Ann M. Barber

Malaria surveillance -- United States, 2009

Problem/Condition Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to provide information on its occurrence (e.g., temporal, geographic, and demographic), guide prevention and treatment recommendations for travelers and patients, and facilitate transmission control measures if locally acquired cases are identified. Period Covered This report summarizes confirmed malaria cases in persons with onset of illness in 2015 and summarizes trends in previous years. Description of System Malaria cases diagnosed by blood film microscopy, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments by health care providers or laboratory staff members. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), the National Notifiable Diseases Surveillance System (NNDSS), or direct CDC consultations. CDC reference laboratories provide diagnostic assistance and conduct antimalarial drug resistance marker testing on blood samples submitted by health care providers or local or state health departments. This report summarizes data from the integration of all NMSS and NNDSS cases, CDC reference laboratory reports, and CDC clinical consultations. Results CDC received reports of 1,517 confirmed malaria cases, including one congenital case, with an onset of symptoms in 2015 among persons who received their diagnoses in the United States. Although the number of malaria cases diagnosed in the United States has been increasing since the mid-1970s, the number of cases decreased by 208 from 2014 to 2015. Among the regions of acquisition (Africa, West Africa, Asia, Central America, the Caribbean, South America, Oceania, and the Middle East), the only region with significantly fewer imported cases in 2015 compared with 2014 was West Africa (781 versus 969). Plasmodium falciparum, P. vivax, P. ovale, and P. malariae were identified in 67.4%, 11.7%, 4.1%, and 3.1% of cases, respectively. Less than 1% of patients were infected by two species. The infecting species was unreported or undetermined in 12.9% of cases. CDC provided diagnostic assistance for 13.1% of patients with confirmed cases and tested 15.0% of P. falciparum specimens for antimalarial resistance markers. Of the U.S. resident patients who reported purpose of travel, 68.4% were visiting friends or relatives. A lower proportion of U.S. residents with malaria reported taking any chemoprophylaxis in 2015 (26.5%) compared with 2014 (32.5%), and adherence was poor in this group. Among the U.S residents for whom information on chemoprophylaxis use and travel region were known, 95.3% of patients with malaria did not adhere to or did not take a CDC-recommended chemoprophylaxis regimen. Among women with malaria, 32 were pregnant, and none had adhered to chemoprophylaxis. A total of 23 malaria cases occurred among U.S. military personnel in 2015. Three cases of malaria were imported from the approximately 3,000 military personnel deployed to an Ebola-affected country; two of these were not P. falciparum species, and one species was unspecified. Among all reported cases in 2015, 17.1% were classified as severe illnesses and 11 persons died, compared with an average of 6.1 deaths per year during 2000–2014. In 2015, CDC received 153 P. falciparum-positive samples for surveillance of antimalarial resistance markers (although certain loci were untestable for some samples); genetic polymorphisms associated with resistance to pyrimethamine were identified in 132 (86.3%), to sulfadoxine in 112 (73.7%), to chloroquine in 48 (31.4%), to mefloquine in six (4.3%), and to artemisinin in one (<1%), and no sample had resistance to atovaquone. Completion of data elements on the malaria case report form decreased from 2014 to 2015 and remains low, with 24.2% of case report forms missing at least one key element (species, travel history, and resident status). Interpretation The decrease in malaria cases from 2014 to 2015 is associated with a decrease in imported cases from West Africa. This finding might be related to altered or curtailed travel to Ebola-affected countries in in this region. Despite progress in reducing malaria worldwide, the disease remains endemic in many regions, and the use of appropriate prevention measures by travelers is still inadequate. Public Health Actions The best way to prevent malaria is to take chemoprophylaxis medication during travel to a country where malaria is endemic. As demonstrated by the U.S. military during the Ebola response, use of chemoprophylaxis and other protection measures is possible in stressful environments, and this can prevent malaria, especially P. falciparum, even in high transmission areas. Detailed recommendations for preventing malaria are available to the general public at the CDC website (https://www.cdc.gov/malaria/travelers/drugs.html). Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient’s age and medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Health care providers should consult the CDC Guidelines for Treatment of Malaria in the United States and contact the CDC’s Malaria Hotline for case management advice when needed. Malaria treatment recommendations are available online (https://www.cdc.gov/malaria/diagnosis_treatment) and from the Malaria Hotline (770-488-7788 or toll-free at 855-856-4713). Persons submitting malaria case reports (care providers, laboratories, and state and local public health officials) should provide complete information because incomplete reporting compromises case investigations and efforts to prevent infections and examine trends in malaria cases. Compliance with recommended malaria prevention strategies is low among U.S. travelers visiting friends and relatives. Evidence-based prevention strategies that effectively target travelers who are visiting friends and relatives need to be developed and implemented to reduce the numbers of imported malaria cases in the United States. Molecular surveillance of antimalarial drug resistance markers (https://www.cdc.gov/malaria/features/ars.html) has enabled CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and internationally. More samples are needed to improve the completeness of antimalarial drug resistance marker analysis; therefore, CDC requests that blood specimens be submitted for all cases diagnosed in the United States.

Malaria-Related Deaths among U.S. Travelers, 1963–2001

Malaria is an enormous global public health problem, responsible for up to 500 million febrile illnesses and approximately 1 million deaths each year (1). The burden of disease is primarily in sub-Saharan Africa, where approximately 90% of all malaria-related deaths occur in children younger than 5 years of age (1). In contrast, nearly 1500 cases of malaria are reported each year in the United States (2). Almost all infections are acquired outside of the United States since indigenous transmission of malaria was interrupted in the United States in the late 1940s (3). Although some cases occur in refugees and immigrants, U.S. travelers overseas are now the largest group of persons given a diagnosis of malaria. In 2000 (the most recent year for which U.S. Department of Commerce data are available), approximately 27.7 million U.S. travelers visited countries affected by malaria (4), and 825 cases of imported malaria among U.S. civilians were reported to the National Malaria Surveillance System (NMSS) (2). Despite attempts at increasing awareness of malaria among travelers and health care workers, malaria-related deaths among travelers occur nearly every year. A previous review of mortality from Plasmodium falciparum malaria in travelers between 1959 and 1987 was published in 1990 (5); no systematic review has been conducted since. We therefore performed a systematic review of malaria deaths in the United States from 1963 (the first year for which complete case reports are still available) through 2001 (the last year for which data are complete) to describe trends, elucidate risk factors, and identify potential public health actions to prevent future malaria-related deaths among U.S. travelers. Methods Malaria is a notifiable disease in the United States. Malaria cases (including fatal cases) are reported to the NMSS, which is administered by the Centers for Disease Control and Prevention (CDC) Malaria Branch. The NMSS is a passive case detection system that relies on U.S. state and local health departments and health care providers to report laboratory-confirmed malaria cases. Cases diagnosed outside the United States or one of its territories are not included. The CDC publishes an annual summary of malaria surveillance in the United States as a supplement to Morbidity and Mortality Weekly Report, which includes case summaries of all fatal malaria cases. We reviewed and screened all fatal cases that occurred between 1963 and 2001, and we included only U.S travelers in our review. We defined a malaria-related death in a U.S. traveler as 1) a death reported to NMSS and subsequently published in the annual surveillance summary for which malaria was a direct or indirect cause of death, 2) a malaria diagnosis and death that occurred in the United States or one of its territories, 3) death from a malarial infection that was acquired outside of the United States or one of its territories, and 4) death of a U.S. resident who traveled abroad for any nonmilitary purpose for any length of time at any point before onset of malaria. We abstracted cases that met these inclusion criteria and entered them into a database (Epi-Info 6.01, CDC, Atlanta, Georgia). We used Stata software, version 7 (Stata Corp., College Station, Texas), for all statistical analyses. We also used several definitions. We defined time to seeking care as the number of days between symptom onset and first visit to a medical provider (coded as unknown if treatment-seeking details were not available in the case summary), time to diagnosis as the number of days between the first visit to a medical provider and the diagnosis of malaria (coded as unknown if these dates were not specified), time to treatment as the number of hours between a diagnosis of malaria and the initiation of antimalarial treatment, appropriateness of chemoprophylaxis regimen as the extent to which CDC recommendations published at the time of travel were followed, and appropriateness of treatment as the determination based on the most recent recommendation from The Medical Letter for that year. We coded adherence to chemoprophylaxis as adherent or nonadherent if this was specifically mentioned; if not, we coded this as unknown. We defined a preventable death as one in which the person 1) took no chemoprophylaxis, 2) took (or was prescribed) inappropriate chemoprophylaxis, 3) took the correct chemoprophylaxis but did not completely adhere to the prescribed regimen, 4) delayed seeking medical care for more than 2 days after the onset of symptoms, 5) sought medical care but did not receive a diagnosis on the day of initial presentation with malaria, 6) was given a diagnosis of malaria but treatment began more than 1 day after diagnosis, or 7) was treated with an antimalarial drug that was inappropriate for the infecting species and region of acquisition. Results From 1963 to 2001, 185 malaria-related deaths were reported to the CDC: 123 (66.5%) occurred among U.S. travelers, 31 (16.8%) occurred among refugees and visitors, 17 (9.2%) occurred among military personnel, and 14 (7.6%) occurred among unknown or other groups (percentages add to 100.1% because of rounding) (Figure 1). The number of deaths among U.S. travelers has remained relatively constant over time, varying between 0 and 10 deaths (median, 3). Among the 123 U.S. travelers, 49 (39.8%) were women and the median age was 51 years (mean, 48.7 years [range, 12 to 91 years]). Most deaths (114 [92.7%]) were attributed to P. falciparum, 4 (3.3%) were attributed to P. vivax, 2 (1.6%) were attributed to P. malariae, and 1 (0.8%) was attributed to P. ovale. In 2 (1.6%) cases, the species was not determined or not reported. The percentage of erythrocytes infected with P. falciparum was reported for 46 cases (mean, 21.4% [range, 1% to 60%]). Figure 1. Number of malaria deaths among travelers, refugees or visitors, and military in the United States, 19632001. Estimated Case-Fatality Rate, Species of Infection, and Origin of Infection The estimated case-fatality rate for U.S. travelers with reported cases of imported malaria (all species) was 0.9% (range, 0% to 4.4% by year). For 1985 to 2001, the only years for which complete computerized data are available, the case-fatality rate was 1.3% for P. falciparum, 0.06% for P. vivax, 0.3% for P. malariae, and 0.3% for P. ovale. These case-fatality rates are probably an overestimate (particularly for nonP. falciparum malaria) because deaths are more likely to be reported than nonfatal cases. Most fatal cases (93 cases [75.6%]) were acquired in Africa: Kenya (25 cases), Nigeria (15 cases), and Liberia (10 cases) were the most probable frequent origins of infections, accounting for 40.6% of fatal cases. The duration of stay varied widely (<1 day to 23 years), with a median stay of 22 days. Tourism was the most frequently identified motive for travel (17.9%), with business (16.3%), missionary work (13.8%), and visiting friends or relatives (11.4%) as the next most common reasons. During the most recent years reviewed (1989 to 2001), the relative importance of these travel motives shifted: Visiting friends and relatives is now the most frequently reported motive for travel among fatal cases (21.3%), followed by business (19.2%), missionary work (10.6%), and tourism (8.5%). Use of Chemoprophylaxis Nearly half of persons (n= 57 [46.3%]) took no chemoprophylaxis, and information on the use of chemoprophylaxis was not available for an additional 32 persons (26%). Of the 34 persons who reported taking chemoprophylaxis, 12 (35.3%) took a drug or drug combination that was inappropriate for the region of travel, and 20 (58.8%) took an appropriate chemoprophylactic drug. Information was insufficient in 2 individuals to determine whether the drug regimen was appropriate. Of the 20 persons who took an appropriate drug, 6 (30%) did not adhere to the prescribed regimen. No information on adherence was available for an additional 7 persons (35%). Therefore, 7 of 123 individuals (5.7%) were known to take appropriate chemoprophylaxis and adhere to the regimen. The reasons these individuals became ill with malaria is not known, but the most likely reasons are unreported nonadherence to the recommended regimen and malabsorption of the antimalarial drug. Table 1 summarizes the chemoprophylaxis regimens currently recommended by the CDC (6). Table 1. Drugs Used in the Prophylaxis of Malaria Presenting Symptoms Fever was the most common presenting symptom, reported for 77.2% of fatal cases, followed by chills (45.9%) (Table 2). Although the classic symptoms of fever and chills or sweats were very common, 23 persons (18.7%) presented with no history of these symptoms. Symptom onset ranged from 18 days before return to 4 years after return (median, 5 days after return; P. ovale was the infecting species for the case 4 years after return). One woman, a 91-year-old who died after developing P. malariae infection, became symptomatic an unknown number of years after traveling to China. Table 2. Presenting Symptoms of 123 U.S. Travelers Who Died of Malaria, 19632001 Time to Seeking Care and Diagnosis Forty-six persons (37.4%) waited more than 1 day after symptom onset before seeking medical care (median, 4.5 days [range, 2 to 28 days]). We could not determine the timing of care-seeking for 58 persons (47.2%). Of the 90 individuals for whom the case report provides adequate information, 61 (67.8%) did not obtain a diagnosis of malaria on the same day as the medical visit. The time to diagnosis ranged from 1 day to 17 days (median, 4 days). In 4 persons, the species was initially misidentified. Diagnosis of P. malariae infection was later changed to P. falciparum infection in 2 cases, P. vivax infection was later changed to P. falciparum infection in 1 case, and P. falciparum infection was later corrected to P. vivax infection in 1 case. In 22 of the 123 U.S travelers (17.9%), malaria was diagnosed only at autopsy. Delay in Initiati

Microplate assay of acetylcholinesterase inhibition kinetics in single-mosquito homogenates

Abstract We have investigated the suitability of microplate assay methods for estimating the bimolecular rate constant ki and I50 for inhibition of acetylcholinesterase by selected organophosphates and carbamates in small portions of single-mosquito homogenates. Dilutions of homogenate up to 1:30 were used to measure these kinetic parameters. Absorbance values (or visual estimations) may be used to evaluate directly inhibitor potency in a particular assay. Practical values for these kinetic parameters may be rapidly and simply obtained using single concentrations of substrate and inhibitor. We determined variability of inhibited enzyme activities within a sample population of Anopheles gambiae using measurements from individual insects. The kinetic treatment used in analysis of microplate assay data is discussed together with the potential role of this technique in studies of enzyme inhibition phenomena associated with insecticide resistance.

A generalized approach to detection of organophosphate resistance in mosquitoes

Abstract. Insecticide bioassays and biochemical microtitre assays were compared for detection of resistance to the organophosphate insecticides malathion and fenitrothion, using inbred laboratory strains of malaria vectors Anopheles albimanus Wiedemann, An.arabiensis Patton and An.stephensi Liston.