TRAVEL MEDICINE INVITED ARTICLE Charles D. Ericsson and Robert Steffen, Section Editors

Diagnosis and Treatment of in Children

William Stauffer1,2 and Philip R. Fischer3 1Division of Infectious Disease and International Medicine, Department of Medicine, University of Minnesota, and 2Regions Hospital/HealthPartners, Center for International Health and International Travel Clinic, St. Paul, and 3Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021

Malaria continues to be a problem for children returning or immigrating to industrialized countries from tropical regions. Proper diagnosis begins with clinical suspicion. In nonimmune children, malaria typically presents with high fever that might be accompanied by chills and headache. Symptoms and signs may be more subtle in partially immune children, and anemia and hepatosplenomegaly may also be present. Children may present with respiratory distress and/or rapidly progressing cerebral malaria that manifests as altered sensorium and, sometimes, seizures. Thick blood smears help to determine when infection is present, but a single smear without parasites is not sufficient to rule out malaria. Thin blood smears aid in identifying the species of parasite. Treatment must include careful supportive care, and intensive care measures should be available for treating children with complicated falciparum malaria. Medical regimens can include mefloquine, atovaquone-, sulfadoxine-pyrimethamine, quinine or quinidine, clindamycin, doxycy- cline, chloroquine, and primaquine.

Malaria is a devastating infection that annually affects 1300 MALARIA PARASITE LIFE CYCLE million people worldwide, resulting in 13000 pediatric deaths AND EPIDEMIOLOGY per day [1–3]. In fact, malaria is the leading cause of mortality The 4 Plasmodium species that infect humans (Plasmodium among children !5 years of age in Africa and is the cause of falciparum, vivax, ovale, and malariae) are usually transmitted ∼20% of all-cause mortality in this age group [1]. Despite the by anopheline mosquitoes. Both P. vivax and P. ovale can be- availability of good preventive measures [4], 110,000 cases of come dormant in the liver, forming hypnozoites that may malaria were reported in US civilian travelers during 1985– emerge months to years after initial infection to cause disease. 2001 [5]. Furthermore, an estimated 20% of cases of malaria Infection caused by P. falciparum is associated with the greatest imported to the United States and Europe occur in patients morbidity and mortality. The clinical severity of P. falciparum !18 years of age [6–9]. In areas where malaria is not endemic, malaria is highly dependent on the malaria-specific immune medical practitioners are frequently unfamiliar with the disease, status of the infected individual. and delays in diagnosis and treatment are common [10–12]. Given the life-threatening potential of this illness, increased awareness and knowledge of proper management is necessary. CLINICAL PRESENTATION Here, we provide a brief overview of the current approach to the diagnosis and treatment of malaria, with special attention It has been reported that 160% of malaria is misdiagnosed at to treatment of patients who, after recent travel or migration, initial presentation in areas where malaria is not endemic [11]. present with malaria in an area where malaria is not endemic. Furthermore, up to 80% of malaria-related deaths in the United States have been deemed preventable and have been attributed to inappropriate chemoprophylaxis, delay in diagnosis, or in-

Received 6 May 2003; accepted 9 July 2003; electronically published 17 October 2003. appropriate treatment [7]. Clinicians should routinely obtain Reprints or correspondence: Dr. Philip R. Fischer, Dept. of Pediatric and Adolescent Medicine, a relevant travel history from the caretakers of any ill child. Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (fi[email protected]). Malaria is, however, occasionally transmitted by mosquitoes in Clinical Infectious Diseases 2003;37:1340–8 areas where it is not endemic [13], as well as through blood 2003 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2003/3710-0010$15.00 transfusions [14] or transplacentally [15], and the lack of his-

1340 • CID 2003:37 (15 November) • TRAVEL MEDICINE tory of travel to an area where malaria is endemic does not may have minimal symptoms and malaria blood smears are exclude the diagnosis. frequently falsely negative. Malaria should be considered and the diagnosis diligently pursued under these circumstances.

GENERAL PRESENTATION COMPLICATED P. FALCIPARUM MALARIA Patients with P. falciparum malaria present with high fever that may be accompanied by chills, rigors, sweats, and headache. Many factors influence a patient’s risk of developing severe Other common findings include generalized weakness, back- malaria, particularly the species of malaria parasite and the ache, myalgias, vomiting, and pallor. In children, these symp- patient’s immune status, which depends on previous exposure toms resemble and are frequently mistaken for a viral syndrome to malaria. As noted, P. falciparum is the most virulent of the or acute gastroenteritis. Children who are partially immune plasmodia. Complications of P. falciparum infection are the Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021 (e.g., newly arrived immigrants or refugees from areas where result of cytokine release and of the parasite’s unique ability to malaria is highly endemic) frequently present with signs such cause parasitized RBCs to adhere to vascular endothelium and as hepatosplenomegaly, anemia, and jaundice. It is not unusual cause RBC sequestration, altered blood flow, and ischemia. The for these patients to have very minimal symptoms, such as patient’s immune status also greatly affects the manifestations anorexia or decreased activity, or even to be asymptomatic. A of malaria. In populations originating from areas of constant, recent study of Liberian children immigrating to Minnesota high-intensity malaria transmission, most mortality occurs found that smears of blood from 28 of 43 patients were positive among younger children, as a result of severe anemia. In the for malaria parasites. Of children with positive test results, one- same populations, infected adults and older children may have third were asymptomatic, and splenomegaly was the only man- minimal symptoms or may be asymptomatic [18]. ifestation of disease in one-third [16]. Conversely, in areas where malaria is less prevalent, partial In addition to specific tests for malaria, several other non- immunity may not develop, or it may develop at an older age. specific laboratory abnormalities are common in patients with In these cases, as is true for nonimmune travelers, the major this disease, such as elevated C-reactive protein levels, elevated cause of mortality is cerebral malaria. Headache, confusion, procalcitonin levels, thrombocytopenia, neutropenia, and ele- and irritability may precede cerebral malaria, but a nonimmune vated liver enzyme levels. Although it is unusual in the travel child’s condition can precipitously decline from normal sen- population, the partially immune patient may have additional sorium to coma within hours [19]. Seizures are common, and laboratory abnormalities on presentation, such as anemia, hy- children, as opposed to adults, frequently have increased in- poalbuminemia, and hematuria. Hyponatremia and hypogly- tracranial pressure [20, 21]. Other typical findings include de- cemia deserve special mention, because they are associated with corticate or decerebrate posturing, nystagmus, dysconjugate more-severe morbidity and occur more commonly in children gaze, papilledema, retinal hemorrhages, and altered respiration than in adults [17]. [20]. The findings of examination of CSF are generally unre- Although P. falciparum generally manifests days to weeks !20 cells/ L, slightly elevated protein after initial exposure, P. vivax and P. ovale, which have the markable (WBC count of m hepatic hypnozoite stage, may present much later. Patients level, and normal glucose level). Imaging studies may reveal with P. vivax infection commonly present with paroxysmal nonspecific findings that are consistent with cerebral edema or fevers, chills, headaches, and myalgias. In chronically infected ischemia. Before a conclusive diagnosis of cerebral malaria can children, anemia and hypersplenism are common. Splenic be made, it is imperative that other causes of neurologic decline rupture is a serious complication in children with hypersplen- be excluded, even when P. falciparum parasitemia has been ism. P. malariae and P. ovale generally cause fever but not a detected [18, 20]. toxic appearance. In some individuals, P. malariae may coexist Hypoglycemia, an important complication of severe malaria as a commensal organism, causing infection but no clinical in children, results from parasite-induced suppression of glu- disease. coneogenesis in the liver and induction of insulin secretion Malaria frequently occurs in patients who have a history of from the pancreas. The excess secretion of insulin is intensified recent or ongoing use of a malaria chemoprophylactic agent. by the initiation of quinine treatment and can result in dev- This may be attributed to several factors, such as drug resis- astating neurologic sequelae. Respiratory distress is another tance, noncompliance with treatment, or inadequate or inap- common complication in children, but, unlike in adults, it is propriate administration (especially in children, because of the rarely primarily the result of pulmonary edema or respiratory difficulties in administering bitter medications). It may be very distress syndrome and instead usually is a consequence of severe difficult to diagnose malaria in these children, because they acidosis. Black water fever (severe hemolysis, hemoglobinuria,

TRAVEL MEDICINE • CID 2003:37 (15 November) • 1341 and renal failure) and algid malaria (vascular collapse, shock, megaly decrease after presumptive antimalarial treatment. Sec- and hypothermia) are rare presentations in children. ond, antibody detection is used when the patient is a returned traveler with a diagnosis and treatment dur- ing recent travels and serologic confirmation is desired. It is DIAGNOSIS interesting to note that evidence suggests that travelers who have received a diagnosis of malaria while in the tropics fre- Diagnostic techniques. Diagnostic tests for malaria include quently were given an incorrect diagnosis [30]. standard thick and thin blood smears, rapid antigen detection Diagnostic approach to the patient. When evaluating a tests, PCR, and antibody tests. Thick and thin blood smears nontoxic child with suspected malaria, the clinician must an- remain the most widely available and used tests, particularly swer 2 questions. First, was the patient in an area where P. in the United States. Thick blood smears test for the presence falciparum malaria is endemic? A nontoxic-appearing child who or absence of parasites, and thin blood smears allow speciation

is exposed only to nonfalciparum malaria may receive outpa- Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021 and quantification. The sensitivity and specificity of blood tient evaluation if no other serious infection is suspected. Sec- smears vary greatly and are influenced by many factors, such ond, if the patient has been exposed to falciparum malaria, is as laboratory skill, timing and quality of smear collection, and he or she partially immune? For clinical purposes, children may level of parasitemia [22, 23]. Most skilled laboratory personnel be considered to be partially immune if they are 16 years of can detect parasite levels as low as ∼50 parasites/mL of blood. age, have a history of malaria, and have recently resided in an One set of negative thick and thin blood smears is never suf- area where malaria is highly endemic. Such children generally ficient to exclude malaria, even when prepared by the most are new immigrants or refugees. Prompt and thorough eval- skilled hands, but 3 sets of negative blood smears are generally uation is necessary, but outpatient evaluation and treatment considered sufficient, although additional smears may be nec- may be sufficient if caregivers are deemed to be reliable and essary in some cases. the child does not appear toxic. A nonimmune, febrile child Many rapid antigen tests are available outside the United who may have been exposed to P. falciparum represents a med- States. Most of these tests will differentiate between P. falciparum ical emergency; an aggressive inpatient evaluation should be and nonfalciparum infections through the detection of histidine- performed, regardless of the child’s appearance (figure 1). rich proteins and/or parasite lactate dehydrogenase. These tests A toxic-appearing child with a history of malaria exposure have shown mixed results in multiple trials, but several seem to should be admitted to an intensive care unit, and aggressive compare favorably with blood smears when performed by trained diagnosis and treatment should be pursued. Appropriate lab- personnel under laboratory conditions [24, 25]. oratory work must be performed, including blood smears for PCR tests are felt to be at least as sensitive and specific as malaria parasites, and empirical parenteral antimalarial therapy the traditional blood smear [26–29] and can detect parasite must be initiated. If no parasites are seen on initial smears, levels of р1 parasite/mL. In the United States, the use of PCR follow-up smears should be obtained every 8 h if there is con- is clinically limited, because the tests generally are only available tinued concern about malaria. A child who emigrates from a from specialized, government-sponsored laboratories. In ad- holoendemic malarious area has a significant chance of having dition, PCR results may continue to be positive for 11 week a positive blood smear, and the presence of malaria parasitemia after treatment because of persistence of antigen in the serum. does not preclude the possibility of other, coexisting illnesses. Currently, PCR is used mainly to confirm positive blood smears and is valuable in identification of malaria species, particularly when the results of smears are not definitive or there is a mixed TREATMENT infection. The detection of antibodies is not useful in the diagnosis of Treatment for malaria must be selected on the basis of the acute malaria, and in the United States, such a test may only infecting Plasmodium species, the severity of disease, the drug be obtained from the US Centers for Disease Control and Pre- susceptibility of the infecting parasites, and the availability of vention under special circumstances. This test is used in 2 medications and resources. The severity of illness will influence common scenarios. First, antibody detection is used when the the drug selected and the route of administration (figure 2). patient is a newly arrived immigrant or refugee with tropical splenomegaly (hyperactive malarial splenomegaly). “Tropical Treatment of P. falciparum Malaria splenomegaly” is a term that has traditionally been used to P. falciparum malaria may be classified as uncomplicated or describe individuals who have a large spleen, are suspected of complicated. Complicated malaria may be suspected when a having chronic malaria, and have multiple blood smears that patient at risk of malaria presents with altered mental status, are negative for malaria parasites. In this cohort, antibody respiratory distress, signs or symptoms of shock, seizures, gross (IgM) levels are markedly elevated, and IgM levels and spleno- hematuria, or severe laboratory abnormalities, including aci-

1342 • CID 2003:37 (15 November) • TRAVEL MEDICINE Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021

Figure 1. Clinical approach to patients with suspected malaria. *A patient should be considered to be partially immune if he or she is 16 years of age, has a history of malaria infection, and has recently (!2 years before presentation) resided in an area where malaria is highly endemic. **A rapid test may become a useful addition to diagnosis. ICU, intensive care unit. demia, profound anemia, signs of disseminated intravascular child. Although this finding may occur in partially immune coagulation, or hyperparasitemia (on the basis of the percentage children, it is more frequently the result of a laboratory error. of RBCs that are infected: 12% in nonimmune children and Managing uncomplicated P. falciparum malaria. Oral 110% in partially immune children). Caution must be exer- quinine (or quinidine, if quinidine is more readily available) cised, particularly in the United States, when a clinician is no- plus sulfadoxine-pyrimethamine has been suggested as the first tified of hyperparasitemia in an apparently well-appearing line of therapy for uncomplicated chloroquine-resistant P. fal-

Figure 2. Treatment approach to patients with laboratory-confirmed malaria. *In children 17 years of age. **If is acquired in an area of high chloroquine resistance (e.g., New Guinea), alternative therapy may be necessary. G6PD, glucose-6-dehydrogenase; ICU, intensive care unit; ID, infectious diseases; SP, sulfadoxine-pyrimethamine.

TRAVEL MEDICINE • CID 2003:37 (15 November) • 1343 Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021 / . falciparum P . falciparum . falciparum . falciparum . falciparum P P P P c Adult dosage 6 h later, then48 500 h mg (300 mg of base) at 24 and 15 mg of base/dayfor (26.3 14 mg days of salt/1 tablet) po Same as for chloroquine-resistant Same as for chloroquine-resistant 650 mg q8h for 3–7 days 1 g (600 mg of base), then 500 mg (300 mg of base) 100 mg b.i.d. for 7 days 4 mg/kg/day for 3 days Same as for chloroquine-sensitive Same dose as for chloroquine-sensitive Same as for chloroquine-resistant Same dosages as above 750 mg, then 500 mg 12 h later /0.3 . falciparum P c . falciparum . falciparum . falciparum . falciparum P P P P Pediatric dosage 5 mg of base/kg24 6 and h 48 later, h then 5 mg of base/kg at mg of base/kg/day po for 14 days 40 kg: 1 g/400 mg (4 adult tablets) qd for 3 days 1 year of age: 1/4 tablet once on last day of quinine 3 tablets at once on last14 day years of of quinine age: 3 tablets 45 kg: 15 mg/kg, then40 10 kg: mg/kg 8 12 mg/kg h q6h later for 3 doses; repeat in 1 week 500 mg q6h for 3 doses; repeat in 1 week Same as for chloroquine-resistant 21–30 kg: 500/200 mg (231–40 adult kg: tablets) 750/300 qd mg for (3 3 adult days tablets) qd for 3 days 10 mg of base/kg (maximum, 600 mg of base), then 1 ! 1 2 mg/kg/day for 7 days ! ! 4 mg/kg/day for 3 days Same as for chloroquine-sensitive 1–3 years of age: 1/24–8 tablet years of age: 19–14 tablet years of age: 2 tablets Same dosages as above 25 mg/kg/day in 3 doses for 3–7 days a Plasmodium vivax: h i b d . vivax . falciparum P P and chloroquine-sensitive f e g by primaquine chloroquine followed by primaquine Quinine sulfate plus sulfadoxine-pyrimethamine followed Quinine sulfate plus doxycycline followed by primaquine Same as for chloroquine-resistant Mefloquine Artesunate plus mefloquine Or plus clindamycinOr plus doxycycline Artesunate 20–40 mg/kg/day in 3 doses for 5 days 900 mg t.i.d. for 5 days Halofantrine Plus sulfadoxine-pyrimethamine Mefloquine followed by primaquine Same as for chloroquine-resistant Alternative: atovaquone-proguanil 11–20 kg: 250/100 mg (1 adult tablet) qd for 3 days 1 g/400 mg (4 adult tablets) qd for 3 days Other alternatives First choice: atovaquone-proguanil Same dose as for chloroquine-sensitive Common alternative: quinine sulfate First choice: chloroquine First choice Chloroquine-resistant Chloroquine-resistant Table 1. Drugs used forPathogen, the drug treatment of malaria. Chloroquine-sensitive

1344 Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021 . falciparum P 48 h of parenteral treatment 1 mal saline, adminstered slowly1–2 over h, the followed course by of kg/min continuous until infusion oral of therapy 0.02 can mg/ be initiated tered over the coursekg of administered 4 over h, the followed(maximum, course by 1800 of 10 mg/day) 2–4 mg/ until hinitiated oral q8h therapy can be 10 mg/kg loading dose iv (maximum, 600 mg) in nor- 20 mg/kg loading dose iv in 5% dextrose, adminis- Rarely recommended Same as for chloroquine-sensitive 3.2 mg/kg im, then 1.6 mg/kg/day . falciparum P mal saline, administered slowly1–2 over h, the followed course by of kg/min continuous until infusion oral of therapy 0.02 can mg/ be initiated tered over the coursekg of administered 4 over h, the followed(maximum, course by 1800 of 10 mg/day) 2–4 mg/ until hinitiated oral q8h therapy can be 10 mg/kg loading dose iv (maximum, 600 mg) in nor- 20 mg/kg loading dose iv in 5% dextrose, adminis- 3.2 mg/kg im, then 1.6Rarely mg/kg/day recommended but treatment failures and resistance have been reported. May lengthen PR and corrected QT intervals, and cardiac arrhythmias have been . falciparum, P 8 years of age. ! k is a significant problem in Papua–New Guinea and Indonesia. Resistance has been reported in Myanmar, India, Irian Jaya, Thailand, the Solomon Islands, Vanuatu, Guyana, , g k , j . vivax chloroquine Same as for chloroquine-sensitive P m species: parenteral therapy l Adapted from Stauffer and Kamat [7], with permission. Quinine dihydrochloride Artemether Chloroquine Quinidine gluconate Extreme caution must be exercised in administering parenteral chloroquine, because there is a very narrow therapeutic window and overdose may result in death. If chloroquine is not available, hydroxychloroquine sulfate isNot effective: 400 approved mg for of usePediatric hydroxychloroquine in sulfate dose children not is approved equivalent by to the 500 US mg Food of and chloroquine Drug phosphate. Administration. Mefloquine should not be given in combination with quinine, quinidine, or halofantrine. It shouldNot not available be used in in the areasShould United of not States. reported be used to treat patients with abnormal glucose-6-dehydrogenase levels, and status should be checked in all patients before use. Assume that malaria parasites are sensitive to chloroquine if exposure occurred in Central America,In west of Southeast the Asia, Panama relative Canal; resistance Mexico; to Haiti; the quinine Dominican has Republic; increased, or the and Middle the East, treatment except Yemen, should be continued for 7 days. Quinidine may have greater antimalarial activity then quinine. The loading dose should be decreased or omitted for patients who have received quinine or mefloquine. If May be effective against multidrug-resistant Chloroquine-resistant Continuous electrocardiographic monitoring and blood pressure and glucose monitoring are recommended. Not available in the United States. Also available in rectal suppository formulation. Plasmodium Alternatives First choice NOTE. a b c d e f g h i j k l m reported. Its use ismonitoring not is recommended suggested when during other dosing. medications Should not known be to taken prolong within PR 1 or h corrected before QT and intervals 2 are h being after administered a or meal. when mefloquine has been used for chemoprophylaxis. Cardiac : All Oman, and Iran. is required, the quinine dose should be reduced by one-third to one-half. mefloquine resistance, such asadverse the effects. Thai-Myanmar and Thai-Cambodia borders. Common adverse effects include nausea, vomiting, diarrhea, and dizziness. Toxic psychosis and seizures are less common Brazil, and Peru.

1345 Table 2. Formulations of medications for malaria available in the United States.

Medication Formulations Comments CQ Tablets (salt/base): 250/150 mg and 500/300 mg May pulverize tablet. The generic form is more easily pulverized. MQ Tablets (salt/base): 250/228 mg May pulverize tablet. Atovaquone-proguanil Tablets: 250/500 mg (“adult tablet”) and 62.5/ May pulverize tablet. Slightly less bitter in 25 mg (“pediatric tablet”) taste than CQ and MQ. Approved for use in patients weighing 111 kg. Sulfadoxine- Tablets: 500/25 mg May pulverize tablet. pyrimethamine Clindamycin Capsules, 75, 150, and 300 mg; oral liquid, 75 … mg/5 mL; iv formulation, 150 mg/5 mL (contains 9.45 mg/mL benzyl alcohol) Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021 Doxycycline Tablets, 50 and 100 mg; syrup, 50 mg/5 mL; Approved for use in children 17 years of age. suspension, 25 mg/5 mL Quinidine As gluconate (62% quinidine): slow-release Also available as sulfate (83% quinidine) and tablets, 324 mg; iv formulation, 80 mg/mL polygalacturonate (80% quinidine). May obtain iv formulation from Eli Lilly. Primaquine Tablet as phosphate (base): 26.3 mg (15 mg) May pulverize tablet. Do not use in infants.

NOTE. All antimalarial drugs are very bitter in taste. To administer in oral form to a child, it is suggested that the pulverized tablet be placed in a very sweet food item, such as chocolate syrup, sweetened condensed milk, jam, jelly, or a creme-filled cookie. CQ, chloroquine; MQ, mefloquine. ciparum malaria in children (tables 1 and 2) [31]. Oral quinine drugs. However, they must be used in combination with a long- plus clindamycin, or, in older children (17 years of age), qui- acting agent to prevent recrudescence of disease. nine/quinidine plus doxycycline, is a reasonable alternative Chloroquine-sensitive P. falciparum is now rarely encoun- [32]. Atovaquone-proguanil has been shown to be effective, tered, except in Haiti. Chloroquine sensitivity may be assumed safe, and well tolerated as a single agent in children weighing and treatment considered if the patient was exposed to P. fal- 111 kg who have uncomplicated chloroquine-resistant P. fal- ciparum in Central America, west of the Panama Canal; Ar- ciparum malaria. Recently, the results of 2 clinical trials have gentina; Egypt; Haiti; the Dominican Republic; and some Mid- demonstrated that atovaquone-proguanil is also effective and dle Eastern countries. safe in children weighing 5–11 kg [33, 34]. When atovaquone- Managing complicated P. falciparum malaria. Patients proguanil is available, it could now be considered the drug of with complicated malaria need immediate parenteral antima- choice for uncomplicated chloroquine-resistant P. falciparum larial drugs and aggressive supportive therapy. Quinidine is the malaria because of its relatively simple dosing, effectiveness, parenteral antimalarial of choice in the United States, and qui- tolerability, and wide therapeutic window and the lack of re- nine and the compounds are available outside the sistance to this drug. Although either atovaquone or proguanil United States. A cardiac monitor should be used and frequent alone induces rapid resistance, it was hoped that the combi- blood pressure measurements should be made when the patient nation would forestall the emergence of drug resistance. Un- is receiving quinine derivatives. These agents must be admin- fortunately, within a couple of years of widespread use, several istered as a gradual intravenous infusion to avoid acute car- case reports of resistance have emerged [35, 36]. diovascular complications, particularly hypotension. Infusion Other alternatives include mefloquine, lumefantrine, halo- rates should be reduced if the QT interval is prolonged by 125% fantrine, and the artemisinin compounds. Mefloquine contin- from its baseline value. Quinidine is becoming increasingly rare ues to be an effective single agent, although it can cause in United States hospital pharmacy formularies but may be significant gastrointestinal and neurologic side effects. Halofan- acquired directly from the manufacturer, Eli Lilly. If quinidine trine demands intensive monitoring of the patient, because it acquisition is delayed, parenteral clindamycin may be initiated is associated with potentially severe cardiac adverse effects, in- until quinidine is available. Oral therapy is initiated as soon as cluding prolongation of the QT interval, and it should never it can be tolerated by the patient. It should be noted that a be used in a patient who has recently received mefloquine, second agent (i.e., sulfadoxine-pyrimethamine or doxycycline) because the combination may precipitate severe arrhythmias. must be used in conjunction with quinine, quinidine, or, es- Although the artemisinin derivatives are unavailable in many pecially, the artemisinin compounds, because when these agents areas, they are extremely effective and inexpensive antimalarial are used alone, excessive rates of recrudescence are seen.

1346 • CID 2003:37 (15 November) • TRAVEL MEDICINE Table 3. Poor prognostic criteria for patients with severe be consulted, and additional support may be obtained through Plasmodium falciparum malaria. the Centers for Disease Control and Prevention malaria hotline (770-488-7788). Clinical feature Impaired level of consciousnessa Treatment of Nonfalciparum Malaria Respiratory distressa a P. vivax and P. ovale are usually susceptible to chloroquine. Jaundice Recent exceptions to this rule have been documented in P. vivax Repeated convulsions from South America and Oceania, particularly New Guinea. In Shock patients for whom the likelihood of chloroquine-resistant P. Laboratory feature a vivax is high, mefloquine or quinine/quinidine plus doxycycline Hypoglycemia (whole-blood glucose level !40 mg/dL) a (for patients 17 years of age) may be used [28, 30]. In patients Elevated bilirubin level (total, 12.5 mg/dL)

with P. vivax or P. ovale malaria, the initial treatment regimen Downloaded from https://academic.oup.com/cid/article/37/10/1340/451166 by guest on 27 September 2021 Acidosis (plasma bicarbonate level !15 mmol/L) should be followed by treatment with primaquine (“radical Lactic acidosis (serum lactate level 145 mg/dL) cure”). Primaquine is effective against the exoerythrocytic liver Elevated aminotransferase levels (13 times normal) phase and is administered to prevent relapse, but occasional Renal insufficiency (serum creatinine level 13 mg/dL) relapses may still occur, despite administration of appropriate a Particularly poor prognostic factor in children (especially the combi- therapy. Glucose-6-dehydrogenase levels should be measured nation of respiratory distress and impaired level of consciousness) [38]. in all patients who receive primaquine before initiation of ther- apy, because severe hemolytic anemia may occur in patients Close monitoring and supportive therapy are imperative for with a deficiency of this enzyme. For patients with glucose-6- good outcome. Initial hypoglycemia should be treated with a dehydrogenase deficiency, primaquine should not be used, and rapid infusion of 25% (for infants and small children) or 50% each subsequent relapse should be treated with chloroquine or dextrose. To prevent and monitor for hyperinsulinemic hy- an acceptable alternative. Primaquine should not be used to poglycemia, administration of a 5% or 10% dextrose solution treat newborn infants. Children who acquired malaria trans- should be started when treatment with quinine derivatives is placentally or via a transfusion do not have hypnozoite forms initiated, and blood glucose levels should be tested frequently. of malaria and need not be treated with primaquine. (Quinine-induced hypoglycemia may develop several days after P. malariae is susceptible to chloroquine, which is the drug the beginning of treatment [19].) Hypovolemia and lactic ac- of choice. This parasite does not have the ability to form a idosis must be managed with intravenous crystalloids or col- hypnozoite in the liver, and, therefore, radical cure with pri- loids, and vasopressors and bicarbonate occasionally are nec- maquine is not needed. essary. Severe anemia may necessitate blood transfusion. Seizures may be acutely treated with benzodiazepines, and other anticonvulsants may be administered when seizures occur re- CONCLUSION peatedly or are prolonged. Renal failure may develop; in a such Malaria parasites continues to infect children around the world. a circumstance, adjustment of drug doses is necessary. With appropriate attention to the possibility of malaria and Multiple smears with parasite quantification should be done appropriate use of laboratory tests, delayed diagnosis can be to monitor therapeutic success. Very high levels of parasitemia avoided. As new diagnostic and therapeutic tools and tech- or failure to respond to treatment may indicate primary drug niques become increasingly available, there is ever-greater po- failure/resistance, and therapy should be adjusted and exchange tential for avoiding the severe morbidity and mortality associ- transfusion considered. Because of the lack of objective data, ated with malaria. Ultimately, an effective and safe vaccine is to what extent exchange transfusion is effective and safe has needed to prevent the tremendous suffering and premature been debated, and the exact criteria for initiating therapy are deaths of millions of children every year that are associated unclear. Some authorities have suggested that exchange trans- with this disease. fusion may be beneficial for any severely ill patient with par- asitemia of 115% or for any patient with parasitemia of 5%– 15% who has signs of poor prognosis (table 3) [37, 38]. Clinical References trials do not demonstrate efficacy for other ancillary treatments, 1. World Health Organization (WHO). The global malaria situation: cur- including anticytokine agents, chelation agents, corticosteroids, rent tools for prevention and control. 55th World Health Assembly. mannitol, dextran, heparin, and malaria hyperimmunoglobulin Global Fund to Fight AIDS, Tuberculosis and Malaria. WHO document no. A55/INF.DOC./6. Available at: http://www.who.int/gb/EB_WHA/ [18, 19]. When managing a severe case of malaria, an experi- PDF/WHA55/ea55id6.pdf. Accessed 7 July 2003. enced infectious diseases or tropical medicine specialist should 2. Greenwood B, Mutabingwa T. Malaria in 2002. Nature 2002; 415:670–2.

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