(Last updated: November 6, 2013; last reviewed: November 6, 2013)
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
†Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
EpidemiologyMalaria is caused by the obligate, intracellular protozoa of the genus Plasmodium, and is transmitted by the bite of an infective female Anopheles mosquito. Worldwide, malaria is a leading killer of children and pregnant women. In the United States, most malaria cases occur in patients who have returned from travels to areas of endemic malaria transmission. Rarely, cases occur as a result of exposure to infected blood products, local mosquito-borne transmission (i.e., autochthonous transmission), or mother-to-child transmission (MTCT) (congenital malaria). Prompt recognition and treatment are essential, and failure to act quickly and appropriately can have grave consequences.
High-Risk GroupsUnited States-born children visiting family in malaria-endemic regions are at highest risk of malaria infection. Children of foreign citizenship, children of unknown resident status, and adopted children who come from countries of endemic malaria transmission are also at high risk. Education regarding the misconception that prior exposure to malaria confers protection against re-infection is important; families should be prepared (with malaria chemoprophylaxis) and educated with travel advice (e.g., such as recommending use of insecticide-treated nets and insect repellants) before returning to endemic areas (AII). Although some parents may assume that their children are protected from disease because of their ethnic background (from high malaria endemic countries),2,3,4 the converse is true, with patients in this group at high risk because of factors such as visiting private residences, sleeping in homes that lack screens or air conditioning, and having longer visits, all of which contribute to a higher risk of contracting malaria (http://www.cdc.gov/malaria/travelers/vfr.html). Adults living in the United States but born in malaria-endemic areas often believe they are not susceptible to malaria because of naturally acquired immunity. Such acquired immunity develops after age 5 years in people who reside in areas of stable malaria transmission, but it is partial (providing relative protection against disease, not infection), wanes quickly once people are no longer living in malaria-endemic areas, and may not be present in HIV-infected populations with advanced immunodeficiency. Therefore, both adults and children living in the United States who were born in malaria-endemic areas should be prescribed the same prophylaxis as any other patients traveling to malaria-endemic areas.
Prevention RecommendationsRecommendations for preventing exposure and for primary chemoprophylaxis are identical for HIV-infected and HIV-uninfected individuals (see http://www.cdc.gov/malaria/travelers/index.html). All travelers to malaria-endemic regions should receive pre-travel counseling on appropriate chemoprophylaxis and avoidance of mosquitos (AII).4,5 Families should be counseled regarding signs and symptoms of malaria and the need for early medical intervention if these signs and symptoms are present. An early appropriate medical evaluation should be completed on all patients returning from a malaria-endemic area who have unexplained fever or other signs or symptoms of malaria.
Preventing ExposureAll travelers should use personal protective measures to prevent mosquito bites when traveling to malaria-endemic areas (AII),6 including sleeping under an insecticide-treated bed net and wearing clothing impregnated with permethrin (effective for weeks and through several washings, but not dry cleaning). Discussions regarding the routine use of bed nets should be individualized as per specific sleeping arrangements (air-conditioned hotel vs. open windows). Long-acting N,N-Diethyl-meta-toluamide (DEET) mosquito repellents are safe, practical, and effective, and the duration of protection increases with increasing DEET concentrations, plateauing between 30% and 50%. DEET should be applied (by patients or their caregivers when appropriate) to skin, but not to wounds, cuts, irritated areas, the mouth, or hands of young children (AIII). Additional information about other recommended mosquito repellants can be found at http://www.cdc.gov/ncidod/dvbid/westnile/qa/insect_repellent.htm.
Primary ChemoprophylaxisPrimary chemoprophylaxis should be prescribed to all individuals traveling to malaria-endemic areas, regardless of ethnicity or prior exposure to or illness with malaria. Antimalarial medications may need special preparation, and some are not easily delivered to children. Therefore, families planning to travel to malaria-endemic areas are advised to visit a travel medicine specialist with training and experience in pediatrics at least 2 weeks before departure (AII). If that is not possible, families can still see a travel medicine specialist up to the day of departure, because some antimalarial prophylaxis regimens can still be prescribed and effectively used even at that late date.
Discontinuing Primary ProphylaxisTravel-related chemoprophylaxis with chloroquine, mefloquine, or doxycycline usually should be continued for 4 weeks after departure from a malaria-endemic area because these drugs are not effective against malarial parasites developing in the liver and kill the parasite only once it has emerged to infect the red blood cells. Atovaquone-proguanil and primaquine may be discontinued 1 week after departure from malaria-endemic areas.
Clinical and Laboratory ManifestationsHIV increases the frequency and severity of clinical malaria episodes in more severely immunosuppressed adults, pregnant women, and older children, possibly reflecting HIV-mediated interference with acquisition of malaria immunity, but not related to failure of initial antimalarial therapy.7,8 In young children, there is no clear evidence that HIV infection is associated with more severe malaria disease, although one case-control study in Uganda found an association between HIV infection and cerebral malaria in children.9
DiagnosisFor early and prompt recognition of malaria, physicians must obtain a complete travel history from every febrile patient and maintain a high index of suspicion for malaria in travelers returning from areas of endemic malaria, remembering that signs and symptoms also can vary depending on chemoprophylaxis and prior partial treatment for malaria (see Table 7 from17 for list of resources or http://wwwnc.cdc.gov/travel/destinations/list.htm). Children who have recently migrated from regions where malaria is endemic should be evaluated for malarial infection upon arrival and/or if they become ill after arriving in the United States. A Giemsa-stained thick blood smear is the most sensitive smear technique for detecting infection, whereas a thin blood smear is used for determination of parasite species and burden (for an example of malaria parasites on smear, please visit http://www.dpd.cdc.gov/dpdx/HTML/Image_Library.htm). Smear accuracy depends upon proper preparation and interpretation of thick and thin smears by experienced laboratory personnel.17 Because symptoms can develop before parasitemia is detectable in a non-immune person, the initial blood-smear examination may be misleadingly negative. Blood smears should be obtained every 12 to 24 hours for a total of 3 sets to fully evaluate for malaria; if all 3 sets are negative, the probability of malaria is extremely low. In all patients in whom malaria is suspected, smears should be read immediately. A qualified person who can perform and read smears should always be available, even at off-hours. Every effort should be made to establish a diagnosis before therapy is initiated. However, if severe malaria is strongly suspected and diagnostic interpretation is not readily available, empiric intravenous therapy for presumed P. falciparum infection should be initiated, with a blood smear preserved for reading as soon as possible. Consultation and aid in the initial diagnosis, speciation, and treatment plan is available via the CDC Malaria Hotline at (770) 488-7788 (Monday–Friday, 9 a.m.-5 p.m., eastern time. For emergency consultation after hours, call (770) 488-7100, and ask to speak with a CDC Malaria Branch clinician).
Treating DiseaseChemoprophylaxis is not completely effective, and malaria should be included in the differential diagnosis of fever or other signs or symptoms consistent with malaria in anyone who traveled to malaria-endemic areas during the previous 12 months (see http://www.cdc.gov/immigrantrefugeehealth/guidelines/overseas/malaria-guidelines-overseas.html#sect2). Malaria medications purchased in sub-Saharan Africa or Southeast Asia may be counterfeit; therefore, the index of suspicion must remain high when evaluating children with fever coming from endemic areas, regardless of prior history of antimalarial therapy.
Unknown SpeciesClinicians should always treat patients who traveled to a region in which chloroquine-resistant P. falciparum malaria is present for chloroquine-resistant P. falciparum malaria if reliable identification of the malaria species is not possible or the patient is severely ill (AIII).
Uncomplicated MalariaUncomplicated malaria is defined by the World Health Organization as “symptomatic infection with malaria parasitemia without signs of severity and/or evidence of vital organ dysfunction.”18 The preferred treatment options for uncomplicated malaria include chloroquine phosphate (if chloroquine-susceptible), atovaquone-proguanil, artemether-lumefantrine, or quinine sulfate plus a second medicine (either tetracycline, doxycycline [in children aged ≥8 years] or clindamycin) (see Dosing Table for details) (AI). Mefloquine also can be used for treatment, but has a higher rate of side effects (AIII). Primaquine also must be administered for radical cure of P. vivax and P. ovale infection. G6PD deficiency must be excluded before first use of primaquine because of the risk of severe hemolytic anemia. Primaquine should not be used in pregnant women because the presence of G6PD deficiency cannot be determined in the unborn child (AIII).
Severe MalariaSevere malaria is defined as acute malaria “with signs of severity and/or evidence of vital organ dysfunction”18 and is most often caused by P. falciparum, but can also be caused by P. vivax. Mixed infections can also occur. These signs, symptoms, and laboratory parameters include diminished consciousness or seizures, respiratory distress (acute respiratory distress syndrome [ARDS], Kussmaul’s respiration), prostration, hyperparasitemia (>5%), severe anemia (hemoglobin <7 g/dL), hypoglycemia, jaundice/icterus, renal insufficiency, hemoglobinuria, shock, cessation of eating and drinking, repetitive vomiting, or hyperpyrexia. Cerebral malaria is usually defined by presence of coma (Glasgow coma scale <11, Blantyre coma scale <3). Severe malaria can present long before hemoglobin goes below the 7 mg/dL threshold because of the hemo-concentrating effects of dehydration.
Malaria Despite ChemoprophylaxisMedication used for chemoprophylaxis should not be used as a part of a new treatment regimen in individuals who develop malaria despite taking chemoprophylaxis; rather, treatment with one of the other options is recommended.
Drug InteractionsThere are multiple potential interactions between ARV and antimalarial drugs, but data from HIV-infected children and adults remain limited.7,23-25 Many antimalarials are metabolized by cytochrome p450 enzymes, while certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) either inhibit or induce cytochrome p450 enzymes.26-28 Tetracyclines have no clinically significant interactions expected with PIs or NNRTIs. Atovaquone is not expected to have any significant interaction with common nucleoside reverse transcriptase inhibitors, although no data are available for proguanil. Ritonavir inhibits quinidine metabolism; therefore, concomitant administration of ritonavir (including co-formulated products like lopinavir/ritonavir that contain ritonavir) and quinidine is not recommended. Replacement of ritonavir in ritonavir-containing cART should be considered. The inhibitory action of ritonavir will still be present for several days after dosing is interrupted; thus, in patients with severe malaria already on ritonavir, artesunate should be considered. Caution is also advised before co-administering quinidine with other PIs (including atazanavir, darunavir, and fosamprenavir).
||PIs: increase quinine levels
||No available data
||Efavirenz, Nevirapine: reduces quinine levels
||Lopinavir/Ritonavir, Atazanavir/Ritonavir: reduces atovaquone and proguanil levels
||Efavirenz: reduces atovaquone and proguanil levels
||Ritonavir: reduces ritonavir levels
||Efavirenz, Nevirapine: reduces mefloquine levels
||PIs: increase lumefantrine or halofantrine levels, which can prolong QT interval
||Efavirenz, Nevirapine: increases lumefantrine or halofantrine levels, which can prolong QT interval
|Amodiaquine plus Artesunate
||Efavirenz: increases amodiaquine concentration which can increase hepatic toxicity; do not co-administer
|Chloroquine, Pyrimethamine, Sulfadoxine-Pyrimethamine
||Ritonavir: alters anti-malarial drug metabolism, may increase chloroquine levels
||Zidovudine: possibly increases risk of anemia
||Nevirapine: possibly increases adverse skin or liver adverse reactions; do not start both drugs simultaneously
||PIs: alter artemisinin metabolism
||Nevirapine: may decrease artemisinin levels
||Saquinavir: alters dapsone metabolism
|Key to Acronyms: NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; PI= protease inhibitor
* Modified from: Flateau, C., G. Le Loup, et al. Consequences of HIV infection on malaria and therapeutic implications: a systematic review. Lancet Infect Dis. 2011. 11(7);541-556.
Special PopulationsBecause primaquine is not routinely prescribed for immigrants as part of a post-treatment/pre-departure regimen, patients who may have had P. vivax or P. ovale infection in the past would be at continued risk of developing malaria months to years after arrival in the United States. Presumptive treatment on arrival (preferable) or laboratory screening to detect Plasmodium infection is recommended for refugees originating in sub-Saharan Africa who have not received pre-departure therapy with a recommended regimen (see http://www.cdc.gov/immigrantrefugeehealth/guidelines/domestic/malaria-guidelines-domestic.html).
Monitoring and Adverse Events (Including IRIS)Severe malaria commonly induces hypoglycemia in children, especially when treated with IV quinine/quinidine because of inhibition of gluconeogenesis and induction of endogenous insulin production. Therefore, monitoring glucose levels and use of a glucose-containing crystalloid solution for fluid maintenance is prudent until IV quinine/quinidine therapy has been completed. Monitoring glucose is especially important for children with altered mental status. Cardiac and intensive-care monitoring is also recommended because IV quinine/quinidine can cause hypotension and widening of the QRS interval. Quinine toxicity, a cluster of symptoms that includes tinnitus, dizziness, disorientation, nausea, visual changes, and auditory deficits, can occur. Many of the adverse events associated with quinine are dose-related, and because of age-related differences in the rate at which quinine is eliminated from the body, the frequency and severity of adverse effects associated with quinine drug products may be lower in children. Tinnitus alone, a common (50%–75%) adverse reaction to both oral and IV quinine, usually resolves after treatment. Use of mefloquine at treatment doses may be associated with neuropsychiatric symptoms. Following antimalarial therapy, HIV-infected children should be monitored closely for hematologic complications (especially anemia and neutropenia), which are more frequent because of both the direct hematologic effects of HIV infection and of HIV treatment with other bone-marrow-suppressive drugs such as TMP-SMX and zidovudine. Immune reconstitution inflammatory syndrome caused by malaria has not been reported.
Managing Treatment FailureFailure of treatment for P. falciparum is uncommon in children who receive a full course of appropriate antimalarial therapy. Patients should be monitored for clinical and laboratory response (thick and thin smear) and for signs of recrudescence after therapy completion. Relapse of P. vivax and P. ovale can occur from the dormant (hypnozoite) liver form but is less common following primaquine treatment. When treatment failure occurs, malaria speciation should be confirmed, as should the geography of where the malaria was acquired. Retreatment with an appropriate first-line regimen (but not the same regimen as initially used) should be given. Discussion with a Pediatric Infectious Disease specialist or consultation through the CDC malaria hotline is appropriate when complex situations arise.
Preventing RecurrenceExcept for re-activation of P. vivax and P. ovale hypnozoites, malaria once successfully treated does not recur, unless re-exposure and re-infection occur. One or even several episodes of malaria infection does not imply protective immunity, and continued exposure to malaria parasites can result in repeated infection, which should be treated as aggressively as the initial event.
||For Travel To Chloroquine-Sensitive Areas:
||Recommendations are the same for HIV-infected and HIV-uninfected children. Please refer to the following website for the most recent recommendations based on region and drug susceptibility: http://www.cdc.gov/malaria/
For travel to chloroquine-sensitive areas. Equally recommended options include chloroquine, atovaquone/proguanil, doxycycline (for children aged ≥8 years), and mefloquine; primaquine is recommended for areas with mainly P. vivax.
G6PD screening must be performed prior to primaquine use.
Chloroquine phosphate is the only formulation of chloroquine available in the United States; 10 mg of chloroquine phosphate = 6 mg of chloroquine base.
|For Travel to Chloroquine-Resistant Areas:
||For travel to chloroquine-resistant areas, preferred drugs are atovaquone/proguanil, doxycycline (for children aged ≥8 years) or mefloquine.|
||For P. vivax or P. ovale:
||This regimen, known as PART, is recommended only for individuals who have resided in a malaria-endemic area for an extended period of time. Adult dose: 30 mg base (52.6 mg salt) orally, daily for 14 days after departure from the malarious area.
|Treatment||Uncomplicated P. Falciparum or Unknown Malaria Species, from Chloroquine-Resistant Areas (All Malaria Areas Except Those Listed as Chloroquine Sensitive) or Unknown Region:
Initial Therapy (Followed by Anti-Relapse Therapy for P. Ovale and P. Vivax):
|For quinine-based regimens, doxycycline or tetracycline should be used only in children aged ≥8 years. An alternative for children aged ≥8 years is clindamycin 7 mg/kg body weight per dose by mouth given every 8 hours. Clindamycin should be used for children aged <8 years.
Before primaquine is given, G6PD status must be verified. Primaquine may be given in combination with chloroquine if the G6PD status is known and negative, otherwise give after chloroquine (when G6PD status is available)
For most updated prevention and treatment recommendations for specific region, refer to updated CDC treatment table available at http://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf
For sensitive and resistant malaria map: http://cdc-malaria.ncsa.uiuc.edu/
High treatment failure rates due to chloroquine-resistant P. vivax have been documented in Papua New Guinea and Indonesia. Treatment should be selected from one of the three following options:
Quinidine gluconate 10 mg/kg body weight IV loading dose over 1–2 hours, then 0.02 mg/kg body weight/minute infusion for ≥24 hours (Treatment duration: 7 days in Southeast Asia, Oceania, otherwise 3 days)
PLUS One of the Following:
PLUS One of the Following:
|Quinidine gluconate is a class 1a anti-arrhythmic agent not typically stocked in pediatric hospitals. When regional supplies are unavailable, the CDC Malaria hotline may be of assistance (see below). Do not give quinidine gluconate as an IV bolus. Quinidine gluconate IV should be administered in a monitored setting. Cardiac monitoring required. Adverse events including severe hypoglycemia, prolongation of the QT interval, ventricular arrhythmia, and hypotension can result from the use of this drug at treatment doses.
IND: IV artesunate is available from CDC. Contact the CDC Malaria Hotline at (770) 488-7788 from 8 a.m.–4:30 p.m. EST or (770) 488-7100 after hours, weekends, and holidays. Artesunate followed by one of the following: Atovaquone-proguanil (Malarone™), clindamycin, mefloquine, or (for children aged >8 years) doxycycline.
Quinidine gluconate: 10 mg = 6.25 mg quinidine base.
Doxycycline (or tetracycline) should be used in children aged ≥8 years. For patients unable to take oral medication, may give IV. For children <45 kg, give 2.2 mg/kg IV every 12 hours and then switch to oral doxycycline. For children >45 kg, use the same dosing as per adults. For IV use, avoid rapid administration.
For patients unable to take oral clindamycin, give 10 mg base/kg loading dose IV, followed by 5 mg base/kg IV every 8 hours. Switch to oral clindamycin (oral dose as above) as soon as a patient can take oral medication. For IV use, avoid rapid administration.
|Key to Acronyms: CDC = Centers for Disease Control and Prevention; G6PD = glucose-6-phosphate dehydrogenase; IND = investigational new drug; IV = intravenous; PART = presumptive anti-relapse therapy