Malaria Surveillance --- United States, 2005

Julie Thwing, MD^1,2
Jacek Skarbinski, MD^1,2
Robert D. Newman, MD²
Ann M. Barber²
Sonja Mali, MPH²
Jacquelin M. Roberts, MS²
Laurence Slutsker, MD²
Paul M. Arguin, MD^2
1Epidemic Intelligence Service, Office of Workforce and Career Development
²Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases

Corresponding author: Julie I. Thwing, MD, Division of Parasitic Diseases, National Center for Zoonotic, Vectorborne, and Enteric Diseases, 4770 Buford Hwy., N.E., MS F-22, Atlanta, GA 30341. Telephone: 770-488-7745; Fax: 770-488-4206; E-mail: [email protected].

Abstract

Problem/Condition: Malaria in humans is caused by any of four species of intraerythrocytic protozoa of the genus Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, or P. malariae). These parasites are transmitted by the bite of an infective female Anopheles sp. mosquito. The majority of malaria infections in the United States occur among persons who have traveled to or from areas with ongoing malaria transmission. In the United States, cases can occur through exposure to infected blood products, congenital transmission, or local mosquitoborne transmission. Malaria surveillance 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 2005 and summarizes trends during previous years.

Description of System: Malaria cases confirmed by blood film or polymerase chain reaction (PCR) are mandated to be 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 (NMSS). Data from NMSS serve as the basis for this report.

Results: CDC received reports of 1,528 cases of malaria, including seven fatal cases, with an onset of symptoms in 2005 among persons in the United States or one of its territories. This number represents an increase of 15.4% from the 1,324 cases reported for 2004. P. falciparum, P. vivax, P. malariae, and P. ovale were identified in 48.6%, 22.1%, 3.5%, and 2.5% of cases, respectively. Twelve patients (0.8% of total) were infected by two or more species. The infecting species was unreported or undetermined in 22.6% of cases. Compared with 2004, the largest increases in cases came from the Americas (23.1%; n = 213) and Asia and the Middle East (18.6%; n = 204). On the basis of estimated volume of travel, the highest estimated case rates of malaria among travelers occurred among those returning from West Africa. Of 870 U.S. civilians who acquired malaria abroad, only 160 (18.4%) reported that they had followed a chemoprophylactic drug regimen recommended by CDC for the area to which they had traveled. Two patients became infected in the United States, both attributed to congenital transmission; both were infected with P. vivax. Seven deaths were attributed to malaria, all caused by infection with P. falciparum.

Interpretation: The 15.4% increase in malaria cases in 2005, compared with 2004, resulted primarily from increases in the number of cases reported from Asia and the Middle East and from the Americas. This increase might in part reflect more complete reporting and in part increased travel to malarious areas. No change was noted in proportions of cases from other areas of the world, or in species responsible for the infection. In the majority of reported cases, U.S. civilians who acquired infection abroad had not adhered to a chemoprophylaxis regimen that was appropriate for the country in which they acquired malaria. U.S. civilians who traveled to West Africa had the highest estimated relative case rate.

Public Health Actions: Additional investigations were conducted for the seven fatal cases and two infections acquired in the United States. Persons traveling to a malarious area should take one of the recommended chemoprophylaxis regimens appropriate for the region of travel and use personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and who subsequently has a fever or influenza-like symptoms should seek medical care immediately and report their travel history to the clinician; investigation should include at least one blood-film test for malaria. Malaria infections can be fatal if not diagnosed and treated promptly. Recommendations concerning malaria prevention can be obtained from CDC at http://www.cdc.gov/travel or by calling the Malaria Hotline (telephone 770-488-7788). Recommendations for malaria treatment can be obtained at http://www.cdc.gov/malaria/diagnosis_treatment/treatment.htm or by calling the Malaria Hotline.

Introduction

Malaria in humans is caused by infection with one or more of four species of Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, and P. malariae) that can infect humans. Other Plasmodium species infect animals. The infection is transmitted by the bite of an infective female Anopheles sp. mosquito. Malaria remains a devastating global problem, with an estimated 350--500* million cases occurring annually (1). Forty-nine percent of the world's population lives in areas where malaria is transmitted (e.g., parts of Africa, Asia, the Middle East, Eastern Europe, Central and South America, Hispaniola, and Oceania), and approximately 1 million persons die from malaria each year, 80% of them in sub-Saharan Africa (1). Before the 1950s, malaria was endemic throughout the southeastern United States; an estimated 600,000 cases occurred in 1914 (2). During the late 1940s, a combination of improved housing and socioeconomic conditions, water management, vector-control efforts, and case management was successful at interrupting malaria transmission in the United States. Since then, malaria case surveillance has been maintained to detect locally acquired cases that could indicate the reintroduction of transmission and to monitor patterns of resistance to antimalarial drugs. Anopheline mosquitoes remain seasonally present in all states except Hawaii.

The majority of reported cases of malaria diagnosed each year in the United States and U.S. territories are imported from regions where malaria transmission is known to occur, although congenital infections and infections resulting from exposure to blood or blood products also are reported in the United States. In addition, a limited number of cases are reported that might have been acquired through local mosquitoborne transmission (3).

State and local health departments and CDC investigate malaria cases acquired in the United States, and CDC analyzes data from imported cases to detect trends in acquisition. This information is used to guide malaria prevention recommendations for international travelers. For example, an increase in P. falciparum malaria among U.S. travelers to Africa, an area with increasing chloroquine resistance, prompted CDC to change the recommended chemoprophylaxis regimen from chloroquine to mefloquine in 1990 (4).

The signs and symptoms of malaria illness are varied, but the majority of patients have fever. Other common symptoms include headache, back pain, chills, increased sweating, myalgia, nausea, vomiting, diarrhea, and cough. The diagnosis of malaria should be considered for persons with these symptoms who have traveled to an area with known malaria transmission. Malaria also should be considered in the differential diagnosis of persons who have fever of unknown origin, regardless of their travel history. Untreated P. falciparum infections can rapidly progress to coma, renal failure, pulmonary edema, and death. This report summarizes malaria cases reported to CDC regarding persons with onset of symptoms in 2005.

Methods

Data Sources

Malaria case data are reported to the National Malaria Surveillance System (NMSS) and the National Notifiable Diseases Surveillance System (NNDSS) (5). Although both systems rely on passive reporting, the numbers of reported cases might differ because of differences in collection and transmission of data. One difference is that NMSS receives more detailed clinical and epidemiologic data regarding each case (e.g., information concerning the area to which the infected person has traveled). This report presents only data from NMSS.

Cases of blood-film-- or polymerase chain reaction (PCR)--confirmed malaria among civilians and military personnel are identified by health-care providers or laboratories. Each confirmed malaria case is reported to local or state health departments and to CDC on a uniform case-report form that contains clinical, laboratory, and epidemiologic information. CDC staff review all report forms when received and request additional information from the provider or the state, if necessary (e.g., when no recent travel to a malarious country is reported). Reports of other cases are telephoned to CDC directly by health-care providers, usually when they are seeking assistance with diagnosis or treatment. Information regarding cases reported directly to CDC is shared with the relevant state health department. All cases that have been reported as acquired in the United States are investigated, including all induced and congenital cases and possible introduced or cryptic cases (see Definitions). Information derived from uniform case report forms is entered into a database and analyzed annually.

A case rate was estimated for each country where cases of malaria were acquired on the basis of estimates of travel volume for U.S. travelers and the number of cases among U.S. travelers attributable to each country. Data used to estimate country-specific relative case rates were extrapolated from World Tourism Organization estimates of annual numbers of U.S. travelers to specified countries (6). The individual country-specific case rates were divided by the median individual country-specific case rate to determine estimated relative case rates.

Definitions

The following definitions are used in this report:

• Laboratory criteria for confirmation of diagnosis: Demonstration of malaria parasites on blood film or by PCR.
• Confirmed case: Symptomatic or asymptomatic infection that occurs in a person in the United States or one of its territories (American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands) 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 if the indicated Plasmodium sp. differs from the initially identified species. A subsequent episode of malaria occurring in a person while in the United States could indicate a relapsing infection or treatment failure resulting from drug resistance if the indicated Plasmodium sp. is the same species identified previously.

This report also uses terminology derived from the recommendations of the World Health Organization (7). 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 (American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands).
• Induced malaria: Malaria acquired through artificial means (e.g., blood transfusion or by using shared common syringes).
• Relapsing malaria: Renewed manifestations (i.e., parasitemia with or without clinical symptoms) of malarial infection that are separated from previous manifestations of the same infection by an interval greater than the usual periodicity of the paroxysms.
• 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

The early and prompt diagnosis of malaria requires that physicians obtain a travel history from every febrile patient. Malaria should be included in the differential diagnosis of every febrile patient who has traveled to a malarious area. If malaria is suspected, a Giemsa-stained film of the patient's peripheral blood should be examined for parasites. Thick and thin blood films must be prepared correctly because diagnostic accuracy depends on blood-film quality and examination by experienced laboratory personnel^† (Appendix). Select reference laboratories and health departments have the capacity to perform PCR diagnosis of malaria, although this usually is reserved for cases for which blood-film diagnosis of malaria or species determination is inadequate.

Results

General Surveillance

For 2005, CDC received 1,528 reports of cases of malaria occurring among persons in the United States and its territories, representing a 15.4% increase from the 1,324 cases reported with a date of onset in 2004 (8; Table 1). In 2005, a total of 870 cases occurred among U.S. civilians and 297 cases among foreign civilians (Table 1). Since 2003, the number of cases among U.S. civilians has been increasing (Figure 1).

Plasmodium Species

Of the 1,528 cases reported in 2005, the infecting species of Plasmodium was identified in 1,183 (77.4%) cases. P. falciparum and P. vivax were identified in blood films from 48.6% and 22.1% of infected persons, respectively (Table 2). The number of reported cases of P. falciparum increased 13.1%, from 656 in 2004 to 742 in 2005, and the number of P. vivax infections increased 7.0%, from 315 to 337. Among 1,081 cases for which both the region of acquisition and the infecting species were known, 83.4% of infections acquired in Africa were attributed to P. falciparum and 6.6% to P. vivax. The converse was true for infections acquired in the Americas and in Asia and the Middle East; 59.1% and 68.1%, respectively, were attributed to P. vivax and 33.9% and 13.2% to P. falciparum.

Region of Acquisition and Diagnosis

All but two reported cases were imported. Of 1,349 imported cases for which the region of acquisition was known, 902 (66.9%) were acquired in Africa, 204 (15.1%) in Asia and the Middle East, and 213 (15.8%) in the Americas (Table 3). A total of 30 (2.0%) imported cases were acquired in Oceania. West Africa accounted for 619 (68.6%) cases acquired in Africa, and India accounted for 137 (67.2%) cases acquired in Asia and the Middle East. In the Americas, 162 (76.0%) cases were acquired in Central America and the Caribbean, followed by 37 (17.3%) cases in South America and 14 (6.6%) cases in Mexico. Information regarding region of acquisition was missing for 177 (11.6%) imported cases. Compared with 2004, the number of reported malaria cases acquired in the Americas increased 23.1% (n = 213), the number acquired in Asia and the Middle East increased 18.6% (n = 204), and the number acquired in Africa increased 11.5% (n = 902). In the United States, the six health departments reporting the highest number of malaria cases were New York City (n = 192), California (n = 162), Texas (n = 144), Maryland (n = 97), New Jersey (n = 83), and Illinois (n = 79) (Figure 2). Of these, New York City was the only health department to report a decrease in the number of cases compared with 2004; all of the others in the top 6 reported increases.

Relative Case Rates in U.S. Civilians

In 2005, the countries with the lowest and highest estimated case rates of malaria among U.S. travelers were China and Nigeria, respectively (Figure 3). Other countries with low estimated relative case rates included Mexico, Thailand, Costa Rica, and South Africa. For many of these countries, malaria risk areas are focally located in small parts of the country. Countries with estimated relative case rates that fell in the middle range included India, Honduras, and Haiti, which had malaria transmission occurring more homogenously throughout the country. Estimated relative case rates were highest in countries in West and Central Africa, including Nigeria and Ghana, but also in two countries in Oceania: Vanuatu and Papua New Guinea. These high estimated case rates probably reflect not only widespread transmission areas but also higher transmission intensity.

Interval Between Arrival and Illness

Both the interval between date of arrival in the United States and onset of illness and the infecting Plasmodium species were known for 668 (43.7%) of the imported malaria cases (Table 4). Symptoms began before arrival in the United States for 81 (12.1%) persons and after arrival for 587 (87.9%) persons. Clinical malaria occurred <30 days after arrival in 380 (81.0%) of the 469 P. falciparum cases and in 61 (40.7%) of the 150 P. vivax cases (Table 4). Five (0.7%) of 668 persons became ill >1 year after returning to the United States.

Imported Malaria Cases

Imported Malaria Among U.S. Military Personnel

In 2005, a total of 36 cases of imported malaria were reported among U.S. military personnel, 30 of whom acquired malaria in Asia and the Middle East. These cases were reported by state health departments and might not include all cases reported through malaria surveillance activities conducted by the U.S. Department of Defense. Of the 32 patients for whom information regarding chemoprophylaxis use was available, 21 (65.6%) reported taking the correct prophylaxis, nine (28.1%) were not using any chemoprophylaxis, and two (6.3%) had adhered to an incorrect regimen.

Imported Malaria Among Civilians

Of 1,167 imported malaria cases reported among civilians, 870 (74.6%) occurred among U.S. residents and 297 (25.4%) among residents of other countries (Table 5). Of the 870 imported malaria cases among U.S. civilians, 611 (70.2%) were acquired in Africa, 100 (11.5%) were acquired in Asia and the Middle East, and 89 (10.2%) were acquired in the Central American and Caribbean regions; these percentages remained stable compared with 2004. Of the 279 imported cases among foreign civilians, 172 (57.9%) were acquired in Africa, a 4.9% decrease since 2004.

Chemoprophylaxis Use Among U.S. Civilians

Information on chemoprophylaxis use and travel area was known for 767 (88.2%) of the 870 U.S. civilians who had imported malaria. Of these 767 persons, 522 (68.1%) had not taken any chemoprophylaxis, and 42 (5.5%) had not taken a CDC-recommended drug for the area visited (9). Only 160 (20.9%) U.S. civilians had taken a CDC-recommended medication (9). Data for the specific drug taken was missing for the remaining 43 (5.6%) travelers. A total of 93 (58.1%) patients on CDC-recommended prophylaxis reported taking mefloquine; 39 (24.4%) had taken doxycycline; 20 (12.5%) had taken atovaquone-proguanil; and seven (4.4%) who had traveled only in areas where chloroquine-resistant malaria has not been documented had taken chloroquine. Information on compliance to the drug regimen for these persons is presented in the following section. Eight patients (5.0%) had taken combinations of drugs that included one or more CDC-recommended drug for the travel region. Of the 42 patients who took a nonrecommended drug, 29 (69.0%) reported taking chloroquine either alone or in combination with another ineffective drug during travel to an area where chloroquine resistance has been documented.

Malaria Infection After Recommended Prophylaxis Use

A total of 190 patients (including 160 U.S. civilians, 21 persons in the U.S. military, four foreign civilians, and five persons for whom information regarding status was missing) contracted malaria after taking a recommended antimalarial drug for chemoprophylaxis. Of these, 72 (37.9%) reported complete compliance with the regimen, and 81 (42.6%) reported noncompliance; compliance was unknown for the remaining 37 (19.5%). Information regarding infecting species was available for 153 (80.5%) patients who had taken a recommended antimalarial drug and was undetermined for the remaining 37.

Cases of P. vivax or P. ovale After Recommended Prophylaxis Use. Of the 190 patients who had malaria diagnosed after recommended chemoprophylaxis use, 62 (32.6%) had cases that were caused by P. vivax, and seven (3.7%) had cases caused by P. ovale. Of the 69 total cases of P. vivax or P. ovale, 31 (44.9%) occurred >45 days after arrival in the United States. These cases were consistent with relapsing infections and do not indicate primary prophylaxis failures. Information was insufficient to assess whether 22 cases were relapsing infections. Sixteen cases, 14 caused by P. vivax and two caused by P. malariae, occurred <45 days after the patient returned to the United States. Six of the 16 patients were known to be noncompliant with their antimalarial chemoprophylaxis regimen. Four patients reported compliance with an antimalarial chemoprophylaxis regimen; two had traveled to Africa, one to Oceania, and one to South America. Two of these four patients who reported compliance reported taking mefloquine, and two reported using doxycycline; blood samples for serum drug levels were not available. Possible explanations for these cases include inappropriate dosing, unreported noncompliance, malabsorption of the drug, or emerging parasite resistance. For six patients, no information was available concerning compliance.

Cases of P. falciparum and P. malariae After Recommended Prophylaxis Use. The remaining 121 cases of malaria reported among persons who had taken a recommended antimalarial drug for chemoprophylaxis included 75 cases of P. falciparum, six of P. malariae, three of mixed infection, and 37 for which the infecting species was unidentified. Of the 75 P. falciparum cases among those who reported taking a recommended antimalarial drug, 70 were acquired in Africa, two in Asia, one in Central America, and two in South America. In 42 (56.0%) of these 75 cases, noncompliance with antimalarials was reported; in 20 (26.7%) cases, patients reported compliance with antimalarial chemoprophylaxis; 18 of these patients had traveled to Africa, one to South America, and one to Asia. Ten had reported taking mefloquine, eight doxycycline, and two took atovaquone-proguanil for malaria chemoprophylaxis. Blood samples were not available for the patients who reported compliance with a recommended regimen.

All of the six P. malariae cases among those who reported taking a recommended antimalarial drug were acquired in Africa. One (14.3%) of these patients reported noncompliance with antimalarials, and five (57.1%) reported compliance with a recommended chemoprophylaxis regimen. Three noncompliant patients used malarone, and two used mefloquine. All five patients had traveled to Africa; blood samples were not available.

Purpose of Travel

Purpose of travel to areas in which malaria is endemic was reported for 788 (90.6%) of the 870 U.S. civilians with imported malaria (Table 6). The largest proportion (56.1%) represented persons who had visited friends or relatives in malarious areas; the second and third highest proportions, 9.5% and 7.5%, represented persons who had traveled as missionaries or as tourists, respectively.

Malaria in Children

Of the 1,460 cases for whom age was known, 276 (18.9%) cases occurred in persons aged <18 years. Of these, 21 (7.6%) were aged <24 months, 50 (18.1%) were aged 24--59 months, 122 (44.2%) were aged 5--12 years, and 83 (30.0%) were aged 13--17 years. Of the 220 cases among those aged <18 years for whom species was known, 156 (70.9%) cases involved P. falciparum and 43 (19.5%) P. vivax. The proportion of children who received a diagnosis of P. falciparum infection was 1.57 times higher than that for adults (confidence interval [CI] = 1.13--2.18; p = 0.005). Of 231 children for whom country of exposure was known, Africa accounted for 176 (76.2%) cases, Asia and the Middle East accounted for 37 (16%) cases, and the Americas accounted for 14 (6.1%) cases. For 194 children whose reason for travel was known, 106 (54.6%) were visiting friends and relatives, and 55 (28.3%) were refugees or immigrants. Tourists and missionaries together accounted for 16 (8.2%) cases, and students accounted for 15 (7.7%) cases. Of the 276 persons aged <18 years who had malaria, 54 (19.6%) had taken prophylaxis. Of these, 28 (51.9%) had taken the correct regimen, and only eight reported complete compliance: seven children on mefloquine and one child on malarone.

Malaria During Pregnancy

A total of 21 cases of malaria were reported among pregnant women in 2005, representing 4.3% of cases among women. Of the 21 cases, 14 (66.7%) occurred among U.S. civilians. Ten women had traveled to Africa, two to Asia, and one each to the Caribbean and to Oceania; nine had traveled to visit friends and relatives. Approximately 28.6% of pregnant women and 21.2% of nonpregnant women reported taking malaria chemoprophylaxis. An infant born to one of the women with malaria during pregnancy received a diagnosis of P. vivax congenital malaria. Birth outcomes were not available for the other 20 women.

Malaria Acquired in the United States

Congenital Malaria

Two cases of congenital malaria were reported in 2005 and are described below:

• Case 1. On May 13, an infant male aged 3 weeks was admitted to an emergency department (ED) with fever and congestion. Routine septic work-up was unrevealing. His mother had emigrated from Honduras in July 2004 and had a history of malaria in 2003. She had been admitted for fever at 30 weeks' gestation, but blood and urine cultures were negative. She was treated with antibiotics, recovered uneventfully, and had a spontaneous vaginal delivery with no complications at 38⁶/₇ weeks. On the basis of this history, a peripheral blood film was performed on the newborn, revealing a low parasitemia with P. vivax. He was treated with chloroquine and primaquine and recovered. Record of subsequent maternal treatment was not available.
• Case 2. On July 15, an infant girl aged 16 days was admitted to a hospital with a history of fever, cough, and congestion. Physical and laboratory examinations did not identify an infectious etiology. While in the hospital, the child was noted to have rigors. Further maternal history was sought. The mother had emigrated from India 2 years before the infant's birth but had no known history of malaria. Her pregnancy and delivery had been uncomplicated. A peripheral blood film was performed on the infant and revealed low parasitemia with P. vivax. She was treated with chloroquine with good outcome. A peripheral blood film was also performed on the mother and demonstrated to be positive for P. vivax; the mother was subsequently treated.

Deaths Attributed to Malaria

Seven deaths attributable to malaria were reported in 2005 and are described in the following case reports:

• Case 1. On January 14, a woman aged 29 years was hospitalized with lethargy and dehydration, with a history of fever, chills, emesis, and weakness for 2 weeks. She was a resident of Mozambique who had left that country on December 28, 2004, to visit relatives in the United States. She had a history of several previous episodes of P. falciparum malaria that had been treated in Mozambique. She was mildly anemic, with a hemoglobin of 10.1 mg/dL and thrombocytopenic with a platelet count of 55,000/µL. She was transferred to a tertiary care center, where a diagnosis of malaria was considered and a peripheral blood film indicated P. falciparum (20% parasitemia). She was treated with IV quinidine and underwent exchange transfusion. She had a cardiac arrest and was resuscitated on January 17, but remained comatose. She died on January 26.
• Case 2. On April 19, a man aged 55 years was taken to an ED with a 4-day history of fever, emesis, and epigastric pain. He was a resident of the United States but had traveled to Uganda, his country of origin, for 3 months and had returned on April 12. He had not taken prophylaxis. On admission, he had sinus tachycardia and a temperature of 100.3^ºF (37.9^ºC). Routine laboratory analysis was significant only for thrombocytopenia (platelet count: 19,000/µL). A differential diagnoses list was generated, including malaria, dengue fever, and Chikungunya fever, but no further evaluation was performed. His symptoms improved with anti-emetics, normal saline, and pain control. He was discharged with a tentative diagnosis of dengue fever. Four days later, on April 23, he died abruptly. Samples sent to CDC were positive for P. falciparum by PCR but negative for other suspected pathogens.
• Case 3. On May 28, a man from the Philippines aged 32 years was taken to an ED with mental status changes and a 3-day history of jaundice. He had recently traveled to the Philippine island of Palawan. He had onset of fever and chills in the Philippines on May 11; he visited a local clinic and was treated with antibiotics, with some relief. He subsequently traveled to the United States on May 20. On admission, his total bilirubin was 14 mg/dL. He was mildly anemic (hemoglobin 9.0 mg/dL), and thrombocytopenic (platelet count: 14,000/µL). Several hours after admission, information was obtained that three colleagues who had traveled with the patient to Palawan had been hospitalized in the Philippines with severe P. falciparum malaria. A peripheral blood film was performed and indicated P. falciparum. He was treated with oral quinine and doxycycline, as intravenous quinidine was not available, and transferred to a tertiary care center. On arrival, he was comatose and his temperature was 104.4^º F (40.2^º C). He was treated with intravenous quinidine and doxycycline and underwent exchange transfusion. He had acute respiratory distress syndrome (ARDS) during the exchange transfusion requiring endotracheal intubation and mechanical ventilation with increasing oxygen requirements. Although his parasitemia level diminished, his neurologic status remained unchanged. He subsequently developed anuric renal failure and died on June 2.
• Case 4. On August 2, a woman aged 23 years was taken to an ED with a 4-day history of fever, confusion, and dyspnea. She had been in Namibia for 10 months, with short visits to South Africa and Mozambique, and had not taken prophylaxis. She had returned to the United States on July 22 and had onset of fever and chills on July 30. She had been brought to another ED on July 31, where a peripheral blood film was negative. Her symptoms continued, and she visited the second ED on August 2, where her peripheral blood film revealed P. falciparum (0.6% parasitemia). She was first treated with oral quinine and intravenous clindamycin because intravenous quinidine was not available and switched the following day to intravenous quinidine and clindamycin. She subsequently had respiratory failure secondary to ARDS, requiring endotracheal intubation and mechanical ventilation, in addition to coma and coagulopathy. She underwent exchange transfusion, but her pulmonary status deteriorated, and she died on August 7.
• Case 5. On September 6, a woman aged 19 years was taken to a local ED with mental status changes and a 5-day history of fever, headache, and influenza-like symptoms. She had traveled to Mozambique for 3 weeks on a mission trip and returned to the United States on August 24. She had not taken chemoprophylaxis. On examination, she was anemic (hemoglobin 9.5 mg/dL) and thrombocytopenic (platelet count: 22,000/µL), and her blood smear was positive for P. falciparum. She was admitted and treated with intravenous quinidine and doxycycline. She deteriorated, went into a coma, and had renal failure. She was intubated, placed on mechanical ventiliation, hemodialyzed, and transferred to a tertiary care center on September 7. She had 15% parasitemia on admission, and underwent an exchange transfusion. Computed tomography (CT) of the head indicated changes consistent with cerebral malaria, but no edema. On September 9, a repeat CT showed cerebral edema. Despite management to control increased intracranial pressure, she suffered cerebral herniation. An electroencephelogram performed on September 12 indicated no brain activity. Life support was withdrawn, and she died on September 13.
• Case 6. On October 29, a man residing in Haiti aged 56 years had emesis, diarrhea, headache, and fever. A blood smear in a local hospital on October 30 was negative, but his symptoms worsened, and mental status changes ensued. A smear performed in Port-au-Prince on November 2 was positive for P. falciparum. Treatment was started with oral chloroquine, but he subsequently had seizures, hematemesis, and hematuria and was hospitalized on November 3. The day after admission, he was comatose, hypotensive, and continued to seize. He was emergently endotracheally intubated, placed on mechanical ventialiation, and evacuated to the United States on November 4, where he suffered cardiac arrest and was resuscitated. Clinical evaluation indicated disseminated intravascular coagulation and renal failure. A blood film at that point indicated rare P. falciparum parasites. He was treated with intravenous quinidine and underwent hemodialysis. Parasitemia cleared on November 5, but he remained in multiorgan failure and on life support. He then had sepsis with Clostridium perfringens and died on November 7. PCR subsequently confirmed that the parasite was susceptible to chloroquine.
• Case 7. On December 12, a man aged 43 years returned from a 17-day trip to the Central African Republic; he had taken no chemoprophylaxis. He had onset of fever, chills, headache, nausea, cough, and hematuria the day of his return to the United States. He continued to work through December 16, although with worsening symptoms. He became unable to work and stayed home starting December 17, but he did not seek medical care. On the morning of December 19, he was found unresponsive. He was transported to an ED with resuscitation efforts in progress, but he remained unresponsive and pulseless and was pronounced dead 30 minutes after arrival. Tissue and blood samples analyzed at autopsy revealed the diagnosis of P. falciparum malaria (39% parasitemia).

Discussion

A total of 1,528 cases of malaria were reported to CDC for 2005, representing an increase of 15.4% from the 1,324 cases reported for 2004, resulting from increases from all major malaria endemic regions. The absolute number of cases among travelers attributable to travel in certain countries can be affected by multiple factors, including the amount of transmission occurring in that country, the compliance with preventive measures (including mosquito avoidance and chemoprophylaxis) by travelers, the style of travel in the country (e.g., business or adventure travel), and the volume of travel to the country. The 15.4% increase in the number of cases in 2005 compared with 2004 also might reflect increased reporting by state health departments.

One reason for conducting malaria surveillance is to monitor for prophylaxis failures that might indicate emergence of drug resistance. However, approximately 80% of imported malaria cases among U.S. civilians occurred among persons who either were not taking prophylaxis or were taking nonrecommended prophylaxis for the region to which they were traveling. The majority of patients for whom information was sufficient to indicate that the infection was a primary one rather than a relapse either reported noncompliance with recommended regimen or provided insufficient information to determine whether these cases represented 1) problems with compliance while using correct antimalarial chemoprophylaxis, 2) malabsorption of the antimalarial drug, or 3) emerging drug resistance. Among patients who reported compliance with a recommended regimen, serum drug levels were not available. Therefore, differentiating among inaccurate reporting of compliance, malabsorption of the antimalarial drug, and emerging drug resistance was not possible. No conclusive evidence existed to indicate a single national or regional source of infection among this group of patients or the failure of a particular chemoprophylactic regimen. Health-care providers are encouraged to contact CDC rapidly whenever they suspect chemoprophylaxis failure to enable CDC to measure serum drug levels of the antimalarial drugs in question.

Of the seven persons with fatal outcomes in the United States in 2005, none had taken prophylaxis, and substantial delays occurred in their seeking care or in diagnosis and treatment, or both. This underscores the importance of taking correct chemoprophylaxis, promptly seeking medical care if symptoms develop, and considering malaria in the differential diagnosis of fever in a returned traveler. An earlier review of deaths attributed to malaria in the United States indicated that failure to take and comply with a recommended antimalarial chemoprophylaxis regimen, promptly seek medical care for post-travel illness, and promptly diagnose and treat suspected malaria all contributed to fatal outcomes (10). In addition, in two cases, intravenous quinidine was not available in the hospital, resulting in a lengthy delay until appropriate therapy could be initiated. All hospitals caring for severely ill patients should maintain a supply of quinidine so it is available to rapidly initiate treatment of a patient with a case of severe malaria.

Pediatric malaria was analyzed separately for the first time this year. Children were more likely than adults to have acquired infection with P. falciparum. They were similar to adults in terms of region of acquisition, reason for travel, the percentage taking prophylaxis, and the percentage taking it correctly. Pediatricians should be aware of prophylaxis recommendations for children and encourage parents to ensure that their children receive chemoprophylaxis.

As in previous years, persons who traveled to visit friends and relatives made up the majority of persons with malaria cases. Foreign-born U.S. civilians should be aware that acquired immunity wanes quickly when exposure to malaria is interrupted and that they should take prophylaxis when returning to malarious areas.

Malaria during pregnancy among nonimmune women poses a high risk for severe disease and contributes to adverse reproductive outcomes (11). Pregnant travelers should be counseled to avoid travel to malarious areas. If deferral of travel is impossible, pregnant women should be informed that the risks for malaria outweigh those associated with prophylaxis and that safe chemoprophylaxis regimens are available. Specific guidance for pregnant travelers is available at http://www.cdc.gov/travel/mal_preg_pub.htm.

The two cases of congenital malaria highlight the importance of obtaining a complete travel and immigration history from pregnant women, including any febrile illnesses or confirmed episodes of malaria. For women with history of travel to or immigration from an area in which malaria is endemic or with a history of malaria before delivery, clinicians should remain alert to the diagnosis of malaria in the neonate or infant. Malaria blood films should be obtained from such neonates and infants should they become ill. For women with a confirmed diagnosis of malaria during the peripartum or postnatal periods, the need for presumptive treatment of the neonate or infant with an antimalarial appropriate for the mother's infecting species and region of acquisition should be considered. In certain cases, educating the mother about the risk for congenital malaria in her infant and instructing her to seek medical care for her infant if the infant had symptoms of malaria might be sufficient. In other cases, presumptive treatment of the newborn might be warranted.

Signs and symptoms of malaria often are nonspecific, but fever usually is present. Other symptoms include headache, chills, increased sweating, back pain, myalgia, diarrhea, nausea, vomiting, and cough. Prompt diagnosis requires that malaria be included in the differential diagnosis of illness in a febrile person with a history of travel to a malarious area. Clinicians should ask all febrile patients for a travel history, including international visitors, immigrants, refugees, migrant laborers, and international travelers.

Prompt treatment of suspected malaria is essential because persons with P. falciparum infection are at risk for experiencing life-threatening complications soon after the onset of illness. Ideally, therapy for malaria should be initiated immediately after the diagnosis has been confirmed by a positive blood film. Treatment should be determined on the basis of the infecting Plasmodium species, the probable geographic origin of the parasite, the parasite density, and the patient's clinical status (12). If a diagnosis of malaria is suspected and cannot be confirmed, or if a diagnosis of malaria is confirmed but species determination is not possible, antimalarial treatment should be initiated that is effective against P. falciparum. Resistance of P. falciparum to chloroquine exists worldwide, with the exception of a limited number of geographic regions (e.g., Central America). Therefore, therapy for presumed P. falciparum malaria should entail the use of a drug effective against such resistant strains (13).

Health-care providers should be familiar with prevention, recognition, and treatment of malaria and are encouraged to consult appropriate sources for malaria prevention and treatment recommendations (Table 7). Physicians seeking assistance with the diagnosis or treatment of patients with suspected or confirmed malaria should call CDC (telephone 770-488-7788) during regular business hours; call CDC's Emergency Operations Center (telephone 770-488-7100) during evenings, weekends, and holidays (ask to page person on call for Malaria Branch); or access CDC's Internet site at http://www.cdc.gov/malaria/diagnosis_treatment/treatment.htm. These resources are intended for use by health-care providers only.

Detailed recommendations for preventing malaria are available to the general public 24 hours a day online at http://www.cdc.gov/travel/diseases.htm/malaria. In addition, CDC biannually publishes recommendations in Health Information for International Travel (commonly referred to as The Yellow Book) (9), which is available for purchase from Elsevier at http://www.elsevierhealth.com or by telephone at 1-800-545-2522. The Yellow Book is also available and updated more frequently on CDC's Internet site at http://www.cdc.gov/travel.

CDC provides assistance for diagnostic parasitology through DPDx, a project developed and maintained by CDC's Division of Parasitic Diseases. DPDx (available at http://www.dpd.cdc.gov/dpdx) provides free Internet-based laboratory diagnostic assistance (i.e., telediagnosis) to laboratorians and pathologists in suspected parasitic disease cases, such as malaria. Digital images captured from diagnostic specimens can be submitted for consultation through electronic mail. Telediagnosis assistance by CDC is available during regular business hours. Because laboratories can transmit images to CDC and obtain a rapid response (average time: minutes to several hours) to their inquiries, this system allows efficient diagnosis of challenging cases and rapid dissemination of information. As of January 2007, approximately 54 public health laboratories in 45 states and Puerto Rico either have or are in the process of acquiring the hardware needed to perform telediagnosis. Implementation of telediagnosis at public health laboratories receives full assistance from CDC, including training of personnel in digital imaging techniques. The DPDx Internet site also contains reference material with images, text, and videos on approximately 100 different species of parasites with information (including laboratory diagnosis, geographic distribution, clinical features, treatment, and life cycles) available for each parasite.

Acknowledgments

The authors acknowledge the state, territorial, and local health departments; health-care providers; and laboratories for reporting this information to CDC.

References

1. Guinovart C, Navia MM, Tanner M, et al. Malaria: burden of disease. Curr Mol Med 2006;6:137--40.
2. Pan American Health Organization. Report for registration of malaria eradication from the United States of America. Washington, DC: Pan American Health Organization; 1969.
3. CDC. Multifocal autochthonous transmission of malaria---Florida, 2003. MMWR 2004;53:412--3.
4. Lackritz EM, Lobel HO, Howell J, Bloland P, Campbell CC. Imported Plasmodium falciparum malaria in American travelers to Africa: implications for prevention strategies. JAMA 1991;265:383--5.
5. Stroup DF. Special analytic issues. In: Teutsch SM, Churchill RE, eds. Principles and practice of public health surveillance. New York, NY: Oxford University Press; 1994:143--5.
6. World Tourism Organization. Yearbook of tourism statistics. 2006 ed. Madrid, Spain: World Tourism Organization; 2006. Available at http://www.unwto.org/pub/doc/UNWTO_pub_cat_06_en.pdf.
7. World Health Organization. Terminology of malaria and of malaria eradication: report of a drafting committee. Geneva, Switzerland: World Health Organization; 1963:32.
8. Skarbinski J, Eliades MJ, Causer LM, et al. Malaria surveillance---United States, 2004. In: Surveillance Summaries, May 26, 2006. MMWR 2006;55(No. SS-4):23--37.
9. CDC. Health information for international travel, 2005--2006. Atlanta, GA: US Department of Health and Human Services, Public Health Service, CDC; 2005.
10. Newman RD, Parise ME, Barber AM, Steketee RW. Malaria-related deaths among U.S. travelers, 1963--2001. Ann Intern Med 2004;141:547--55.
11. Duffy PE, Fried M. Malaria in the pregnant woman. Curr Top Microbiol Immunol 2005;295:169--200.
12. Baird JK. Effectiveness of antimalarial drugs. N Engl J Med 2005;352:1565--77.
13. CDC. Malaria treatment. Atlanta, GA: US Department of Health and Human Services, CDC; 2005. Available at http://www.cdc.gov/malaria/diagnosis_treatment/treatment.htm.

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Date last reviewed: 5/9/2007