Malaria Surveillance — United States, 2014

Surveillance Summaries / May 26, 2017 / 66(12);1–24

Kimberly E. Mace, PhD1; Paul M. Arguin, MD1 (View author affiliations)

Abstract

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 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 identify episodes of local transmission and to guide prevention recommendations for travelers.

Period Covered: This report summarizes cases in persons with onset of illness in 2014 and trends during previous years.

Description of System: Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments by health care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System, National Notifiable Diseases Surveillance System, or direct CDC consultations. CDC conducts antimalarial drug resistance marker testing on blood samples submitted by health care providers or local or state health departments. Data from these reporting systems serve as the basis for this report.

Results: CDC received reports of 1,724 confirmed malaria cases, including one congenital case and two cryptic cases, with onset of symptoms in 2014 among persons in the United States. The number of confirmed cases in 2014 is consistent with the number of confirmed cases reported in 2013 (n = 1,741; this number has been updated from a previous publication to account for delayed reporting for persons with symptom onset occurring in late 2013). Plasmodium falciparum, P. vivax, P. ovale, and P. malariae were identified in 66.1%, 13.3%, 5.2%, and 2.7% of cases, respectively. Less than 1.0% of patients were infected with two species. The infecting species was unreported or undetermined in 11.7% of cases. CDC provided diagnostic assistance for 14.2% of confirmed cases and tested 12.0% of P. falciparum specimens for antimalarial resistance markers. Of patients who reported purpose of travel, 57.5% were visiting friends and relatives (VFR). Among U.S. residents for whom information on chemoprophylaxis use and travel region was known, 7.8% reported that they initiated and adhered to a chemoprophylaxis drug regimen recommended by CDC for the regions to which they had traveled. Thirty-two cases were among pregnant women, none of whom had adhered to chemoprophylaxis. Among all reported cases, 17.0% were classified as severe illness, and five persons with malaria died. CDC received 137 P. falciparum-positive samples for the detection of antimalarial resistance markers (although some loci for chloroquine and mefloquine were untestable for up to nine samples). Of the 137 samples tested, 131 (95.6%) had genetic polymorphisms associated with pyrimethamine drug resistance, 96 (70.0%) with sulfadoxine resistance, 77 (57.5%) with chloroquine resistance, three (2.3%) with mefloquine drug resistance, one (<1.0%) with atovaquone resistance, and two (1.4%) with artemisinin resistance.

Interpretation: The overall trend of malaria cases has been increasing since 1973; the number of cases reported in 2014 is the fourth highest annual total since then. Despite progress in reducing global prevalence of malaria, the disease remains endemic in many regions and use of appropriate prevention measures by travelers is still inadequate.

Public Health Action: Completion of data elements on the malaria case report form increased slightly in 2014 compared with 2013, but still remains unacceptably low. In 2014, at least one essential element (i.e., species, travel history, or resident status) was missing in 21.3% of case report forms. Incomplete reporting compromises efforts to examine trends in malaria cases and prevent infections. VFR travelers continue to be a difficult population to reach with effective malaria prevention strategies. Evidence-based prevention strategies that effectively target VFR travelers need to be developed and implemented to have a substantial impact on the number of imported malaria cases in the United States. Fewer U.S. resident patients reported taking chemoprophylaxis in 2014 (27.2%) compared with 2013 (28.6%), and adherence was poor among those who did take chemoprophylaxis. Proper use of malaria chemoprophylaxis will prevent the majority of malaria illnesses and reduce risk for severe disease (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, likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Recent molecular laboratory advances have enabled CDC to identify and conduct molecular surveillance of antimalarial drug resistance markers (https://www.cdc.gov/malaria/features/ars.html) and improve the ability of CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and globally. For this effort to be successful, specimens should be submitted for all cases diagnosed in the United States. Clinicians should consult CDC Guidelines for Treatment of Malaria in the United States and contact the CDC Malaria Hotline for case management advice, when needed. Malaria treatment recommendations can be obtained online at https://www.cdc.gov/malaria/diagnosis_treatment/ or by calling the Malaria Hotline at 770-488-7788 or toll-free at 855-856-4713.

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Introduction

Malaria parasites of the Plasmodium genus are transmitted through the bite of infective mosquitoes. Female Anopheles mosquitoes transmit four Plasmodium species that commonly cause illness in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. Mixed infections with multiple species might occur in areas where more than one species is in circulation (1). Rarely, humans can be infected with P. knowlesi, a predominantly simian malaria found in Southeast Asia. In 2013, malaria was endemic in a total of 97 countries and territories in the tropics and subtropics, with 3.3 billion persons estimated at risk for infection. In 2013, an estimated 198–214 million cases of malaria occurred worldwide, resulting in 438,000–584,000 deaths (2,3). The African region accounts for an estimated 90% of all malaria deaths (4). P. falciparum and P. vivax contribute the most morbidity worldwide. P. falciparum, the most pathogenic malaria species, has the highest prevalence in sub-Saharan Africa and is most commonly associated with severe illness and death, typically among children aged <5 years. P. vivax is less prevalent in sub-Saharan Africa because much of the population lacks the Duffy antigen required for P. vivax invasion of red blood cells. Because of its ability to survive at lower temperatures and higher elevations, P. vivax has a broader geographic range than P. falciparum, and beyond the African continent it is estimated that P. vivax accounts for 41% of malaria infections (4). Malaria relapses are common with P. vivax and P. ovale parasites, which have dormant liver stages (hypnozoites) that can reactivate months or years after the acute infection. P. malariae parasites mature slowly in human and mosquito hosts and, although they do not typically cause severe symptoms, they can result in persistent low-density infections that can last for years or even a lifetime (5).

Through the mid-20th century, malaria was endemic in much of the United States,* with approximately 300 cases per 100,000 population in 1920 (6). By 1942, malaria was limited to the southeastern United States, where the Office of Malaria Control in War Areas, the precursor of CDC, was established to reduce the impact of vectorborne diseases, especially malaria. Transmission of malaria was interrupted as a result of efforts that started in the late 1940s; these efforts included improved housing and socioeconomic conditions, case management, vector control, and environmental management (7). 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. citizens. The majority of malaria cases diagnosed in the United States are imported from countries with ongoing mosquitoborne transmission. Occasionally, congenital transmission occurs or induced cases result from exposure to blood products. The last case of transfusion-acquired malaria in the United States occurred in 2011 (8). Malaria vectors exist throughout the United States (9). In 2003, the last occurrence of local mosquitoborne transmission resulted in eight cases in Palm Beach, Florida (10,11). Consequently, state and local health departments and CDC investigate cryptic cases for which exposure cannot be explained.

Clinical illness results from the asexual intraerythrocytic stage of the parasite; severity of symptoms ranges from absent or mild to severe illness and death. Factors that contribute to variability in illness severity are complex and include the parasite species; the patient’s age, immune status, general health, and nutritional constitution; chemoprophylaxis effects; and time to initiate appropriate treatment (5). Malaria symptoms vary, but the majority of patients have fever (12). Symptoms associated with uncomplicated malaria include chills, sweating, headache, fatigue, myalgia, cough, and nausea. Infections, if not treated promptly, can affect multiple organ systems and result in altered consciousness (cerebral malaria), renal and liver failure, respiratory distress, coma, permanent disability, and death. Travel history should be routinely requested for patients who have fever in the United States. Malaria should be considered in the differential diagnosis for all persons who have fever who recently traveled to areas where malaria is endemic and for persons who have fever of unknown origin, regardless of travel history. This report summarizes malaria cases reported to CDC with onset of symptoms in 2014 and describes trends during previous years.

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Methods

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) (13). Both systems rely on passive reporting, but the number of cases might vary because of differences in date classifications (NNDSS reports are assigned according to the date reported to the health department and NMSS assigns date according to illness onset). The two systems differ in that NNDSS provides only basic case demographic information while NMSS collects detailed epidemiologic data, including laboratory confirmation and travel and clinical history, which facilitate investigation and classification of each case. Typically, NMSS cases are reported by health care providers or laboratories to local or state health departments and then to CDC. Some cases are also reported through direct consultation with CDC malaria staff via the Malaria Hotline or sent to CDC directly from clinics, physicians, and laboratories. Diagnostic confirmation of cases is often facilitated by the CDC reference laboratory. The Armed Forces Health Surveillance Branch (AFHSB) provided military malaria case reports to NMSS. This report summarizes data from the integration of all NMSS and NNDSS cases and CDC reference laboratory reports after deduplication and reconciliation.

Malaria cases are classified as confirmed or suspected using the 2014 Council of State and Territorial Epidemiologists (CSTE)/CDC case definition (14). Malaria cases are further categorized by infecting species: Plasmodium falciparum, P. vivax, P. malariae, and P. ovale. When more than a single species is detected, the case is categorized as a mixed infection. All categories are mutually exclusive. Diagnosis of malaria is made by blood film microscopy or polymerase chain reaction (PCR). A rapid diagnostic test (RDT) can be used to detect malaria antigens; however, the diagnosis must be confirmed by either microscopy or PCR to be counted as a case. Only data from confirmed cases are included in this report. Seven suspected cases were omitted from analysis because they were tested by RDT and not validated with microscopy or PCR as required in the case definition for confirmed malaria. CDC staff review all reports, when received, and request additional information from the provider or the state, if necessary. Cases classified as being acquired in the United States are investigated further, including induced, congenital, introduced, and cryptic cases. Information derived from the structured malaria case report form is entered into a database and analyzed (15).

The chi-square test was used to calculate p values and assess differences between variables reported in 2013 compared with previous years. A p value of <0.05 was considered statistically significant. Linear regression using least-squares methods (the Pearson product-moment correlation coefficient [R2]) was used to assess the linear association of the number of cases during 1973–2014.

Definitions

The following definitions are used in malaria surveillance for the United States:

U.S. residents: Persons residing in the United States, including both civilians and U.S. military personnel, regardless of legal citizenship.
U.S. civilians: Any U.S. residents, excluding U.S. military personnel.
Foreign residents: Persons who hold resident status in a country other than the United States.
Travelers visiting friends and relatives: 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. Included in the visiting friends and relatives (VFR) category are family members (e.g., spouse or children) who were born in the country of residence.
Laboratory criteria for diagnosis: Demonstration of malaria parasites on blood film, PCR, or by RDT (followed by blood film confirmation).
Confirmed case: Symptomatic or asymptomatic infection that occurs in a person in the United States or one of its territories who has laboratory-confirmed (by microscopy or PCR) malaria parasitemia, regardless of whether the person had previous episodes of malaria while in other countries. A subsequent episode of malaria is counted as an additional case, regardless of the detected Plasmodium species, unless the case is indicated as a treatment failure.
Suspected case: Symptomatic or asymptomatic infection that occurs in a person in the United States or one of its territories who has Plasmodium species detected by RDT without confirmation by microscopy or PCR, regardless of whether the person experienced previous episodes of malaria while in other countries.
Partial immunity: Immunity in persons born in areas where malaria is endemic who have survived multiple infections with malaria. Although these persons remain susceptible to malaria, their subsequent infections are less likely to be severe. This protection from severe malaria wanes if the person is no longer exposed to repeated malaria infections. Several antibodies have been identified that are a part of the immune response to malaria, but no test can classify persons as immune or not.

This report also uses terminology derived from recommendations of the World Health Organization (16). Definitions of the following terms are included for reference:

Autochthonous malaria:
- Indigenous. Mosquitoborne transmission of malaria in a geographic area where malaria occurs regularly.
- Introduced. Mosquitoborne transmission of malaria from a person with an imported case in an area where malaria does not occur regularly.
Imported malaria: Malaria acquired outside a specific area. In this report, imported cases are those acquired outside the United States and its territories.
Induced malaria: Malaria acquired through artificial means (e.g., blood transfusion, organ transplantation, or by using shared syringes).
Relapsing malaria: Recurrence of disease after it has been apparently cured. In malaria, true relapses are caused by reactivation of dormant liver-stage parasites (hypnozoites) of P. vivax and P. ovale.
Severe malaria: A case of malaria with one or more of the following manifestations: neurologic symptoms, renal failure, severe anemia (defined by hemoglobin [Hb] <7 g/dL), acute respiratory distress syndrome (ARDS), jaundice, or ≥5% parasitemia (17). To attempt to include severe cases in which clinical criteria were not reported, persons who were treated for severe malaria (i.e., with artesunate or quinidine gluconate, an exchange blood transfusion, or both) despite having no specific severe manifestations reported also are counted as severe cases in this analysis.
Cryptic malaria: A case of malaria for which epidemiologic investigations fail to identify a plausible mode of acquisition (this term applies primarily to cases found in countries where malaria is not endemic).

Laboratory Diagnosis of Malaria

To diagnose malaria promptly, physicians must obtain a travel history from every patient who has fever. Malaria should be included in the differential diagnosis for every patient with fever who has traveled to an area where malaria is endemic. If malaria is suspected, a Giemsa-stained film of the patient’s peripheral blood should be examined by microscopy for parasites as soon as possible. Thick and thin blood films must be prepared correctly because diagnostic accuracy depends on blood film quality and examination by experienced laboratory personnel (18,19). This test can quickly detect the presence of malaria parasites and also can be used to determine the species and percentage of red blood cells that are infected, which are all essential to guiding appropriate treatment of persons infected with malaria. During the Ebola virus disease (Ebola) outbreak in West Africa that began in 2014, concern was expressed that the Ebola virus might not be inactivated by the smear preparation process. As a result, CDC developed additional steps to inactivate viruses, including Ebola, during the slide preparation process (20). PCR cannot be performed quickly enough to be of use in the initial diagnosis and treatment of acute malaria; however, PCR is useful to confirm the species and to guide treatment, especially to prevent relapses from P. vivax and P. ovale infections. PCR is available from some reference and health department laboratories, and CDC recommends that PCR be performed for all cases of malaria to confirm the infecting species.

The BinaxNOW malaria RDT (Inverness Medical Professional Diagnostics, Scarborough, Maine, USA) detects circulating malaria-specific antigens and is approved for use by hospital and commercial laboratories. Therefore, the test should be used in a clinical laboratory by trained staff and not by clinicians or the general public (21,22). In the United States, use of RDTs can decrease the amount of time required to determine whether a patient is infected with malaria but does not eliminate the need for standard blood film tests. RDTs are not able to fully speciate or quantify malaria parasites. Positive and negative RDT results must be confirmed by microscopy (21), which is necessary to provide additional information about species and density of infection. If microscopy is not performed, PCR can be performed to confirm an RDT result and determine the species.

Drug Resistance Marker Surveillance

In 2012, CDC’s Malaria Branch began molecular surveillance for malaria drug resistance markers. The goal is to detect and characterize malaria parasites that carry genetic markers (typically single nucleotide polymorphisms [SNPs] in one or more loci) associated with drug resistance. These data will help to understand where foci of resistance to drugs might be present or emerging in specific parts of the world where malaria is endemic. For each sample submitted, species confirmation testing is conducted using a duplex real-time PCR capable of detecting the four human-infecting Plasmodium species. For mixed infections, samples are also processed by nested PCR using species-specific primers that accurately detect the minority population of the coinfecting malaria species. Molecular fingerprinting methods derived from microsatellite markers and SNPs are used to identify antimalarial drug resistance markers for P. falciparum samples only at this time. Additional species will be similarly evaluated as new laboratory methods are developed. Each sample submitted is tested for molecular markers associated with resistance to sulfadoxine, pyrimethamine, chloroquine, mefloquine, atovaquone, and artemisinin.

Parasite DNA is subjected to PCR amplification using appropriate primers and sequenced by the Sanger method using the ABI 3130 capillary sequencer (Thermo Fisher Scientific, Waltham, Massachusetts, USA) according to described methods (23). Fragments of genes encoding molecular targets of chloroquine (chloroquine resistance transporter gene, pfcrt), pyrimethamine (dihydrofolate reductase gene, dhfr), sulfadoxine (dihydropteroate synthase gene, dhps), atovaquone (cytochrome b gene, pfcytb), mefloquine (multidrug resistance 1 protein gene, pfmdr-1 and pfmdr-1 copy number), and artemisinin (MAL10-688956, MAL13-1718319, and kelch K13-propeller domain) were analyzed for polymorphisms by comparing each sequence to the reference genome. All reactions were conducted in triplicate on a Stratagene MX3005P (Agilent Technologies, Santa Clara, California, USA) real-time PCR machine.

Chloroquine resistance markers. The pfcrt gene sequence was analyzed to identify polymorphism at codons C72S, M74I, N75E, and K76T.

Pyrimethamine resistance markers. The pfdhfr gene sequence was analyzed to identify polymorphism at codons A16V, C50R, N51I, C59R, S108T/N, and I164L.

Sulfadoxine resistance markers. The pfdhps gene sequence was analyzed to identify polymorphism at codons S436A, A437G, and K540E.

Atovaquone resistance markers. The pfcytb gene sequence was analyzed to identify polymorphism at codons I258M and Y268S (24).

Mefloquine resistance markers. The pfmdr-1 gene sequence was analyzed to identify polymorphism at codons N86Y, Y184F, S1034C, N1042D, and D1246Y.

pfmdr-1 copy number. A real-time PCR assay was used to determine the copy number of pfmdr-1 relative to that of a single copy gene, seryl-T synthetase, using the comparative cycle threshold (ΔΔCT) method (25). The measured copy number of the pfmdr-1 gene relative to that of a standard calibrator parasite, 3D7, which has a single copy of pfmdr-1. In addition, DNA from Indochina W2 and Dd2 was used as multiple copy number controls.

Artemisinin resistance markers. Pyrosequencing was used to test for artemisinin resistance as previously reported (26) polymorphisms located on chromosome 10 (MAL10-688956) and chromosome 12 (MAL13-1718319) that are associated with artemisinin resistance in P. falciparum parasites. Another artemisinin resistance gene (K13-propeller domain) has been reported (27). The K13-propeller domain was amplified using a nested PCR method previously described (27,28). The sequence data were analyzed using Geneious Pro R8 (Biomatters, Auckland, New Zealand) to identify polymorphisms associated with artemisinin resistance.

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Results

General Surveillance

In 2014, CDC received 1,724 reports of confirmed malaria cases among persons in the United States and its territories with onset of symptoms during the calendar year. The number of confirmed malaria cases in 2014 did not significantly differ from that reported in 2013 (n = 1,741†). Since 1973, the overall trend has been increasing in the number of cases, with an average gain of 28.7 cases per year (R2 = 0.669) ( Figure 1). In 2014, a total of 1,145 (66.4%) cases were among U.S. residents, 384 (22.3%) were among foreign residents, and 195 (11.3%) were among patients with unknown or unreported resident status ( Table 1).