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EXPERIENCE & REASON |
a Sections of Infectious Diseases
c Critical Care, Department of Pediatrics, University of Chicago, Chicago, Illinois
b Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
ABSTRACT
Malaria is a disease of global importance and accounts for up to 500 million cases per year. Nearly all malaria cases in the United States occur among persons who have traveled to areas with ongoing malaria transmission. Among the cases of malaria reported in the United States in 2000–2005, 695 were in US residents under the age of 18 years. The association of malaria with the sickle cell hemoglobin is well described in Africa but is a rare occurrence in the United States. Here we report 5 cases of Plasmodium falciparum malaria in siblings of a family who had traveled to Africa without taking chemoprophylaxis. Two of the children had sickle cell anemia, and 1 of them developed severe life-threatening malaria and hemolysis. The 3 other siblings had sickle cell trait, 2 of whom had complicated malaria. Patients who have sickle cell disease and are infected with malaria are prone to hyperhemolytic crisis; therefore, this complication should be anticipated. The patients we describe emphasize the significance of prompt recognition of malaria and comorbidities and institution of appropriate treatment. The importance of antimalarial prophylaxis should be communicated to parents of children who are traveling to endemic areas as part of routine child care.
Key Words: malaria • children • sickle cell disease • chemoprophylaxis • United States
Abbreviations: CDC; Centers for Disease Control and Prevention • PCR; polymerase chain reaction
Human malaria is a parasitic disease that is transmitted through the bite of infective female Anopheles mosquitoes. Malaria remains an overwhelming global problem and accounts for up to 500 million febrile illnesses and millions of deaths annually.1 In 2004, 1324 patients with malaria that occurred in the United States were reported to the Centers for Disease Control and Prevention (CDC), nearly all of whom had traveled to areas with ongoing malaria transmission.2 In 2000–2005, among 4647 cases of malaria in US civilians with known age information, 695 (15%) occurred in children younger than 18 years. Among US civilians with imported malaria reported in 2004, only 21% had taken prophylaxis that conformed to CDC recommendations. Failure to take prophylaxis is a major contributing factor to death of patients with malaria in the United States.3
The association of malaria with sickle cell hemoglobin is well described in Africa but is rare in the United States. We recently cared for 5 siblings with Plasmodium falciparum malaria in Chicago, Illinois, who acquired the disease while traveling in Nigeria. All the children had sickle cell disease or trait; their clinical course demonstrated the full spectrum of malarial severity, from asymptomatic to complicated, life-threatening malaria that required hospitalization in an ICU. Complicated malaria was evident in 2 of the 3 patients with sickle cell trait, and hyperhemolytic crisis complicated the course of a patient with sickle cell disease. None of the family members (children and parents) took antimalarial prophylaxis. These cases highlight the various associations between malaria and sickle cell disease and trait. They also underscore the importance of malaria-prevention measures for travelers to malaria-endemic areas as well as prompt diagnosis and treatment.
CASE REPORTS
In February 2006, 3 boys aged 4, 6, and 10 years were hospitalized in the PICU at the University of Chicago Comer Children's Hospital for complicated P falciparum malaria (patients 1, 2, and 3, respectively, in Table 1). They were members of a family of 7 (3 boys, 2 girls [patients 4 and 5], and their parents), all of whom traveled in 2005 and early 2006 to Nigeria to visit friends and family. Nigeria was the native country for the parents and the older daughter; the parents had moved to the United States 10 years before and lived near Chicago. Before the trip to Nigeria, the parents enquired about malaria medications. They were told that antimalarial drugs were available. However, the parents assumed incorrectly that the drugs were to be taken for treatment only and did not realize that the drugs should also be used for prophylaxis. The family members visited friends and relatives in various locations of Nigeria (Abuja, Ilorin, Kano, and Lagos) for 5 to 12 weeks, and they all returned to the United States in January 2006. All areas of Nigeria are at risk for malaria acquisition. While in Nigeria, all the children were bitten by mosquitoes; 3 of them (patients 1, 2, and 5) had separate febrile episodes and were treated uneventfully with antibiotics, ibuprofen, and sulfadoxine-pyrimethamine (Fansidar) by a local physician.
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All 3 boys had at least 1 manifestation of complicated malaria (eg, acidosis, hypoglycemia, severe anemia, or jaundice). They were treated with intravenous quinidine for 3 days combined with either doxycycline or clindamycin (for patients younger than 8 years of age) for 7 days. The 10-year-old boy had hyperhemolytic syndrome with markedly decreased hemoglobin concentration (hemoglobin nadir of 5.1 g/dL) and required intubation, dextrose infusion, and transfusions of red blood cells and fresh-frozen plasma. He also received a red blood cell exchange transfusion and plasmapheresis. Patients 1 and 2 had prolonged QT intervals noted on the last day of quinidine treatment, which resolved after discontinuation of the drug. Parasitemia in all 3 patients resolved by the third day of hospitalization, and all 3 children were discharged in good condition after 7 to 10 days.
The day after hospitalization of the 3 boys, the 2 sisters (aged 2 and 11 years) were tested by blood smears and determined to be infected with P falciparum, albeit at lower parasite densities. The 11-year-old (patient 4) had fever and headache; her 2-year-old sister was asymptomatic. Both were hospitalized on a general pediatric floor and treated successfully with oral quinine for 3 days combined with doxycycline or clindamycin for 7 days; parasitemia resolved by the third day (Table 1).
The parents reported that patients 3 and 5 had sickle cell disease. They received no prophylactic antibiotics or blood transfusions in the past. Subsequent hemoglobin electrophoresis indicated that all 5 children had either sickle cell disease or sickle cell trait.
Infection with P falciparum was additionally confirmed by polymerase chain reaction (PCR) performed at the CDC on pretreatment blood specimens of patients 1 through 4.4 No pretreatment blood specimen was available for patient 5, and results of testing on the posttreatment specimen were negative according to PCR.
Both parents were asymptomatic. They consulted their primary physician, who treated them presumptively with mefloquine without a blood smear.
DISCUSSION
A distinguishing feature of our patients was the presence of malaria and sickle cell disease or trait. This association is frequent in Africa where both conditions coexist. In the United States, sickle cell disease is common and affects 
1 in 350 black newborns each year,5 but because malaria is not endemic, the association of the 2 diseases is rare and seldom discussed. The sickle cell gene is found more commonly among persons of African descent because the sickle cell trait confers a selective advantage: resistance to severe malaria.6 The mechanism of this protection however, remains incompletely understood. Proposed mechanisms include decreased parasite growth in the red cells and enhanced removal of parasitized cells.1,7 In a recent large cohort study of Kenyan children, sickle cell trait was found to be 50% protective against mild clinical malaria, 75% protective against hospitalization for malaria, and 90% protective against severe or complicated malaria.7 Still, the protection is not complete,1 as is evident with our patients; 2 of our 3 patients with sickle cell trait had complicated malaria that necessitated admission to the ICU. Although patients with sickle cell trait are relatively protected, malaria is a major cause of morbidity and mortality in children with sickle cell disease; malaria precipitates hyperhemolytic crises with markedly decreased hemoglobin concentration and infarctive crises.8,9 Patient 3, who had sickle cell disease, had low-level parasitemia but severe disease, mainly because of the hyperhemolytic crisis.
The high attack rate in this family demonstrates the increased risk for acquiring malaria by travelers to sub-Saharan Africa. Indeed, a recent study of diagnoses among travelers returning from developing regions of the world who sought medical care found malaria to be the most common diagnosis in the travelers returning from sub-Saharan Africa.10 Among US civilian children who were diagnosed with malaria in the United States during 2000–2005, 81% acquired the disease in Africa; the majority of cases were attributed to P falciparum, the species that most often causes severe malaria in humans.
Pediatric malaria continues to be diagnosed in the United States. In 2000–2005, 695 US residents under the age of 18 years were diagnosed with malaria; all age groups were represented. The yearly rate did not show major fluctuations in these 6 years. The mortality in the pediatric age group was low; only 1 child died among 28 deaths reported for all age groups, but the morbidity can be substantial. The geographic distribution of malaria and its resistance pattern are constantly evolving (eg, in 2006, outbreaks of malaria were reported from the Bahamas and Jamaica, countries where malaria transmission does not normally occur11), necessitating physicians to have access to a reliable source of information when considering appropriate prophylaxis for travelers or treatment. Updated information can be found at the CDC's travelers' health Web site (www.cdc.gov/travel); the CDC also operates a malaria hotline for health care providers who need advice regarding treatment (770-488-7788).
As noted, immigrants travel frequently to their native country to visit friends and relatives. Therefore, the country of malaria (and other preventable diseases) acquisition for their children will be, in most cases, the parent's country of origin.12,13 The peak incidence of travel-related malaria cases is in late summer or January, which corresponds to return from summer or Christmas vacation,12 as was true for our patients.
Our 5 patients underscore the need for preventive measures, including avoidance of mosquito bites and appropriate chemoprophylaxis for travelers to malaria-endemic areas. Failure to take appropriate prophylaxis is a major contributing factor for malaria acquisition and mortality among US travelers.2,3 Breakthrough infections are uncommon when appropriate antimalarial medications are used.1 Many barriers to appropriate taking of antimalarial prophylaxis are found among US residents who were born in malaria-endemic areas and return to their country of origin to visit friends and relatives. Examples include inadequate health insurance coverage that prohibits visits to travel clinics, travelers' misperceptions that malaria is not a serious illness (sometimes regarded as "normal," "expected," or "like the flu"), or a primary care providers' inadequate knowledge of travel medicine.13 Some of these barriers likely played an important role in the case of the family we describe.
Diagnosing malaria correctly in a timely manner requires a high level of suspicion and mandates taking the patient's travel history. Malaria can present as an undifferentiated febrile illness, sometimes diagnosed incorrectly (as happened in our cases) as influenza or a viral upper respiratory infection. In the United States, malaria is not endemic and, therefore, rarely considered,14 a factor that can contribute to delayed diagnosis and increased severity of illness. Delayed diagnosis of malaria has been shown to be a risk factor for fatal outcome.3 Patients suspected of having malaria infection should be evaluated urgently. Light microscopy of Giemsa-stained blood smears is the accepted standard for malaria diagnosis. If the initial blood smear is negative and malaria remains a possible diagnosis, the smear should be repeated every 12 hours until a diagnosis of malaria is made or ruled out.1,15 Parasite nucleic acid detection using PCR is available at the CDC and is used mainly to identify the specific Plasmodium species in cases of mixed Plasmodium infections and to confirm diagnosis and species in equivocal microscopy cases.4 Patients with severe or complicated P falciparum malaria should be treated in an ICU. In practice, because of the ability of P falciparum infection to progress in just a few hours to severe and life-threatening complications, it is advisable to hospitalize all individuals with P falciparum malaria and those in whom P falciparum infection cannot be excluded.1,15 Guidelines for treatment of malaria for clinicians are found on the CDC Web site.15
Three of the children were treated with sulfadoxine-pyrimethamine (Fansidar) by a local physician in Nigeria. However, recent reports that showed a high percentage of counterfeit antimalarial drugs (including sulfadoxine-pyrimethamine) in countries endemic for malaria16,17 and widespread drug resistance, including in Nigeria,1 may have limited the value of this intervention. Currently, resistance to sulfadoxine-pyrimethamine is found in a large part of south and east Asia, southern China, western Oceania, the Amazon basin, and the Pacific coast of South America, and in Africa resistance is rapidly gaining ground, mainly in east Africa but also in focal areas throughout the continent.18 We cannot rule out that this treatment had a partial effect on the malarial illness in our children. For example, patient 5 was not immune to malaria and had malaria parasites in her blood, but she was asymptomatic.
CONCLUSIONS
International travel is increasing, and visiting-friends-and-relatives travelers make up a large and growing number of visits to developing regions of the world. Malaria, therefore, will continue to be diagnosed in the United States in pediatric patients of all ages. The clinical presentation is often a nonspecific fever and requires a high index of suspicion and elucidation of travel history. In patients with sickle cell trait, although some protection against malaria and its complications is present, severe or complicated malaria can occur, and in patients with sickle cell disease, severe hemolytic and infarctive crises should be anticipated. Barriers to appropriately taking antimalarial prophylaxis still exist, especially among travelers who are visiting friends and relatives abroad. Primary care providers should anticipate exposure to malaria in travelers and provide guidance on the risks and prevention. One of the best opportunities for educational intervention is during routine well-child or adolescent visits and in hematology clinics that care for patients with sickle cell disease.
FOOTNOTES
Accepted Mar 27, 2007.
Address correspondence to Daniel Glikman, MD, University of Chicago, Department of Pediatrics, Section of Infectious Diseases, MC 6054, 5841 S Maryland Ave, Chicago, IL 60637. E-mail: dglikman{at}peds.bsd.uchicago.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
This article has been cited by other articles:
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  K. D J Jones Malarial chemoprophylaxis BMJ, October 1, 2008; 337(oct01_3): a1875 - a1875. [Full Text]
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