations in liver clearance Ͻ30 mL/min) orally per day ϫ 3d aminotransferase Should be taken with food to increase Ͼ10-20 kg: 1 adult tablet levels absorption of atovaquone orally per day ϫ 3d Ͼ20-30 kg: 2 adult tablets orally per day ϫ 3d Ͼ30-40 kg: 3 adult tablets orally per day ϫ 3d Ͼ40 kg: 4 adult tablets orally per day ϫ 3d Chloroquine P falciparum from 600-mg base (= 1000 mg 10-mg base/kg orally Nausea, vomiting, Safe in children and pregnant women phosphate chloroquine- salt) orally immediately, immediately, followed by rash, headache, Give for chemoprophylaxis (500 mg sensitive areas followed by 300-mg 5-mg base/kg orally at 6, dizziness, urticaria, salt orally every week) in pregnant P vivax from base (= 500 mg salt) 24, and 48 h abdominal pain, women with chloroquine-sensitive chloroquine- orally at 6, 24, and 48 h Total dose: 25-mg base/kg pruritus P vivax sensitive areas Total dose: 1500-mg base Contraindicated if retinal or visual field All P ovale;all (= 2500 mg salt) change; hypersensitivity to P malariae 4-aminoquinolines Use with caution in those with impaired liver function since the drug is concentrated in the liver Clindamycin P falciparum from Oral: 20-mg base/kg/d Oral: 20-mg base/kg/d orally Diarrhea, nausea, rash Always use in combination with (oral or IV) chloroquine- orally divided 3 times divided 3 times daily ϫ 7d quinine-quinidine resistant areas daily ϫ 7d IV: 10-mg base/kg loading Safe in children and pregnant women P vivax from IV: 10-mg base/kg loading dose IV followed by 5-mg chloroquine- dose IV followed by base/kg IV every 8 h; resistant areas 5-mg base/kg IV every 8 switch to oral clindamycin (in combination with h; switch to oral (oral dose as above) as quinine-quinidine) clindamycin (oral dose as soon as patient can take above) as soon as oral medication; treatment patient can take oral course = 7 d medication; treatment course=7d Doxycycline P falciparum from Oral: 100 mg orally twice Oral: 2.2 mg/kg orally every Nausea, vomiting, Always use in combination with (oral or IV) chloroquine- daily ϫ 7d 12 h ϫ 7d diarrhea, abdominal quinine-quinidine resistant areas IV: 100 mg IV every 12 h IV: IV only if patient is not able pain, dizziness, Contraindicated in children Ͻ8y, P vivax from and then switch to oral to take oral medication; for photosensitivity, pregnant women, and persons with chloroquine- doxycycline (as above) children Ͻ45 kg, give 2.2 headache, known hypersensitivity to resistant areas (in as soon as patient can mg/kg IV every 12 h and esophagitis, tetracyclines combination with take oral medication; then switch to oral odynophagia While food, milk, and divalent and quinine-quinidine) treatment course = 7 d doxycycline (dose as Rarely hepatotoxicity, trivalent cations decrease the above) as soon as patient pancreatitis, and absorption of tetracycline, can take oral medication; benign intracranial doxycycline can be taken with food, for children Ն45 kg, hypertension seen including milk products, which use same dosing with tetracycline helps to decrease gastrointestinal as for adults; treatment class of drugs disturbances course = 7 d To prevent esophagitis, the tetracyclines should be taken with large amounts of fluids, and patients should not lie down for 1 h after taking the drugs Concurrent treatment with barbiturates, carbamazepine, or phenytoin may cause a reduction in serum concentrations of doxycycline Hydroxychlo- Second-line alternative 620-mg base (= 800 mg 10-mg base/kg orally Nausea, vomiting, Safe in children and pregnant roquine for treatment of: salt) orally immediately, immediately, followed by rash, headache, women (oral) P falciparum from followed by 310-mg 5-mg base/kg orally at 6, dizziness, urticaria, Give for chemoprophylaxis (310-mg chloroquine- base (= 400 mg salt) 24, and 48 h abdominal pain, base orally every week) in pregnant sensitive areas orally at 6, 24, and 48 h Total dose: 25-mg base/kg pruritus† women with chloroquine-sensitive P vivax from Total dose: 1550-mg base P vivax chloroquine- (= 2000 mg salt) Contraindicated if retinal or visual field sensitive areas change; hypersensitivity to All P ovale;all 4-aminoquinolines P malariae Use with caution in those with impaired liver function (continued)

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Table. Antimalarial Drugs Available in the United States Recommended for Use in the Treatment of Malaria (cont) Drug Indication Adult Dosage Pediatric Dosage* Potential Adverse Effects Comments Mefloquine‡ P falciparum from 684-mg base (= 750 mg salt) orally 13.7-mg base/kg Gastrointestinal complaints Contraindicated if hypersensitive to chloroquine- as initial dose, followed by (= 15 mg salt/kg) (nausea, vomiting, diarrhea, thedrugortorelated resistant areas, 456-mg base (= 500 mg salt) orally as initial abdominal pain), mild compounds; cardiac conduction except orally given 6-12 h after dose, followed by neuropsychiatric complaints abnormalities; psychiatric Thailand- initial dose 9.1-mg base/kg (dizziness, headache, disorders; and seizure disorders Burmese and Total dose = 1250 mg salt (= 10 mg salt/kg) somnolence, sleep disorders), Do not administer if patient has Thailand- orally given 6-12 h myalgia, mild skin rash, and received related drugs Cambodian after initial dose fatigue; moderate to severe (chloroquine, quinine, quinidine) border regions Total dose = 25 mg neuropsychiatric reactions, less than 12 h ago P vivax from salt/kg electrocardiographic changes, May be used for chemoprophylaxis chloroquine- including sinus arrhythmia, (250 mg salt orally every week) in resistant areas sinus bradycardia, first degree pregnant women with atrioventricular block, chloroquine-resistant P vivax prolongation of QTc interval, and abnormal T waves Primaquine Radical cure of 30-mg base orally per day ϫ 14 d 0.5-mg base/kg Gastrointestinal disturbances, Must screen for G6PD deficiency phosphate P vivax and orally per day ϫ methemoglobinemia prior to use P ovale (to 14 d (self-limited), hemolysis in Contraindicated in persons with eliminate persons with G6PD deficiency G6PD deficiency; pregnant hypnozoites) women Should be taken with food to minimize gastrointestinal adverse effects Quinine sulfate P falciparum from 542-mg base (= 650 mg salt)§ 8.3-mg base/kg Cinchonism,࿣ sinus arrhythmia, Combine with tetracycline, (oral) chloroquine- orally 3 times daily ϫ 3d (= 10 mg salt/kg) junctional rhythms, doxycycline, or clindamycin, resistant areas (infections acquired outside orally 3 times daily atrioventricular block, except for P vivax infections in P vivax from Southeast Asia) to 7 d ϫ 3 d (infections prolonged QT interval, children Ͻ8 y or pregnant women chloroquine- (infections acquired in acquired outside ventricular tachycardia, Contraindicated in hypersensitivity resistant areas Southeast Asia) Southeast Asia) to ventricular fibrillation (these including history of blackwater 7 d (infections are rare and more commonly fever, thrombocytopenic purpura, acquired in seen with quinidine), or thrombocytopenia associated Southeast Asia) hypoglycemia with quinine or quinidine use; many cardiac conduction defects and arrhythmias¶; myasthenia gravis; optic neuritis Quinidine Severe malaria 6.25-mg base/kg (= 10 mg salt/kg) Same as adult Cinchonism, tachycardia, Combine with tetracycline, gluconate (all species, loading dose IV over 1-2 h, then prolongation QRS and QTc doxycycline, or clindamycin (IV) independently of 0.0125-mg base/kg/min (= 0.02 intervals, flattening of T-wave Contraindicated in hypersensitivity; chloroquine mg salt/kg/min) continuous (effects are often transient) history of blackwater fever resistance) infusion for at least 24 h Ventricular arrhythmias, including history of blackwater Patient unable to Alternative regimen: 15-mg base/kg hypotension, hypoglycemia fever, thrombocytopenic purpura take oral (= 24 mg salt/kg) loading dose IV or thrombocytopenia associated medication infused over 4 h, followed by with quinine or quinidine use; Parasitemia Ͼ10% 7.5-mg base/kg (= 12 mg many cardiac conduction defects salt/kg) infused over 4 h every and arrhythmias#; myasthenia 8 h, starting 8 h after the loading gravis; optic neuritis dose (see package insert); once parasite density Ͻ1% and patient can take oral medication, complete treatment with oral quinine, dose as above Quinidine-quinine course=7din Southeast Asia (3 d in Africa or South America) Tetracycline P falciparum from Oral: 250 mg orally 4 times daily ϫ 25 mg/kg/d orally See doxycycline See doxycycline (oral or IV) chloroquine- 7d divided 4 times resistant areas IV: dosage same as for oral daily ϫ 7d P vivax from IV: dosage same as chloroquine- for oral resistant areas (in combination with quinine- quinidine) Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous. *Pediatric dosage should never exceed adult dosage. †Extrapolated from chloroquine literature. ‡Mefloquine should not be used to treat P falciparum infections acquired in the following areas: borders of Thailand with Burma (Myanmar) and Cambodia, western provinces of Cam- bodia, eastern states of Burma (Myanmar), border between Burma and China, Laos along borders of Laos and Burma (and adjacent parts of Thailand-Cambodia border), and southern Vietnam due to resistant strains. §Quinine sulfate capsule manufactured in the United States is in a 324-mg dose; therefore, 2 capsules should be sufficient for adult dosing. ࿣Nausea, vomiting, headache, tinnitus, deafness, dizziness, and visual disturbances. ¶Refer to quinine sulfate, package insert (Mutual Pharmaceutical Inc, Philadelphia, Pa, August 2005). #Refer to quinidine gluconate, package insert (Eli Lilly Co, Indianapolis, Ind, February 2002).

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Figure 2. Malaria Treatment Algorithm

History of Travel to Malaria-Endemic Area or Clinical Suspicion of Malaria

Perform Thick and Thin Blood Films and Read in <12 h

No Blood Film Yes Positive?

Repeat Blood Films Every 12 to 24 h for 48 to 72 h

No Blood Film Yes Positive? Calculate Parasite Density

Consider Alternate Diagnosis Evaluate Clinical Status and Disease Severity

Uncomplicated Malaria Severe Malaria and/or Patient Unable to Take Oral Medication Determine Infecting Species Using Blood Film

Non-Falciparum Species Plasmodium falciparum or Species Not Yet Identified∗ Regardless of Infecting Species or Geographic Region of Acquisition

Plasmodium malariae Plasmodium ovale or P vivax Acquired in Acquired in Chloroquine- Acquired in Chloroquine- Plasmodium vivax Papua New Guinea Sensitive Area† Resistant Area‡ Acquired Outside or Indonesia Papua New Guinea or Indonesia

Chloroquine Chloroquine Atovaquone-Proguanil Chloroquine Oral Quinine Plus Intravenous Quinidine Plus (Second-Line (Second-Line Alternatives: (Second-Line Tetracycline,§ or Tetracycline,§ Treatment: Treatment: Quinine Plus Treatment: Doxycycline,§ or Doxycycline,§ or Clindamycin Hydroxychloroquine)|| Hydroxychloroquine)|| Tetracycline,§ or Hydroxychloroquine)|| Clindamycin Doxycycline,§ or Admit to Intensive Care Unit or Atovaquone-Proguanil Monitor Cardiac Function Mefloquine or Continuously and Monitor Mefloquine If Above Blood Pressure Frequently Not Available Monitor Parasitemia, Glucose, Hemoglobin, and Electrolytes Periodically Primaquine If Not G6PD Deficient Admit to Hospital Prevent and Treat Complications If G6PD Deficient, Counsel About Monitor Symptoms Daily Possibility of Recurrence Consider Exchange Transfusion Repeat Blood Films Daily Until If Parasite Density >10% Negative or If Discharged Prior to or If Patient Has Altered a Negative Film, at Day 7 Mental Status, Nonvolume Overload Pulmonary Edema, or Renal Complications Switch to Oral Antimalarial Repeat Blood Films If Symptoms Recur Medication When Possible

*If species not yet identified is subsequently diagnosed as a non-falciparum infection, then complete treatment as per the identified species recommendations. G6PD indicates glucose-6-phosphate dehydrogenase. †Central America west of the Panama Canal, Mexico, Hispaniola, parts of China, and the Middle East. ‡All malaria- endemic countries except those listed in second footnote. §Contraindicated in pregnant women and children younger than 8 years of age. ࿣Drug options for chloroquine- resistant P falciparum may also be used if chloroquine or hydroxychloroquine cannot be used.

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associated with blindness and deafness of the related compound to minimize the prevent potential relapses. To achieve after self-poisoning, and which are risk of adverse events such as electro- more reliable eradication of hypnozo- common during the treatment of malaria, cardiographic abnormalities.119,120 ites, the CDC now recommends a regi- extremely rarely cause such adverse Antimalarial drugs that are not rec- men of 0.5 mg/kg to a maximum of 30 effects in patients with malaria.91,92 Life- ommended, even though they may be mg of primaquine base daily for 14 days. threatening toxicity is rare and the symp- available in other countries, include sul- The most common severe adverse effect toms of cinchonism are rarely sufficient fadoxine-pyrimethamine, amodia- associated with primaquine is intravas- to warrant discontinuing quinine or quine, and halofantrine because of re- cular hemolysis in persons with glucose- quinidine treatment.93 sistance and/or toxicity problems. 6-phosphate dehydrogenase (G6PD) de- The tetracyclines (tetracycline and ficiency, a contraindication to the use of doxycycline) and clindamycin should Uncomplicated Non-Falciparum this drug. Patients must be screened for always be used in combination with a Malaria G6PD prior to use of primaquine. Pri- faster-acting antimalarial drug such as Chloroquine remains the treatment of maquine treatment should, if possible, quinine and never as monotherapy. choice for all P malariae and P ovale in- overlap with the blood schizonticidal Atovaquone-proguanil has reported fections and for P vivax infections ac- treatment.138-140 cure rates of 94% to 100% for P falcipa- quired outside Papua New Guinea and Patients who are not able to take pri- rum infections acquired in Southeast Indonesia; hydroxychloroquine is a maquine should be counseled on the pos- Asia, Africa, and South America.52,94-109 second-line alternative. Currently, there sibility of having a relapsing infection (es- To date, there have been 12 published are limited data on optimal treatment op- timated to be approximately 20% [range, cases of atovaquone-proguanil failure for tions for P vivax infections acquired in 5%-80%])5 and the need to seek treat- the treatment of P falciparum malaria areas with highly prevalent chloroquine ment if similar symptoms recur. An- (from East, West, and Central Africa), resistance (Papua New Guinea and In- other potential option for patients un- 7 of which have had isolates with ge- donesia). The best option may be able to take primaquine who are netically confirmed markers of resis- atovaquone-proguanil, with mefloquine experiencing frequent relapses is chlo- tance (ie, mutations in the cytochrome or quinine plus tetracycline or doxycy- roquine (or mefloquine, in the case of b gene),110-117 and thus, clinicians should cline as alternatives. Both quinine (3 CRPV) prophylaxis for the period of time remain aware of the rare possibility of days) and either tetracycline or doxycy- that relapses are most likely to occur (ie, atovaquone-proguanil treatment failures. cline (7 days)121-128 and mefloquine129-135 a few years). Although atovaquone- Mefloquine should not be used to have been historically used successfully proguanil has “causal prophylactic ac- treat P falciparum infections acquired on in case reports or small case series. More tivity” (ie, the ability to prevent blood the borders of Thailand with Burma recently, both atovaquone-proguanil, in stage infection by killing developing liver (Myanmar) and Cambodia, in the west- a relatively small study,99 and mefloquine stage parasites), it does not appear to ern provinces of Cambodia, in the east- (at 15 mg/kg)136 have effectively treated eradicate hypnozoites101,102 and may not ern states of Burma (Myanmar), on the P vivax malaria in Indonesia, where high prevent the establishment of hypnozo- border between Burma and China, in rates of CRPV exist. Of note, although ites.141,142 Thus, patients with P vivax or Laos along the borders of Laos and initial studies of atovaquone-proguanil P ovale malaria who have been treated Burma and the adjacent parts of the showed high (68%) rates of recurrent with atovaquone-proguanil also need pri- Thailand Cambodia border, as well as parasitemiabefore28daysoffollow-up101 maquine. Although a modified regimen in southern Vietnam, because of re- (some of which may have been relapses), of 45 mg (base) of primaquine weekly ports of a high prevalence of mefloquine- subsequent (albeit small) studies have for 8 weeks has been suggested as an al- resistant P falciparum in these areas.118 demonstrated excellent efficacy (Ͼ95%) ternative for patients with mild G6PD de- Although mefloquine is contraindi- of atovaquone-proguanil against P vivax ficiency,143,144 the data on both safety and cated for chemoprophylactic use in per- malaria.99,137 Data are too limited to rec- efficacy of such a regimen are very lim- sons with active or recent history of de- ommendquinine-clindamycin69 forfirst- ited. Primaquine for “radical cure” (ie, pression, generalized anxiety disorder, line treatment of P vivax, including primaquine used in conjunction with an psychosis, or other major psychiatric dis- CRPV, infections. Baird and colleagues effective blood schizonticide for the treat- order, or in persons with a history of sei- demonstrated 85% efficacy of chloro- ment of a patient with P vivax or P ovale zures, it can be used for treatment in per- quine and high-dose (2.5 mg/kg base malaria) in a known G6PD-deficient in- sons with these conditions if the benefits over 3 days) primaquine for treatment dividual should be used only after a care- are judged to outweigh the risks.119 If re- of CRPV.138 The CDC has not recom- ful risk/benefit assessment and under lated compounds (chloroquine, qui- mended this regimen due to relative in- strict medical supervision.140 nine, or quinidine) have been given for experience with high-dose primaquine chemoprophylaxis or initial treatment, and suboptimal efficacy. Severe Malaria mefloquine administration should be de- Infections with P vivax and P ovale The single most important step in the layed at least 12 hours after the last dose should be treated with primaquine to management of severe malaria is im-

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mediate initiation of appropriate par- received more than 40 mg/kg quinine duction of toxic byproducts, and/or enteral treatment. In the United States, in the previous 2 days or has received improved rheology with transfused the only parenteral drug currently avail- mefloquine in the previous 12 hours (in cells.161,162 The technical aspects of ex- able is quinidine gluconate. Blood films which case the loading dose is not given change transfusion have been dis- should be examined every 12 hours un- but a continuous quinidine infusion is cussed in an excellent review by Pow- til negative for malaria parasites.91 Para- still administered).93 The quinidine in- ell and Grima.162 However, exchange site density typically decreases by 90% fusion should be temporarily slowed or transfusion and its indications will re- over the first 48 hours with quinine or stopped if the QT interval increases to main controversial until a carefully con- quinidine therapy.145-149 If parasitemia greater than 0.6 seconds, the QRS com- trolled, adequately powered compara- has not decreased as expected, poten- plex increases greater than 50%, the tive study is conducted, an unlikely tial causes of the problem should be in- QTc interval is prolonged by more than probability.163,164 In the decision to use vestigated (eg, by checking the quini- 25% of the baseline value, or if hypo- exchange transfusion, the potential risks dine level). Quinidine levels should be tension unresponsive to fluid chal- of exchange transfusion, including fluid maintained in the range of 3 to 8 lenge develops.150,155 If significant elec- overload, febrile and allergic reac- mg/L.91,150 trocardiographic changes persist or tions, metabolic disturbances, red blood Quinidine is more cardiotoxic than malignant arrhythmias develop, phy- cell alloantibody sensitization, trans- quinine and should be administered in sicians should treat the arrhythmias and missible infection, cerebral hemor- an intensive care unit with continu- consider expert consultation through rhage, and line sepsis, must be weighed ous electrocardiographic and frequent the CDC Malaria Hotline or other tropi- against potential benefits.163 The CDC blood pressure monitoring.145 Quini- cal medicine experts. Options in such recommends that exchange transfu- dine-related cardiovascular adverse ef- severe situations may include admin- sion be strongly considered for per- fects are potentially serious and may be istration of alternative antimalarial sons with a parasitemia higher than 10% more frequent if the drug is adminis- drugs via nasogastric tube along with or if complications such as cerebral ma- tered rapidly.151 The risk of cardiotox- exchange transfusion. Quinidine con- laria, nonvolume overload pulmonary icity is increased with bradycardia, hy- tinuous infusion should be continued edema, or renal compromise exist.150 pokalemia, and hypomagnesemia152 and during exchange transfusion. Various adjunctive treatments ap- if the patient has received other drugs Initial (including loading) doses of pear in the literature that are either un- that may prolong the QTc interval (eg, parenteral quinine or quinidine need proven or are harmful in the treat- quinine, mefloquine, or macrolide not be reduced in persons with renal ment of severe malaria and are not antibiotics). failure. The pharmacokinetic proper- currently recommended. They in- Because newer antiarrhythmic agents ties of the cinchona alkaloids are al- clude phenobarbital for prophylaxis of have displaced quinidine gluconate, tered in malaria, with a contraction in seizures165-167; dexamethasone for treat- quinidine is often not stocked in many the volume of distribution that is pro- ment of cerebral malaria156,168,169; hep- hospitals.152-154 Hospital drug services portional to the severity of malarial ill- arin for treatment of thrombocytope- should maintain or add quinidine glu- ness.91,157 If renal failure persists or the nia and/or fibrinogenemia170-176; iron conate to their formularies. If they do patient’s clinical condition does not im- chelators that aim to reduce parasite not stock the drug, they must be able prove, the maintenance dosage should clearance time125,177,178; pentoxifylline for to immediately locate a nearby source. be reduced by one third to one half on inhibition of tumor necrosis factor syn- Otherwise, the hospital should con- the third treatment day.91 thesis179; and dichloroacetate for treat- tact their local or regional distributor The artemisinin derivatives clear ment of metabolic acidosis.180 to request the drug or contact the Eli parasites very rapidly, are now a key Potential complications of severe Lilly Co directly (telephone: 1-800- component of malaria treatment world- malaria181 should be recognized and 821-0538).152 Assistance from the com- wide, and have been shown to reduce treated. Hypoglycemia may be masked pany to arrange a rapid shipment of the mortality in severe malaria compared by the manifestations of cerebral drug is available between the hours of with parenteral quinine.158 These drugs malaria, and thus frequent plasma glu- 6 AM and 6 PM. If further assistance is are not yet available in the United States, cose determination is essential. Severe needed in managing patients with ma- but the CDC hopes to make intrave- and recurrent hypoglycemia may be laria, health care professionals can con- nous artesunate available under an In- caused by hyperinsulinemia induced tact the CDC Malaria Hotline. vestigational New Drug protocol in by quinine or quinidine or by endo- Because most deaths from severe ma- 2007. toxin or by parasite consumption.182,183 laria occur within the first 24 to 48 Exchange transfusion has been used Hyperpyrexia can be treated with ace- hours of treatment, an initial loading in the treatment of severe malaria since tominophen; nonsteroidal anti- dose of quinidine is recommended to 1974 with apparent benefit,145,159,160 po- inflammatory drugs are not recom- achieve therapeutic levels as rapidly as tentially due to rapid reduction of para- mended, given the frequency of possible145,155,156 unless the patient has sitemia by direct parasite removal, re- thrombocytopenia and coagulation

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abnormalities. Pulmonary edema may sultation with their clinician, to take birth weight, congenital infection, be due to either fluid overload or adult along a dose of antimalarial medica- and/or neonatal death. For uncompli- respiratory distress syndrome and can tion for self-treatment. The only drug cated P falciparum infections acquired be minimized by keeping patients recommended for self-treatment for US in regions with chloroquine-resistant euvolemic. Acute renal failure is gen- travelers is atovaquone-proguanil. It strains, quinine plus clindamycin has erally oliguric. With dialysis, renal should not be used in patients on atova- been shown to be safe and efficacious function can be expected to return quone-proguanil prophylaxis because of and is recommended.65 Concerns that after a median of 4 days, although the risk of breakthrough parasitemia due quinine may cause fetal toxicity or in- some patients may require dialysis for to a resistant organism in those pa- duce labor when given late in preg- 2 to 3 weeks.184 Thrombocytopenia is tients. In such cases, specialized tropi- nancy have not been substantiated at common in severe malaria. Laboratory cal medicine consultation should be the doses used for treatment of ma- evidence of activated coagulation is sought. Quinine-doxycycline is a sub- laria.198 An important adverse effect of more common than is disseminated optimal alternative due to potential ad- quinine in pregnant patients is hyper- intravascular coagulation with bleed- verse drug reactions and the complex- insulinemia, which can precipitate or ing.181,185,186 Hyponatremia,187 hypocal- ity of the regimen. Travelers should be worsen hypoglycemia.198 Late in preg- cemia, hypophosphatemia and hyper- advised that self-treatment of a pos- nancy, quinine is distributed to the fe- phosphatemia, and hypomagnesemia sible malaria infection is only a tempo- tus, raising concerns about quinine trig- and hypermagnesemia188 have all been rary measure and that prompt medical gering insulin release and resulting in reported in patients with P falciparum evaluation is imperative.4 fetal hypoglycemia.182 However, the malaria.181 risks of untreated falciparum malaria In patients with suspected cerebral Malaria in Children during pregnancy outweigh the poten- malaria, a lumbar puncture should be Tetracycline and doxycycline have a tial risk of adverse drug effects from qui- performed to rule out bacterial menin- relative contraindication for use in in- nine or quinidine. gitis,157 and magnetic resonance imaging fants and children younger than 8 years Atovaquone-proguanil or meflo- or computed tomographic scans should of age due to reports of drug deposi- quine are not currently recommended for be performed to rule out intracerebral tion in calcifying areas of bones and treatment in pregnancy and should only bleeding, cerebral edema, and cerebral/ teeth that result in permanent tooth be used if quinine plus clindamycin or medullary herniation. Most survivors staining, enamel hypoplasia, and de- quinine monotherapy is not available or with cerebral malaria regain conscious- creased linear skeletal growth rate190,191; is not being tolerated. Tetracycline and ness within 2 to 3 days, although it may clindamycin in combination with qui- doxycycline are contraindicated. Al- occasionally take more than a week.189 nine should be used instead. While the though 2 recent studies of the atova- US package insert recommends meflo- quone-proguanil and artesunate combi- Induced Malaria quine for use in children older than 6 nation treatment for P falciparum Because malaria acquired through months of age,119 the drug is generally infections in pregnant women showed bloodborne transmission (eg, blood well tolerated in children weighing the regimen to be well-tolerated with no transfusion or organ transplantation) more than 5 kg,192-195 with vomiting as evidence of toxicity to the mother or fe- has no exoerythrocytic stage, prima- the principal adverse effect.192-196 Al- tus,199,200 further study is needed before quine treatment is not needed in in- though few studies document the safety atovaquone-proguanil can be recom- duced P vivax or P ovale infections. and tolerability of primaquine in chil- mended for use during pregnancy. dren, the drug has been used for more Because primaquine can potentially Self-treatment than 50 years with no apparent safety cause hemolytic disease in a G6PD- The CDC recommends the use of ma- problems. There is no evidence to sug- deficient fetus, primaquine is contra- laria prophylaxis, rather than self- gest that the drug cannot be used in indicated in pregnancy. Pregnant treatment, for travelers to malarious children of any age who do not have women treated for P ovale and P vivax areas. However, travelers who elect not G6PD deficiency.140 Neither the Ameri- infections should also receive chemo- to take prophylaxis, who do not choose can Academy of Pediatrics nor US4 or prophylaxis until delivery. The pro- an optimal drug regimen (eg, chloro- Canadian197 public health authorities list phylaxis regimen should consist of quine for travel to an area with chloro- a lower age limit for primaquine use. either chloroquine, 300-mg base (=500 quine-resistant P falciparum malaria), or mg salt) orally once per week; or, for those who require a less than optimal Malaria in Pregnant Women P vivax infections acquired in areas with drug regimen are at greater risk for ac- Malaria infection in pregnant women chloroquine-resistant strains, meflo- quiring malaria and needing prompt is associated with high risks of both maquine 228-mg base (=250 mg salt) treatment. Travelers who are taking ef- ternal and perinatal morbidity and mor- orally once per week. While meflo- fective prophylaxis but who will be in tality, including spontaneous abor- quine is not recommended for malaria very remote areas may decide, in con- tion, stillbirth, premature delivery, low treatment during pregnancy,201 sev-

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eral studies support its safety as che- drug, were substantial contributing fac- Malaria, Principles and Practice of Malariology, Vol- 202-206 2 ume 2. Edinburgh, Scotland: Churchill Livingstone; moprophylaxis during pregnancy. tors in malaria deaths. Clinicians must 1988:927. After delivery, women should be treated remain alert to the possibility of this dis- 14. Garnham P. Malaria parasites of man: life-cycles and morphology. In: Wernsdorfer WH, McGregor I, with primaquine as recommended for ease and take immediate measures to- eds. Malaria: Principles and Practice of Malariology, nonpregnant adult patients. ward prompt accurate diagnosis and Volume 1. London, England: Churchill Livingstone; treatment. 1988:69. Congenital Malaria 15. Dorsey G, Gandhi M, Oyugi JH, Rosenthal PJ. Dif- Author Contributions: Drs Griffith, Lewis, and Parise ficulties in the prevention, diagnosis, and treatment There are approximately 2 cases of con- had full access to all of the data in the study and take of imported malaria. Arch Intern Med. 2000;160:2505- genital malaria reported in the United responsibility for the integrity of the data and the ac- 2510. curacy of the data analysis. 16. Moore TA, Tomayko JF Jr, Wierman AM, Ren- States annually. Infants typically pre- Study concept and design: Griffith, Lewis, Parise. simer ER, White AC Jr. Imported malaria in the 1990s: sent at 1 to 2 months of age with fever, Acquisition of data: Griffith, Lewis, Mali, Parise. a report of 59 cases from Houston, Tex. Arch Fam Med. Analysis and interpretation of data: Griffith, Lewis, 1994;3:130-136. anemia, failure to thrive, and spleno- Parise. 17. Singh K, Wester WC, Trenholme GM. Problems megaly. As with induced malaria, there Drafting of the manuscript: Griffith, Lewis, Parise. in the therapy for imported malaria in the United States. Critical revision of the manuscript for important in- Arch Intern Med. 2003;163:2027-2030. is no exoerythrocytic phase and thus no tellectual content: Griffith, Lewis, Mali, Parise. 18. Svenson JE, MacLean JD, Gyorkos TW, Key- need for primaquine treatment in P Administrative, technical, or material support: Griffith, stone J. Imported malaria: clinical presentation and ex- Lewis, Mali. amination of symptomatic travelers. Arch Intern Med. vivax or P ovale congenital infections. Study supervision: Parise. 1995;155:861-868. For mothers who are parasitemic either Financial Disclosures: None reported. 19. Lynk A, Gold R. Review of 40 children with during pregnancy or at delivery, clini- Disclaimer: The findings and conclusions in this re- imported malaria. Pediatr Infect Dis J. 1989;8:745- port are those of the authors and do not necessarily 750. cians should judge management of the represent the views of the Centers for Disease Con- 20. McCaslin RI, Pikis A, Rodriguez WJ. Pediatric Plas- infant in each case individually, factor- trol and Prevention. modium falciparium malaria: a ten-year experience Acknowledgment: We thank Phuc Nguyen-Dinh, MD, from Washington, DC. Pediatr Infect Dis J. 1994;13: ing in such issues as reliability of fol- MPH, Malaria Branch, Division of Parasitic Diseases, 709-715. low-up and access to medical care. In Centers for Disease Control and Prevention (retired 21. World Health Organization. WHO Guidelines for in February 2007), for his thorough review and criti- the Treatment of Malaria. Geneva, Switzerland: WHO some cases it may be appropriate to sim- cal comments on the manuscript. He did not receive Press; 2000. ply educate the mother about the risk any compensation for his contribution. 22. 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