Malaria Surveillance — United States, 2018

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. Most malaria infections in the United States and its territories occur among persons who have traveled to regions with ongoing malaria transmission. However, among persons who have not traveled out of the country, malaria is occasionally acquired through exposure to infected blood or tissues, congenital transmission, nosocomial exposure, or local mosquitoborne transmission. Malaria surveillance in the United States and its territories provides information on its occurrence (e.g., temporal, geographic, and demographic), guides prevention and treatment recommendations for travelers and patients, and facilitates rapid transmission control measures if locally acquired cases are identified. Period Covered This report summarizes confirmed malaria cases in persons with onset of illness in 2018 and trends in previous years. Description of System Malaria cases diagnosed by blood smear microscopy, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments through electronic laboratory reports or by health care providers or laboratory staff members directly reporting to CDC or health departments. 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 clinical consultations. CDC reference laboratories provide diagnostic assistance and conduct antimalarial drug resistance marker testing on blood specimens submitted by health care providers or local or state health departments. This report summarizes data from the integration of all cases from NMSS and NNDSS, CDC clinical consultations, and CDC reference laboratory reports. Results CDC received reports of 1,823 confirmed malaria cases with onset of symptoms in 2018, including one cryptic case and one case acquired through a bone marrow transplant. The number of cases reported in 2018 is 15.6% fewer than in 2017. The number of cases diagnosed in the United States and its territories has been increasing since the mid-1970s; the number of cases reported in 2017 was the highest since 1972. Of the cases in 2018, a total of 1,519 (85.0%) were imported cases that originated from Africa; 1,061 (69.9%) of the cases from Africa were from West Africa, a similar proportion to what was observed in 2017. Among all cases, P. falciparum accounted for most infections (1,273 [69.8%]), followed by P. vivax (173 [9.5%]), P. ovale (95 [5.2%]), and P. malariae (48 [2.6%]). For the first time since 2008, an imported case of P. knowlesi was identified in the United States and its territories. Infections by two or more species accounted for 17 cases (<1.0%). The infecting species was not reported or was undetermined in 216 cases (11.9%). Most patients (92.6%) had symptom onset <90 days after returning to the United States or its territories from a country with malaria transmission. Of the U.S. civilian patients who reported reason for travel, 77.0% were visiting friends and relatives. Chemoprophylaxis with antimalarial medications are recommended for U.S. residents to prevent malaria while traveling in countries where it is endemic. Fewer U.S. residents with imported malaria reported taking any malaria chemoprophylaxis in 2018 (24.5%) than in 2017 (28.4%), and adherence was poor among those who took chemoprophylaxis. Among the 864 U.S. residents with malaria for whom information on chemoprophylaxis use and travel region were known, 95.0% did not adhere to or did not take a CDC-recommended chemoprophylaxis regimen. Among 683 women with malaria, 19 reported being pregnant. Of these, 11 pregnant women were U.S. residents, and one of whom reported taking chemoprophylaxis to prevent malaria but her adherence to chemoprophylaxis was not reported. Thirty-eight (2.1%) malaria cases occurred among U.S. military personnel in 2018, more than in 2017 (26 [1.2%]). Among all reported malaria cases in 2018, a total of 251 (13.8%) were classified as severe malaria illness, and seven persons died from malaria. In 2018, CDC analyzed 106 P. falciparum-positive and four P. falciparum mixed species specimens for antimalarial resistance markers (although certain loci were untestable in some specimens); identification of genetic polymorphisms associated with resistance to pyrimethamine were found in 99 (98.0%), to sulfadoxine in 49 (49.6%), to chloroquine in 50 (45.5%), and to mefloquine in two (2.0%); no specimens tested contained a marker for atovaquone or artemisinin resistance. Interpretation The importation of malaria reflects the overall trends in global travel to and from areas where malaria is endemic, and 15.6% fewer cases were imported in 2018 compared with 2017. Of imported cases, 59.3% were among persons who had traveled from West Africa. Among U.S. civilians, visiting friends and relatives was the most common reason for travel (77.1%). Public Health Actions The best way for U.S. residents to prevent malaria is to take chemoprophylaxis medication before, during, and after travel to a country where malaria is endemic. Adherence to recommended malaria prevention strategies among U.S. travelers would reduce the number of imported cases. Reported reasons for nonadherence include prematurely stopping after leaving the area where malaria was endemic, forgetting to take the medication, and experiencing a side effect. Health care providers can make travelers aware of the risks posed by malaria and incorporate education to motivate them to be adherent to chemoprophylaxis. Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient’s age, pregnancy status, medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Antimalarial use for chemoprophylaxis and treatment should be determined by the CDC guidelines, which are frequently updated. In April 2019, intravenous (IV) artesunate became the first-line medication for treatment of severe malaria in the United States and its territories. Artesunate was approved by the Food and Drug Administration (FDA) in 2020 and is commercially available (Artesunate for Injection) from major U.S. drug distributors (https://amivas.com). Stocking IV artesunate locally allows for immediate treatment of severe malaria once diagnosed and provides patients with the best chance of a complete recovery and no sequelae. With commercial IV artesunate now available, CDC will discontinue distribution of non–FDA-approved IV artesunate under an investigational new drug protocol on September 30, 2022. Detailed recommendations for preventing malaria are online at https://www.cdc.gov/malaria/travelers/drugs.html. Malaria diagnosis and treatment recommendations are also available online at https://www.cdc.gov/malaria/diagnosis_treatment. Health care providers who have sought urgent infectious disease consultation and require additional assistance on diagnosis and treatment of malaria can call the Malaria Hotline 9:00 a.m.–5:00 p.m. Eastern Time, Monday–Friday, at 770-488-7788 or 855-856-4713 or after hours for urgent inquiries at 770-488-7100. 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 public health efforts to prevent future infections and examine trends in malaria cases. Molecular surveillance of antimalarial drug resistance markers enables CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and globally. A greater proportion of specimens from domestic malaria cases are needed to improve the completeness of antimalarial drug resistance analysis; therefore, CDC requests that blood specimens be submitted for any case of malaria diagnosed in the United States and its territories.


Introduction
Malaria, a febrile parasitic illness transmitted through the bite of an infective mosquito, was estimated to cause 241 million illnesses in 2020 and 627,000 deaths worldwide (1). In 2018, there were an estimated 228 million cases of malaria, globally, and 405,000 deaths (2). Malaria is transmitted in 85 countries, and approximately one half of the world population is at risk for infection (1). Since 2000, the global community has funded and implemented malaria control efforts and achieved an estimated 23 million fewer malaria cases in 2018 alone, compared with 2010, and cumulatively, these efforts have prevented millions of malaria deaths. However, during 2014-2018, the number of cases globally was stable (2), and in 2020 the number of malaria cases increased compared with previous years, in part because of disruption of health services and interventions from the COVID-19 pandemic (1). In October 2021, the first malaria vaccine was recommended by the World Health Organization to protect infants and children aged 5-24 months living in moderate-to-high transmission areas (3).
Plasmodium parasites that cause malaria are transmitted through the bite of an infective Anopheles mosquito, resulting in an intraerythrocytic illness, which can range from asymptomatic or mild to severe and fatal. Four species of Plasmodium cause illness in humans: P. falciparum, P. vivax, P. ovale species (caused by P. ovale curtisi and P. ovale wallikeri), and P. malariae. Simian malarias can also cause illness in humans, particularly P. knowlesi in Southeast Asia. P. falciparum causes the most infections worldwide; it is predominant in Africa where an estimated 95% of cases occur (1,2), and partly because of a rapid replication rate, infections from this species can rapidly progress to severe illness, especially for infants and children aged <5 years and among persons who do not have acquired immunity (4). In 2018, P. vivax accounted for approximately 3% of cases worldwide. P. vivax is found in a broad geographical area and although it contributed <1% of cases in Africa, it made up 75% of cases in the Americas, 50% of cases in Asia, and approximately 30%-35% of cases in the Eastern Mediterranean and Western Pacific regions (2). Compared with P. vivax and P. falciparum, transmissions of P. ovale spp., P. malariae and P. knowlesi species are limited. Approximately 95% of P. ovale spp. cases were identified in Africa, with 5% in Asia (5). P. vivax and P. ovale parasites have a dormant stage (hypnozoite) in the liver, making relapse common during the period of 45 days to 3 years after an initial illness (4). P. vivax parasites transmitted in some areas of Asia can have a long incubation period, lasting 6 or more months from inoculation to symptom onset (6)(7)(8). P. malariae parasites are found throughout the tropics and subtropics and are often detected in mixed species infections. P. malariae parasites mature slowly in human and mosquito hosts and, although they do not typically cause severe symptoms in humans, can result in persistent low-density infections that can last for years, providing opportunities for ongoing transmission and health sequelae (4,9). P. knowlesi is predominantly a simian malaria found in Southeast Asia; however, it can be transmitted to persons, and in Malaysia, it has become the predominant species that causes malaria illness in humans (10)(11)(12). Exposure to forested areas with simian habitat is a risk factor for P. knowlesi, and these infections can be serious or fatal (10,13).
Although malaria was eliminated from the United States* in the mid-1950s (14), the Anopheles mosquito vector still exists throughout the United States (15). Since 1957, malaria surveillance has been supported to detect cases and prevent reintroduction, monitor antimalarial resistance, assess trends in case acquisition, and guide malaria prevention and treatment recommendations for U.S. residents. Most malaria cases diagnosed in the United States are imported from countries with ongoing mosquitoborne transmission. Occasionally, congenitally acquired cases, induced cases (resulting from exposure to blood or tissue products), and cryptic cases (for which exposure cannot be easily explained despite investigation by state and local health departments and CDC) occur. During 1957-2003, a total of 63 malaria outbreaks occurred in the United States. The last well-documented local mosquitoborne transmission occurred in 2003, when eight cases were diagnosed among nontravelers in Palm Beach, Florida (16)(17)(18).
Clinical illness results from the presence of an asexual, intraerythrocytic stage of the parasite in red blood cells. Factors that contribute to variability in illness severity are complex and include the parasite species and density of infection, the patient's age and immune response to the infection, the presence of acquired or protective immunity, the patient's general health and nutritional constitution, chemoprophylaxis effects, and time to initiate appropriate treatment (4). Persons that live in areas with high malaria transmission who experience repeated malarial illnesses might develop partial protective immunity that can result in less severe illness or even asymptomatic parasitemia. However, without continual exposure, this semi-immunity will be lost within a few years (19)(20)(21), and thus it is assumed that U.S. residents do not have any degree of protective immunity * The term "United States" includes all U.S. states and territories.
to malaria and are susceptible to severe illness and death. Although malaria symptoms vary by age and immunologic status, fever is the predominant symptom (22). Symptoms associated with uncomplicated malaria include chills, sweating, headache, fatigue, myalgia, cough, nausea, and mild anemia. If not treated promptly, malaria can rapidly progress and affect multiple organ systems and result in altered consciousness (cerebral malaria), seizures, severe anemia, acute kidney injury, liver failure, respiratory distress, coma, permanent disability, and death. Travel history should be routinely requested for patients with fever. All persons who have fever and who recently traveled to areas where malaria is endemic as well as persons who have unexplained fever, regardless of travel history, should be tested immediately for malaria.
To prevent malaria, CDC recommends that U.S. residents use chemoprophylaxis (i.e., antimalarial medication taken before, during, and after travel to a country with malaria transmission).
Persons who intend to travel should ask their physician for a prescription for an antimalarial that is appropriate for the country or region of travel, the age of the patient, pregnancy status, and individual preferences (e.g., cost or regimen type [daily versus weekly]). CDC provides chemoprophylaxis guidelines to health care providers and the public (Table 1). Implementing mosquito avoidance measures provides additional protection and includes the use of repellents, use of permethrintreated clothing, sleeping in screened sleep spaces, and using an insecticide-treated bed net (23).
This report summarizes malaria cases reported to CDC with onset of symptoms in 2018, describes trends during previous years, and highlights information on risk factors and prevention. The intended audience includes public health authorities, health care providers, and persons traveling to areas with malaria transmission. Information on chemoprophylaxis, diagnosis, and treatment is provided for health care professionals and the public, and links to additional malaria information and resources are provided.

Data Sources and Analysis
Malaria case reports were submitted to CDC through the National Malaria Surveillance System (NMSS) and the National Notifiable Diseases Surveillance System (NNDSS) (24). The Armed Forces Health Surveillance Division provides reports of malaria among military personnel to NMSS. As a notifiable condition, positive malaria laboratory test results are automatically reported from hospital, commercial, public health, and other laboratories to state and local health departments through the electronic laboratory reporting system (25). The electronic laboratory reports prompt investigations by state and local health departments that are submitted to CDC via NNDSS and NMSS (26). Both systems rely on passive reporting from the jurisdictions, and the number of cases might differ (e.g., because of differences in date classifications). NNDSS report dates might be assigned according to the date of diagnosis or the date reported to the health department, and NMSS assigns dates according to illness onset. In addition, the NNDSS reporting system provides only basic case demographic information, whereas NMSS collects detailed epidemiologic data, including laboratory results, travel history, and clinical history, which facilitate investigation and classification of each case. Certain cases are reported through direct consultation with CDC staff members via the Malaria Hotline. Diagnostic confirmation of cases often is facilitated by the CDC reference laboratory. This report summarizes data from the integration of all NMSS and NNDSS cases and CDC reference laboratory reports after deduplication and reconciliation. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. † Malaria cases are classified as confirmed or suspected using the 2014 case definition from the Council of State and Territorial Epidemiologists and CDC (27). Malaria cases are further categorized by infecting Plasmodium species. When more than a single species is detected, the case is categorized as a mixed infection. All categories are mutually exclusive. A confirmed case is diagnosed via blood smear microscopy or polymerase chain reaction (PCR). If a rapid diagnostic test (RDT) is used to initially diagnose malaria (28), the diagnosis must be confirmed either by microscopy or PCR to be counted as a case. Only data from confirmed cases are included in this report. CDC reviews all reports and might request additional information from the reporting jurisdiction or provider. Rare cases classified as acquired in the United States are investigated further, as are those classified as induced, congenital, or cryptic according to the malaria surveillance definitions. The malaria case report form and instructions for completing it are available from the CDC malaria website (29). All data management was done by a CDC malaria surveillance subject matter expert. Data from the structured malaria case report form were entered into the NMSS Microsoft Access database; alternatively, spreadsheets extracted from department of health surveillance systems were normalized and imported into the NMSS Microsoft Access database. For the 2018 analysis, data from electronic case report forms (30) Pearson's chi-square test was used to calculate p values and assess differences between variables reported in 2018 compared with previous years. A p value of <0.05 was considered statistically significant. Linear regression using the least squares method was used to assess the linear trend in the number of cases during 1972-2018. The Pearson product-moment correlation coefficient (R 2 ) was used to describe the proportion of variation explained by the model. States with one or more cases were categorized into quartiles using the QNTLDEF = 5 option in SAS.

Definitions
The following definitions are used in malaria surveillance for the United States (27) (https://www.cdc.gov/malaria/ report.html): • Adherence to chemoprophylaxis: Reported response (yes or no) to the question, "Was chemoprophylaxis taken as prescribed?" • Confirmed case: Symptomatic or asymptomatic infection that occurs in a person in the United States who has laboratory-confirmed (by microscopy or PCR) malaria parasitemia, regardless of whether the person had previous episodes of malaria. A subsequent episode of malaria in the same person is counted as an additional case unless the case is indicated as a treatment failure within 4 weeks of initial presentation. • Laboratory criteria for diagnosis: Demonstration of malaria parasites by blood smear microscopy or PCR. • Non-U.S. residents: Persons who are residents of a country other than the United States. Immigrants and refugees who are establishing residence in the United States are classified as non-U.S. residents if their exposure occurred while they were residents in their originating country.
• Suspect case: A positive malaria RDT result in a person in the United States without confirmation by microscopy or PCR.

• Transfusion transmitted malaria (TTM): A Plasmodium
infection that is accidentally caused by the transfusion of whole blood or blood components from an infected donor to a recipient. In NMSS, the recipient is classified as having induced malaria. • Treatment according to CDC recommendations (i.e., appropriate treatment): Treated with a CDC-recommended regimen appropriate for species, region, and severity of disease (32). Patients who received more antimalarial medication than recommended were classified as appropriately treated because the precise sequence and circumstances of excess treatment are not included in the malaria case report and characterizing the purpose or appropriateness of the additional antimalarial treatment is often not possible. Cases also were counted as severe if the person received treatment for severe malaria (i.e., artesunate, quinidine, or an exchange transfusion) despite having no specific severe manifestations reported. All fatal cases, for which malaria was the cause of death, were classified as severe. • Travelers visiting friends and relatives (VFR): Immigrants, ethnically and racially distinct from the major population of the country of residence (a country where malaria is not endemic), who return to their homeland (a country where malaria is endemic) to visit friends and relatives; family members of immigrants (e.g., spouse or children) are included in this group, even if they were born in the country of residence (38,39). Non-U.S. residents who travel to visit friends and relatives in the United States also are classified as VFR travelers; however, characteristics of these persons are assessed separately from U.S. resident VFR travelers.

Diagnosis of Malaria
Three laboratory tests can be used to diagnose malaria: 1) microscopic analysis of a peripheral blood smear, 2) PCR, and 3) RDT; a blood smear is recommended as the preferred first-line test. If malaria is suspected, a Giemsa-stained smear of the patient's peripheral blood should be examined by microscopy for parasites as soon as possible. Microscopy provides both speciation and an estimation of the level of parasitemia, which is necessary to prescribe appropriate treatment. Diagnostic accuracy depends on blood smear quality and examination by experienced laboratory personnel (40,41). Three sets of thick and thin blood smears spaced 12-24 hours apart are needed to rule out malaria. PCR, although not timely enough to be useful in the initial diagnosis and treatment of acute malaria, is used to confirm the species, which is important for P. vivax and P. ovale infections that require additional treatment to prevent relapse (32), and for the confirmation of mixed species infections.
The BinaxNow malaria RDT (Abbott Laboratories) detects circulating malaria-specific antigens and is the only RDT approved by the Food and Drug Administration (FDA) for use by hospital and commercial laboratories (28); the test is not approved as a point-of-care test by clinicians or the general public (28,42). RDTs are less sensitive than blood smear microscopy and not able to determine all Plasmodium species or quantify malaria parasites; therefore, the results require confirmation and species identification by microscopy (43). If microscopy is not performed, although suboptimal because it is not timely for immediate treatment decisions, PCR can confirm an RDT result and determine the species.

Drug Resistance Marker Surveillance
In 2012, CDC began molecular surveillance of imported malaria cases, with the goal of detecting and characterizing parasites that carry genetic markers (typically single nucleotide polymorphisms in one or more loci or gene copy number variation) associated with antimalarial drug resistance (44). Molecular surveillance data are used to identify where drugresistant foci might be present or emerging in specific parts of the world where malaria is endemic. For each specimen submitted, species confirmation is conducted using a real-time PCR assay capable of detecting the four primary humaninfecting Plasmodium species. Submitted specimens containing P. falciparum parasites are tested for molecular markers associated with resistance to sulfadoxine, pyrimethamine, chloroquine, mefloquine, atovaquone, and artemisinin. Additional markers of resistance in P. falciparum or other species will be similarly evaluated as they become available and as new laboratory methods are developed.
Chloroquine resistance markers: The pfcrt gene sequence is amplified using a nested PCR method as previously described (45) and analyzed to identify polymorphisms at codons C72S, M74I, N75E, and K76T.
Pyrimethamine and proguanil resistance markers: The pfdhfr gene sequence is amplified using a nested PCR method as previously described (45) and analyzed to identify polymorphisms at codons A16V, C50R, N51I, C59R, S108T/N, and I164L.
Sulfadoxine resistance markers: The pfdhps gene sequence is amplified using a nested PCR method as previously described (45) and analyzed to identify polymorphisms at codons S436A, A437G, K540E, A581G, and A631S/T.

Atovaquone resistance markers:
The pfcytb gene sequence is amplified using a nested PCR method as previously described (46) and analyzed to identify polymorphisms at codons I258M and Y268S.
Mefloquine resistance markers: A real-time PCR assay is used to determine the variation in the number of copies of the pfmdr-1 gene using the comparative cycle threshold (ΔΔC T ) method as previously described (47). DNA from the 3D7 laboratory control, which has a single copy of pfmdr-1, is used as the calibrator. In addition, DNA from Indochina W2mef and Dd2 are used as multiple copy number controls.

General Surveillance
CDC received 1,823 reports of confirmed malaria cases among persons tested in the United States with onset of symptoms in 2018 (Table 2). These cases represented a 15.6% relative decrease from 2017 (n = 2,161), which had the most reported confirmed cases since 1971 when there were 3,180 cases (51) (Figure 1). Of the 1,823 cases reported in 2018, a total of 1,788 (98.1%) were imported from countries where malaria was endemic, one case was induced from a bone marrow transplant, and one was investigated and classified as cryptic. Of the 33 (1.8%) cases that were unable to be classified, 15 of these reports contained only laboratory or demographic information, and 18 patients were lost to follow-up for the case investigation. In 2018, of the 1,823 confirmed cases, 58.5% occurred among U.S. civilians, 2.1% among U.S. military personnel, 20.6% among non-U.S. residents, and 18.9% among persons for whom residence status was not reported ( Table 2 and Table 3). In 2018, seven persons in the United States died from malaria. Since 1972, the numbers of malaria cases have been increasing, with an average gain of 29.2 cases per year (R 2 = 0.753) ( Table 2 and Figure 1). The number of malaria cases among the U.S. civilian population has increased over time, with approximately 22 cases added each year during 1972-2018 (R 2 = 0.888). In contrast, the trajectory of the accumulation of military and non-U.S. resident cases was flat during this period (R 2 = 0.021 and R 2 = 0.016, respectively) ( Figure 1).
Among all cases identified in the United States, a total of 61.8% of patients were male, 76.6% were adults aged 18-64 years, and 67.1% were Black or African American (76.1% among patients with known race), and 2.0% were Hispanic or Latino (Table 3). A total of 294 (16.1%) infants, children, and adolescents aged <18 years received a diagnosis of malaria in the United States in 2018, and 66 (22.5%) of these were aged <5 years. In 2018, a total of 132 persons with malaria were aged ≥65 years.
The primary reason for travel was reported for 1,330 (74.4%) of 1,788 imported cases (Table 3). Of these, more than one half of all cases (833 [62.6%]) and more than three fourths of U.S. civilian cases (673 [77.0%]) reported traveling to visit friends and relatives (VFR). In 2018, the number and proportion of cases in non-U.S. residents that traveled to the United Sates to visit family or friends decreased ( Among the 1,788 cases of malaria imported into the United States in 2018, a total of 1,768 cases (98.9%) had information reported for the month of illness onset ( Figure 2). Overall, the mean number of imported cases per month was 147.3. More cases than average were reported for May-September; the highest number of cases (231) was reported in August followed by July (210) and September (198 (52,53). The adult patient had traveled to Southeast Asia and reported mosquito exposures while in forests. It is unknown if the patient took chemoprophylaxis to prevent malaria. The patient experienced uncomplicated malaria, was treated with atovaquone-proguanil, and recovered.
In 2018, a total of 17 (1.1%) malaria cases with mixed species were reported, a similar proportion to that in 2017 (22 cases [1.1%]). Of the mixed species malaria cases, 14 were from Africa, two from South America, and one from an unknown region. Nine malaria cases with mixed infections were P. falciparum and P. ovale (seven were PCR confirmed; eight cases came from Africa and one from an unknown country); four cases were P. falciparum and P. malariae (all PCR confirmed; all came from Africa); two cases were P. falciparum and P. vivax (both PCR confirmed; both came from South America); one case was P. malariae and P. ovale (not PCR confirmed; came from Africa); and one was P. vivax and P. ovale (PCR confirmed; came from Africa).
Of the 1,788 imported malaria cases in 2018, a total of 692 (38.7%) were PCR confirmed ( Among the 1,584 imported malaria cases with the Plasmodium species determined, 1,238 (78.2%) had complete information on the travel return and illness onset dates allowing for calculation of the interval between these dates (Table 6). Among these patients, regardless of infecting species, 173 (14.0%) had illness onset before the return to the United States and 1,063 (85.9%) had illness onset before or within 29 days of arrival to the United States. Among patients with P. falciparum, 99% had illness onset before return to, or less than 90 days from the date of arrival to the United States (994 of 1,004 cases). In contrast, approximately 40% of P. vivax and P. ovale patients had illness onset 90 or more days after their return to the United States (51 [40.8%] of P. vivax cases, and 26 [40.6%] of P. ovale cases), consistent with the potential for these species to relapse because of the persistence of liver hypnozoites, or to have an extended incubation period before symptom onset (4,(6)(7)(8). Of infections with any species reported, 98.9% (1,224 cases) had illness onset within 1 year of returning from a country where malaria is endemic. Twelve of 14 infections that occurred more than 1 year after return to the United States were P. vivax (eight cases) and P. ovale (four cases).
Of the two P. falciparum cases with illness reported more than 1 year after return, one was a PCR-confirmed infection in an asymptomatic bone marrow transplant donor (see induced case summary for more information), and the other case was blood smear confirmed infection in a U.S. resident who had traveled to West Africa, § with no reason for travel or travel duration reported.
Among all 1,823 malaria cases, information on history of malaria for the infected patient in the previous year was available for 1,285 (70.5%) cases; of these, 244 (19.0%) patients had malaria previously, and all cases were imported. Of the 14 mixed species infections with information, eight (57.1%) patients reported a previous history of malaria, as did 48.0% (61 of 127 cases) of patients with P. vivax, 27.8% (20 of 72 cases) with P. ovale, 22.2% (eight of 36 cases) with P. malariae, and 13.8% (128 of 927 cases) with P. falciparum infections. Among cases where the species of the current illness was known, the species of the previous infection was identified for 43 patients with a history of malaria (22 were P. falciparum, 19 were P. vivax, and one each was P. ovale and P. malariae). Concordance between the species of the acute illness and the reported prior illness was observed for 37 (86.1%) of 43 reports containing information on the species of the prior infection (19 were P. vivax infections, 17 were P. falciparum, and one was P. ovale). The 20 cases in patients currently and previously infected with P. vivax or P. ovale were considered possible relapses because these species can retain dormant hypnozoites, and the previously reported infection was with the same species; other relapse cases might have occurred, although they could not be classified as such because of missing information reported. Fourteen (70.0%) possible relapse cases had information on the time between the previous and current illnesses; the mean number of days between previous and relapsing illness was 187.6 days (range: 52-377 days). Of the 19 likely P. vivax relapse cases, eight originated from Africa, six cases from Asia, three cases were from South America, and one each from Oceania and Central America. One likely P. ovale relapse case was from Africa. Date information for the previous illness was reported for six of 17 P. falciparum infections with a history of malaria and concordant prior species reported, and three (50.0%) of these indicated that the prior illness occurred within 35

Region of Acquisition and Diagnosis
The region of travel was reported for 1,722 (96.3%) of the 1,788 imported cases (Table 3)   Of 146 patients who reported the name of the chemoprophylaxis antimalarial taken to prevent malaria, 144 (98.6%) also had the country of acquisition reported so that the appropriateness of the regimen could be ascertained. Of these, 134 (93.1%) reported taking an antimalarial that was correct for the region of travel and 10 (6.9%) did not take a recommended medication. Of 134 patients who took a correct prophylaxis regimen for the region of travel, adherence information was reported for 119 (88.8%) patients and 76 (63.9%) reported missing doses.
Of the 43 persons who reported taking all doses of an appropriate chemoprophylaxis regimen, 23 (53.5%) had P. falciparum infections, 11 (25.6%) P. vivax, five (11.6%) P. ovale, two (4.7%) P. malariae, and two (4.7%) an undetermined species. Primary prophylaxis can prevent acute illness of P. vivax and P. ovale infections, although patients might experience a relapsing infection unless primaquine was taken to eliminate dormant hypnozoites (radical cure). For the 16 patients who reported adherence to chemoprophylaxis and were infected with P. vivax or P. ovale parasites, seven patients had traveled in Asia; six in Africa; and one each in Central America and the Caribbean, South America, and Oceania. Of these 16 patients, five took mefloquine for prophylaxis, four took atovaquone-proguanil, two took doxycycline, and five patients took two or more antimalarials for chemoprophylaxis. The time between return to the United States and onset was available for 14 of 16 patients with P. vivax or P. ovale infections; of these, 11 (78.6%) had onset dates more than 45 days from return, suggesting that the infection could be consistent with a relapsing illness.
Of the 25 patients who reported complete adherence to an appropriate chemoprophylaxis regimen and were infected with P. falciparum (n = 23) and P. malariae (n = 2), all had traveled to Africa. Twenty-one had information on the interval between the return date and onset of illness; of these, 20 (95.2%) had illness onset within 30 days of return to the United States, nine took atovaquone-proguanil, seven took doxycycline or mefloquine, and two took two or more antimalarials for prevention.
In 2018, specimens were not tested for molecular markers of resistance for any of the patients who reported adherence to chemoprophylaxis. Possible explanations for nonrelapsing Plasmodium infections (e.g., P. falciparum or P. malariae) in patients who adhered to chemoprophylaxis include inadequate dosing or malabsorption of the medication, inaccurate reporting of adherence, emerging parasite resistance, or chemoprophylaxis failure.

Uncomplicated Malaria
Among the 1,823 confirmed malaria cases in 2018, a total of 1,572 (86.2%) were uncomplicated, a similar proportion to 2017 (85.6%). Treatment information was reported for 1,296 (82.4%) of cases with uncomplicated malaria, and the most common antimalarial treatment administered was atovaquone-proguanil, given to 789 (60.9%) of 1,296 patients with medications recorded, followed by artemetherlumefantrine for 213 ( Of the 176 U.S. residents with imported severe malaria (civilian and military), chemoprophylaxis use was reported for 165 (93.8%), and 138 (83.6%) reported taking no chemoprophylaxis medication for malaria prevention before, during, or after travel. Of the 27 who reported taking any chemoprophylaxis, 10 did not provide information on the regimen or adherence, 14 took a regimen that was not consistent with CDC guidelines or missed doses of a correct regimen, and three reported taking all doses of a correct regimen. Of the three patients with severe malaria who adhered to a recommended chemoprophylaxis regimen, two took atovaquone-proguanil, and one took doxycycline. Potential reasons for chemoprophylaxis failure in these patients with severe malaria include inadequate dosing or malabsorption of the chemoprophylaxis medication, inaccurate reporting of adherence, or emerging parasite resistance.
Patients with severe malaria can have multiple clinical complications. Among patients with severe malaria in 2018, acute kidney injury was the most common complication and was experienced by 38 ( The species for the current, acute illness was reported for 19 of 21 patients with a history of malaria, and 11 of these were P. falciparum (57.9%), four (21.1%) were P. ovale, two (10.5%) were P. vivax and one each (5.3%) were P. malariae and mixed species infection. Among the 234 patients with severe malaria and the current infecting species determined, a higher proportion of patients with non-falciparum infections (eight of 20 [40.0%]) had recent illness compared with 11 (5.1%) of 214 patients with a current P. falciparum infection.

Special Populations
Military personnel. Among the 38 cases of malaria confirmed in U.S. military personnel, 25 cases were acquired from Asia (19 cases from Afghanistan and six cases from South Korea), 12 were from Africa (three cases from Africa, unspecified; five from West Africa; three from Eastern Africa; and one from Central Africa); and the country of acquisition was not reported for one case. Four military patients acquired malaria after traveling to Africa to visit friends and relatives, and travel was not deployment related. Twenty-five (65.8%) U.S. military personnel reported taking any prophylaxis; of these, seven (28.0%) took all doses of a correct regimen. Eleven P. falciparum and one P. ovale infections were acquired by U.S. military members who had traveled to Africa. Of the 25 military patients who had traveled to Asia, 24 infections were confirmed as P. vivax, and one patient did not have the species confirmed. The one military patient for whom the country of origin was unknown was infected with P. falciparum. Of the 25 military personnel who acquired malaria in Asia, complete information on the date of return to the United States after travel and the onset date was available for 22, and the mean time from the travel return date to symptom onset was 186.6 days. Four U.S. military patients had severe illness, two with P. falciparum acquired in Africa or an unknown country, and two with P. vivax acquired in Afghanistan. All four military patients with severe illness were treated with IV medication for severe malaria (three with quinidine and one with artesunate). All U.S. military patients recovered from their illness.
Pregnant women. Of 683 women, 19 (2.8%) were pregnant, 15 had uncomplicated illness, and four pregnant women had severe malaria. All pregnant women acquired malaria in Africa; 15 were P. falciparum, one was P. vivax, and three had infections where the species was not determined. The residence status for all pregnant women was reported, and 11 were U.S. residents (nonmilitary). Of the 11 pregnant women who were U.S. residents, nine traveled to visit friends and relatives, one for tourism, and one for an unknown reason. Of the eight non-U.S. residents who traveled to the United States, four were refugees or immigrants, two visited friends or family, and one each traveled to the United States for a medical reason or for an unknown reason. Five pregnant women reported having a history of malaria in the 12 months before the current illness, and four of them were non-U.S. residents.
Antimalarial drug choices to prevent or treat malaria during pregnancy are limited because of the safety profile of medications approved for pregnancy and drug resistance patterns. In most areas where malaria is endemic, only mefloquine is approved for chemoprophylaxis; until 2018, only mefloquine or quinine with clindamycin was recommended as treatment for uncomplicated malaria during pregnancy (32). Chloroquine for chemoprophylaxis or treatment of uncomplicated malaria is recommended only for pregnant women to use when their travel is within limited geographical areas where chloroquine-sensitive malaria is transmitted. Primaquine can cause hemolytic anemia among persons with G6PD deficiency and should not be administered during pregnancy. Of 11 pregnant women who were U.S. residents, 10 provided information on chemoprophylaxis use, nine did not take chemoprophylaxis to prevent malaria during travel, and one reported adhering to an unnamed medication for the prevention of malaria.
Of the 15 pregnant women with uncomplicated malaria, two were missing treatment information. Among the 13 pregnant women with uncomplicated malaria and sufficient information to assess the appropriateness of treatment, six were treated according to CDC guidelines (four with quinine and clindamycin and two with mefloquine). In April 2018, the treatment guidelines changed to recommend artemether-lumefantrine for pregnant women in the second or third trimester or in the first trimester if other options are not available and the benefits outweigh the risks (54). Five pregnant women with uncomplicated malaria were treated with artemether-lumefantrine in 2018; three had onset dates after the guidelines changed, and two were treated with artemether-lumefantrine before April 2018. The gestational age of the pregnancy was not documented on the malaria case report for any of the women receiving artemether-lumefantrine, making it difficult to assess the appropriateness of treatment for those treated after the update in recommendations. Two women with P. falciparum infections were administered inappropriate treatment; one was treated with atovaquone-proguanil and one with chloroquine and clindamycin. None of the pregnant women with uncomplicated malaria were administered primaquine.
Severe malaria in pregnant women should be treated aggressively with IV regimens; in the United States during 2018, the treatment options for severe malaria were quinidinegluconate or artesunate. Three of the four patients with severe malaria were not treated according to guidelines. Two pregnant women with severe malaria were treated with oral medications only, and two women were treated with a parenteral antimalarial (quinidine-gluconate). Although pregnancy outcomes are not known, all pregnant women with severe malaria recovered, and no case of congenital malaria was reported in 2018.

Drug Resistance Markers
CDC received 154 (8.4%) whole blood specimens for molecular surveillance from patients who received a malaria diagnosis in 2018. A total of 43 of these specimens were PCR confirmed as P. vivax (n = 16), P. ovale (n = 17), P. malariae (n = 7), or as Plasmodium genus (n = 3); no molecular resistance testing was performed. For one specimen that was PCR confirmed as a mixed infection with P. falciparum and P. ovale, no amplification of resistance markers was achieved because of a low level of parasitemia. A total of 110 specimens, including 106 P. falciparum and four mixed species infections (three P. falciparum and P. malariae and one P. falciparum and P. ovale) underwent amplification and analysis of resistance mutations for at least one antimalarial drug ( Table 8). The region of acquisition was known for 108 (98.2%) of 110 specimens tested for antimalarial resistance; of these, 107 (99.1%) were acquired from Africa and one (<1%) from Asia.
Of the 101 (98.2%) specimens that amplified for five pyrimethamine loci, two specimens (acquired from Africa) had no resistance markers, six (5.9%) had two resistance markers, and 93 (92.1%) had three or more resistance markers. A total of 103 specimens (96.6%) had five sulfadoxine resistance loci analyzed; 54 (52.4%) of these had no markers of resistance, 27 (26.2%) had one resistance marker, 15 (14.6%) had two resistance markers, and seven (6.8%) had three or more resistance marker mutations. All 110 specimens were examined for chloroquine resistance at five loci. No chloroquine resistant markers were identified for 60 (54.5%) specimens, one (<1%) specimen (from Asia) had two resistant markers, and 49 (44.5%) had three chloroquine resistance markers. Copy number variation of the mefloquine locus (pfmdr1) is associated with mefloquine resistance, and 99 (90.0%) specimens were examined; two (2.0%) specimens from Africa had more than one copy of pfmdr1. The genes associated with atovaquone and artemisinin (pfk13) resistance were evaluated in 96 (87.3%) and 110 (100%) specimens, respectively, and no markers of resistance were identified for either antimalarial.
Because of widespread resistance to pyrimethamine and sulfadoxine, CDC does not recommend using drugs containing these components to treat patients with malaria in the United States (32). All patients with chloroquine resistance markers had exposure to malaria in Africa or Asia, which are considered regions with chloroquine resistance, so this antimalarial is not recommended as treatment for these patients. The two patients with multiple copies of the mefloquine (pfmdr1) gene had traveled to Ivory Coast and Liberia to visit friends and relatives, both had uncomplicated malaria, and both were treated appropriately with atovaquone-proguanil and recovered; no prophylaxis use was reported for either patient.

Cryptic Case
Patient. In early October, an otherwise healthy man aged 43 years developed onset of fever, weakness, arthralgias, and dark urine. Four days later, he was admitted to the hospital and received a diagnosis of severe P. falciparum malaria with 10.7% parasitemia and acute kidney injury. Quinidine was not available at the hospital or in the surrounding area, and he was started on an oral antimalarial regimen while artesunate was requested from CDC. The morning of his second day of admission, artesunate treatment was initiated and followed by oral atovaquone-proguanil, and the patient recovered.
Investigation. Patient blood specimens were sent to CDC, and PCR confirmed P. falciparum infection. The patient was interviewed twice, once by the health care provider and a second time by the state health department. The man was born in Ghana but had not lived there since 1995; he moved to the United States from Germany in 2008. His most recent international travel to a country where malaria is endemic was approximately 10 years earlier, and he denied having a recent history of malaria. The patient did not agree to a passport review, and no official travel documents could be verified. The patient did not report exposure to blood products, IV drug use, or another unusual exposure. No family or friends had been ill with a febrile illness, and the patient did not have an immunosuppressive condition. To rule out the possibility of local transmission, the state health department identified two additional patients who had received diagnoses of P. falciparum malaria with geographical and temporal proximity to the patient with cryptic malaria. One patient who lived approximately 20 miles away was diagnosed with P. falciparum that was acquired from travel to Togo 7 weeks before the patient with cryptic malaria had symptom onset. The other patient with P. falciparum had symptom onset approximately 4 weeks before the symptom onset of the patient with cryptic malaria and lived 6 miles from the patient with the cryptic case; this infection was acquired in Tanzania. Specimens from all three cases were submitted to CDC for PCR species confirmation and genetic characterization to determine parasite relatedness; drug resistance markers were evaluated, and neutral microsatellite analysis was conducted. Mutations observed in the pfcrt, pfdhps, pfdhfr, and pfmdr1 genes from all specimens were indicative of parasites acquired in Africa. Seven neutral microsatellites were examined, and the three specimens had different microsatellite profiles indicating that the parasites were unrelated. County mosquito surveillance data were reviewed to assess the possibility of local mosquitoborne transmission, but there were no Anopheles mosquitos trapped during the 2018 summer season in the county where the patient resides. It is unlikely that this case-patient with cryptic malaria acquired P. falciparum infection through local mosquitoborne transmission. Possible explanations for this cryptic case include nondisclosed travel or, less likely after 10 years, recurrence of malaria from late emergence of asymptomatic parasitemia.

Recipient.
A woman aged 24 years with sickle cell disease received a familial bone marrow transplant (BMT). Fifteen days after the transplant, she experienced fever, and the following day Plasmodium parasites with 10% parasitemia were identified on a routine blood smear. The patient had no clinical complications documented, was treated with parenteral quinidine-gluconate, doxycycline, and atovaquone-proguanil, and recovered. CDC confirmed P. falciparum infection by microscopy and PCR.
Investigation. The recipient had never traveled to an area where malaria is endemic nor had she experienced a previous malaria illness. The BMT donor had traveled to Ghana 1.5 years before donation. Upon returning from travel, the donor reported malaria-like symptoms that eventually resolved. Blood smears at the time were negative, and the donor was not treated for malaria.
Donor specimens collected after the BMT were tested by CDC. No Plasmodium parasites were detected in the donor blood smear. A donor whole blood specimen was positive for P. falciparum by real-time PET-PCR with a cycle threshold value of 38, which is close to the threshold for positivity (40), indicating a low level of parasitemia. The donor was also positive for Plasmodium genus and P. falciparum antibodies, but negative for parasite antigens. Microsatellite genotype testing was performed on both recipient and donor specimens; however, this was successful only for the recipient specimen so the genetic signatures could not be compared. The investigation concluded that the recipient acquired a P. falciparum infection after a BMT from a donor with asymptomatic parasitemia.

Seven Fatal Cases
Six men and one woman died from severe malaria in the United States in 2018. Their mean age was 59.1 years; the youngest was aged 41 years and the oldest was aged 72 years.
Three were Black or African American, three were White (one of whom was of Hispanic or Latino), and one had an unreported race. The residence status was reported for six of seven fatal cases, and all were among U.S. residents. All had traveled to countries in Africa and were infected with P. falciparum. The reason for travel was reported for six patients; three had traveled for business, one for tourism, one for education purposes, and one to visit friends or relatives. All patients sought care for their symptoms (range: within 2-14 days after symptoms onset), and six were hospitalized; the mean time from symptom onset to hospital admission was 7.2 days (range: 2-14 days). Two patients sought care 2-3 days after symptom onset, but received diagnoses of influenza, were discharged, and did not receive a prompt workup for malaria. One of these patients was found deceased at home 6 days after the first medical evaluation and received a diagnosis of malaria upon autopsy. Parasitemia was reported for five of seven patients, with a mean of 17.5% (range: 4%-30%). Clinical complications were reported for six cases and included renal failure (five patients), cerebral malaria (four patients), and acute respiratory distress syndrome (one patient). Antimalarial medication was administered to six patients: one was treated with oral medication alone, two were treated with quinidine-gluconate, one was treated with artesunate, and two were treated with both quinidine-gluconate and artesunate. Each fatal case had delayed diagnosis, delayed treatment, or inappropriate treatment for severe malaria. Four patients received appropriate parenteral treatment for severe malaria, but initial care seeking was delayed by 5-14 days. One patient sought care within 2 days of symptom onset, but the diagnosis of malaria was missed, and the patient died without further care. One patient sought care from a primary care provider within 3 days of symptom onset, but the diagnosis of malaria was missed, and the patient did not receive a diagnosis until 3 days later when brought to the emergency department in poor condition 6 days after symptom onset; appropriate treatment was given, but the patient died. One patient sought care within 2 days of symptom onset and received inappropriate (oral antimalarial) treatment for severe malaria.

Discussion
Since the mid-1970s, an increasing number of U.S. civilians received diagnoses of malaria in the United States, while the number of cases among U.S. military personnel and non-U.S. residents has not increased ( Table 2 and Figure 1). The increase in malaria cases coincides with the increasing trend in the annual number of international airline flights taken by U.S. citizens (55). In contrast to non-U.S. residents who might live in endemic areas, malaria among U.S. residents is preventable with compliance to chemoprophylaxis. For most military deployments to areas where malaria is endemic, except for the Republic of South Korea (8,56), there are mandatory chemoprophylaxis measures that promote adherence, and the low number of malaria cases in recent years among this group demonstrates the success of these measures to prevent malaria, even in areas of high malaria transmission (57,58). In addition to taking certain mosquito avoidance measures (23,59), adhering to an antimalarial chemoprophylaxis regimen is the best way for travelers to prevent this potentially lifethreatening illness. Chemoprophylaxis should be appropriate for the traveler's age, pregnancy status, destination country, preferences (e.g., daily or weekly drug regimen), and potential medication side effects.
In 2018, as in previous years, approximately 60% of all cases imported into the United States were attributable to persons who had traveled in West Africa, and two thirds of VFR travelers went to West Africa. This large contribution of imported malaria among VFR travelers from West Africa has been observed in other settings (60)(61)(62)(63). Changes in travel because of disease outbreaks, like 2015-2017 during and after the Ebola virus disease outbreak in West Africa where travel restrictions were implemented (64), can result in fewer U.S. numbers of malaria imported cases during the time of travel restriction and an increase in cases subsequent to the disease outbreak when persons might travel at similar times after the interruption ceases (51,55,65). Likewise, the hypothesis is that the COVID-19 pandemic might result in an initial decrease in cases while recommendations to limit travel are in place and perhaps an increase in cases compared with previous years after travel limitations are removed.
Among U.S. civilians with malaria, the most common reason for travel is VFR (51,55,(65)(66)(67). However, among those with malaria, VFR travelers were less likely to take chemoprophylaxis to prevent malaria (17.7% among VFR travelers versus 28.0% among non-VFR travelers). Focus group studies and antimalarial pricing studies identified complex barriers that might be encountered by VFR travelers to obtain and adhere to chemoprophylaxis (68)(69)(70)(71)(72). Although one of the identified barriers is an incorrect perception of being low risk for acquiring malaria or having severe illness, the other barriers identified deal with care seeking and access to pretravel care. In the United States, obtaining malaria prophylaxis involves a consultation and prescription from a health care provider, which requires knowledge about the need for pretravel care, and having the time and financial resources to pay for the visit and medications, all potential challenges for the VFR traveler. Additionally, the cost of antimalarials varies widely, and even if the patient has insurance, the insurance might not cover any or all of the medications because of dispensing limitations (68,72,73); VFR travelers often visit an endemic area for a long duration and might require more than a 1-month supply. Also, during travel they might face pressure not to inconvenience their hosts with prevention measures, possibly resulting in lower adherence (69)(70)(71).
Among those with malaria and information on chemoprophylaxis adherence, stopping a recommended chemoprophylaxis regimen prematurely upon completion of travel was given as a reason for nonadherence. Chemoprophylaxis regimens that need to be taken for a shorter duration after travel might improve adherence (74). In 2018, FDA approved tafenoquine (Arakoda) for malaria chemoprophylaxis in nonpregnant women and adults aged ≥18 years who are not G6PD deficient as confirmed by a quantitative G6PD test result (75). Arakoda chemoprophylaxis offers protection from acute Plasmodium infections, in addition to protection from relapsing infections. Although Arakoda chemoprophylaxis offers a potentially convenient and abbreviated dosage schedule (including a single dose during the week after departing the area where malaria is endemic) and protection from relapsing malaria infections, use of Arakoda requires enough time to acquire pretravel care and G6PD testing results (74).
Malaria is a medical emergency. Prompt diagnosis and treatment of malaria is necessary to prevent severe disease or death. All species of Plasmodium can cause severe illness, and any delay in the diagnosis and treatment of malaria can result in complications, regardless of the effectiveness of the treatment regimen. In 2018, all seven patients who died experienced a delay in the diagnosis of or proper treatment for malaria; four patients did not promptly seek care for their illness and died despite receiving appropriate treatment for severe malaria, two patients were not diagnosed with malaria during the initial provider consultation, and one patient with a prompt diagnosis of malaria was given oral antimalarials (an inappropriate treatment) for severe illness. Malaria is the most common single etiology of fever in the returned traveler (76,77). With international travel increasing over the past decades, returning travelers with fevers will increasingly be seen by front-line health workers who should be prepared to diagnose or rule out malaria rapidly.
Travelers should be educated about the importance of seeking care as soon as possible if fever develops after travel in a country where malaria is endemic and told to notify care providers of their travel history. Although malaria symptoms typically occur within 3 months of travel, P. vivax and P. ovale cases can have a delayed initial onset of 6 months or more after travel; this delay in symptom onset is likely because of relapsing infections commonly associated with these species. In this report, a delay in symptom onset was particularly relevant for military personnel who were deployed to Afghanistan and South Korea, and due to the drug effect on the parasites, chemoprophylaxis use might contribute to an even later onset of symptoms. To facilitate a prompt diagnosis, providers should ask all febrile patients for a travel history and include malaria in the differential diagnosis of fever in a person who has traveled to a country with malaria transmission or for those who are originally from an area where malaria is endemic. Signs and symptoms of uncomplicated malaria are often nonspecific but typically include fever. Other symptoms include headache, chills, increased sweating, back pain, myalgia, diarrhea, nausea, vomiting, and cough.
Blood smears done and read immediately are the primary test for malaria diagnosis. Thick blood smears are more sensitive than thin blood smears for detecting malaria parasites because a greater volume of blood is examined in each microscopic field. Thin blood smears facilitate identification and quantification of the parasite species (78). The percentage of parasitized red blood cells should be calculated and provided promptly to the clinical team so that disease severity and appropriate treatment can be initiated. Health care providers should assess the diagnostic and treatment resources present in their facilities, including availability at night and on weekends. The resources required to perform a malaria blood smear examination are similar to those for the commonly performed complete blood count with a manual differential. Having qualified personnel who can perform this task on call 24 hours per day can facilitate timely diagnosis. Sending specimens to offsite laboratories can incur a delay in results. In 2017, results from a follow-up to a 2010 nationwide survey of laboratories conducted in the United States (79,80) found that although most laboratories offered malaria diagnostic testing services, only 12% were in complete compliance with all the Clinical and Laboratory Standards Institute guidelines for analysis and reporting of results (https://clsi.org/standards/products/ microbiology/documents/m15). Limited laboratory experience with malaria specimens can be a barrier to accurate diagnoses, and three fourths of laboratories surveyed reported diagnosing five or fewer cases annually (80). Despite some progress in laboratory performance, opportunities are available to further improve adherence to malaria diagnosis recommendations; specifically, 19% of laboratories did not offer malaria testing at all times, 43% did not return results within 4 hours, and 57% did not return percentage parasitemia within 6 hours (80). CDC provides telediagnosis assistance to laboratories and care providers for blood smear diagnosis (81) in addition to training resources for malaria and other parasitic diseases (82). Clinicians evaluating patients with suspected or confirmed malaria should obtain a timely infectious disease consultation and consider additional assistance from the CDC Malaria Hotline (770-488-7788 or toll-free 855-856-4713 during regular business hours, or CDC's Emergency Operations Center at 770-488-7100 during evenings, weekends, and holidays). Additional information is available online at https:// www.cdc.gov/malaria/diagnosis_treatment/index.html.
Laboratories unable to provide immediate blood smear microscopy should maintain a supply of BinaxNow malaria rapid diagnostic tests (RDTs) to assist with the immediate diagnosis of malaria; however, blood smears should be prepared in parallel, with results available as soon as possible to confirm the RDT results and to provide the percentage of red blood cells infected to aid in determining uncomplicated versus severe disease (43). The BinaxNow malaria RDT detects an antigen found in all Plasmodium species in addition to the histidine-rich protein-2 (HRP2) antigen found in many P. falciparum infections. False negative results are more likely with non-falciparum infections (42,43) and with emerging P. falciparum strains that harbor hrp2 gene deletions; users should be aware of these limitations when administering malaria RDTs (83). Empiric treatment for malaria is not recommended because if a patient has malaria, then an assessment of disease severity, which includes the percent parasitemia, is not possible, which could result in improper treatment. If the patient does not have malaria, then failing to diagnose and treat the real reason for illness can lead to poor outcomes because of progression of the underlying illness.
PCR testing should not be relied on for the initial diagnosis of malaria because it does not provide timely results and diagnostic PCRs do not provide information on the level of parasitemia. However, PCR is the most definitive test to determine the infecting species and should be used to confirm the results of blood smear microscopy and evaluate for mixed infections. In 2014, the Council of State and Territorial Epidemiologists released a revised malaria case definition highlighting the importance of determining the species and the percent parasitemia at the time of diagnosis and encouraging PCR testing for each case (27). If PCR testing is not available locally to confirm the Plasmodium species, then whole blood and blood smears can be sent to state public health laboratories or to CDC for diagnostic confirmation and drug resistance marker analysis (81). Increasing the proportion of cases with species confirmation and drug resistance marker analysis will improve the epidemiologic understanding of malaria diagnosed in the United States. Specifically, drug resistance marker surveillance of imported cases might be able to detect changes in the prevalence of drug resistance markers in the countries of malaria acquisition, in which case the U.S. treatment guidelines could be revised. In addition, understanding the regional molecular profiles of parasites acquired worldwide could provide additional evidence that would help explain the malaria cases investigated in the United States, especially cryptic cases of malaria. Public health laboratories should consider developing standardized procedures for sending blood specimens from persons with malaria to CDC for molecular surveillance monitoring.
The choice of an antimalarial treatment regimen should be based on several factors, including the probability of drug resistance based on geographic origin of the parasite, the Plasmodium species, the percent parasitemia, and the patient's pregnancy and clinical status (32,36). Oral regimens are less effective than parenteral regimens for treatment of severe malaria and are not the standard of care. Severely ill patients should be treated aggressively with parenteral antimalarial therapy to ensure rapid adequate drug levels, with the goal to decrease parasitemia to <1% as soon as possible to minimize the likelihood of complications or death (32). Quinidine gluconate was the only FDA-approved medication for parenteral malaria therapy in 2018; however, as of April 2019, quinidine gluconate is no longer available in the United States (84). Beginning in April 2019, CDC made IV artesunate, the WHO-recommended first-line drug for severe malaria, available through an investigational new drug (IND) protocol for every patient in the United States with severe malaria (85). In 2020, FDA approved an IV artesunate product (86,87), and the commercial product has been available from major drug distributors for hospitals to procure since March 2021. With the IV artesunate supply and distribution adequate, CDC will discontinue distribution of investigational artesunate under the IND protocol on September 30, 2022 (88). An urgent infectious disease consultation can facilitate timely management of malaria, and CDC has resources on malaria prevention and treatment (Table 1). In 2018, as in most previous years, malaria cases were detected in all U.S. states. To give patients with malaria the best chance of a complete recovery and no sequelae, hospitals can develop a plan for rapid malaria diagnosis via blood smear microscopy and malaria RDTs, stock antimalarials like artemether-lumefantrine (Coartem) and IV artesunate for treatment and, if stocking IV artesunate is not possible, there should be a plan for emergency procurement of IV artesunate (87).
The findings in this report indicate a need for better knowledge among health care providers on diagnosis and treatment of severe malaria, relapsing malarias, and malaria in pregnancy. In 2018, fewer than one half of patients with severe malaria were treated according to CDC guidelines, whereas 91.7% of patients with uncomplicated malaria were treated appropriately. Less than one half of patients with relapsing species of malaria received antirelapse treatment. Approximately 30% of pregnant women with information available were administered treatment inconsistent with CDC guidelines. CDC malaria treatment guidelines are updated regularly to reflect the most current evidence for efficacy and safety. Clinicians can consult the CDC website (32) for the most current treatment guidelines. Imported malaria accounted for more than 99% of the classified cases of malaria in 2018; one nonimported case was acquired from a familial BMT, and one was investigated as cryptic, with the origin remaining uncertain. During and after international outbreaks of infectious diseases such as Ebola virus disease, Zika virus, and COVID-19, CDC and public health officials investigated potential cryptic malaria cases among patients who did not disclose a complete or accurate travel history. For most of the potential cryptic cases, nondisclosed travel was discovered (CDC, unpublished data, 2022); when possible, a passport review can be helpful to identify nondisclosed travel.
Few cases of malaria in the United States are induced from a blood transfusion or transplant (solid organ, bone marrow, or stem cells). Three cases of malaria from a blood transfusion were reported in 2016 and 2017, the first cases since 2011 (51,65,89). Because of blood supply shortages, in April 2020, FDA updated the malaria blood donor recommendations to reduce deferrals (90). Residents of countries where malaria is not endemic will be deferred for 3 months after travel to a country where malaria is endemic as long as they have no signs or symptoms of malaria at the time of deferral. The recommendation that persons who recently resided in countries where malaria is endemic should be deferred for 3 years has not changed. Former residents of countries with malaria transmission who have lived in countries where malaria is not endemic for 3 or more years can be deferred for 3 months after short-term travel if they are free of malaria during this time (90).
The Health Resources and Services Administration reported that in 2018, a total of 4,992 unrelated and 4,275 related bone marrow and cord blood transplants were performed in the United States (91). In 2018, a BMT recipient became ill with P. falciparum parasitemia 15 days after transplant from a familial donor; there were no other recipients affected. Investigation findings confirmed that the BMT donor had an asymptomatic infection with PCR-detectable P. falciparum parasites. Although the recipient had severe malaria illness, the patient received prompt and appropriate care and recovered.
Before 2018, the treatment choices for pregnant women with uncomplicated malaria were limited to mefloquine or quinine plus clindamycin. After a systematic review of existing data, in April 2018, CDC recommended artemether-lumefantrine for the treatment of uncomplicated malaria among women in the second and third trimesters of pregnancy (32). Artemetherlumefantrine can also be considered during the first trimester when other treatment options are unavailable and when the benefits outweigh the risks (54). This recommendation is consistent with WHO treatment guidelines and reflects data on treatment efficacy and birth outcomes (37,92). In 2018, approximately 30% of pregnant women in the United States received artemether-lumefantrine for treatment. In contrast, a recent evaluation of the evidence for the use of atovaquoneproguanil during pregnancy was inconclusive because of the lack of data on birth outcomes, and therefore remains not recommended for the treatment of malaria in any trimester of pregnancy (93,94). IV artesunate, the first-line therapy for severe malaria in the United States, is also the recommended treatment for severe malaria in pregnant women regardless of trimester.
Although malaria is not endemic in the United States, malaria causes illness and deaths in this country. Surveillance of malaria, a potentially deadly disease, is a collaboration between health care providers, local and state health departments, CDC, and other U.S. government departments and agencies, and vigilance is important to prevent local cases that could be induced via blood or tissue donation or acquired from local mosquito transmission. Imported cases of malaria can reintroduce Plasmodium parasites into receptive areas (16)(17)(18) where the disease is not endemic but potential vectors are present and environmental conditions can support the parasite lifecycle (15). Competent Anopheles mosquitoes and conditions conducive to malaria transmission continue to exist in the United States (95). CDC, state and local health departments, and partners are engaging to improve case surveillance reporting for malaria and other nationally notifiable diseases (24,96). Regardless of the efficiency of the surveillance system, the quality of malaria surveillance can be limited if the data are incomplete or if definitions are incorrectly used. Incomplete reporting of antimalarial treatments and the infecting species could result in the patient being misclassified for receiving treatment according to CDC guidelines. All sections of the malaria case report form should be completed because they provide information for examining malaria trends used to develop recommendations for malaria treatment and chemoprophylaxis.
The increasing trend of imported malaria parallels an increase in international travel over the decades, making improved use of chemoprophylaxis more critical for the population at highest risk, specifically VFR travelers, and preparedness for rapid diagnosis and treatment of malaria. Efforts to improve chemoprophylaxis use among VFR travelers could include working with VFR traveler communities and their providers to improve their understanding of malaria risk, encourage pretravel care, and other efforts to improve access and adherence to chemoprophylaxis. Improving preparedness to rapidly diagnose and treat malaria could include educating front-line providers on the diagnosis and treatment of malaria and having diagnostic tools and antimalarials, especially artemetherlumefantrine and IV artesunate, in stock at hospitals.
Detailed recommendations for preventing malaria are available online at https://wwwnc.cdc.gov/travel/ yellowbook/2020/travel-related-infectious-diseases/malaria. Prevention recommendations tailored for each country are available online at https://www.cdc.gov/malaria/ travelers/country_table/a.html. CDC biannually publishes recommendations in Health Information for International Travel (commonly referred to as the Yellow Book), which is available and updated on the CDC Travelers' Health website (https://wwwnc.cdc.gov/travel/page/yellowbook-home-2020) ( Table 1).