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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclaimer
  7. Declaration of Interests
  8. References

Background. Imported malaria remains a public health concern in the United States, but the health impact on children and the financial costs to society have not been well defined.

Methods. Inpatient and outpatient malaria cases diagnosed at Children's National Medical Center (CNMC) in Washington, DC over an 8-year period are retrospectively reviewed. Cases are mapped against Census Bureau population data. These observations are compared with the national burden of pediatric malaria, including both disease severity and cost, by reviewing inpatient malaria cases in the Pediatric Health Information System (PHIS), January 2003 to June 2008.

Results. At CNMC, malaria most commonly affects children who traveled to West Africa to visit friends and relatives. Poor adherence to prophylaxis and self-treatment with antimalarial medications were commonly identified. Mapping demonstrates case clustering in communities with large sub-Saharan African populations. The cumulative incidence (CI) of malaria at CNMC of 9.0 per 10,000 admissions is 7.6 times the national average. The CI of malaria at PHIS hospitals is 1.2 per 10,000 admissions with an average cost of $17,519.

Conclusions. Malaria is a preventable disease for which the risk to life and costs of treatment are significant. Patterns of risk can be used by health planners to target prevention strategies at the community level. In regions with a high density of immigrants, particularly from sub-Saharan Africa, physicians must be aware of the risk, understand recommended prophylaxis and treatment regimens, and advocate for their appropriate use in the community.

In 2008, 1,298 cases of malaria in the United States were reported to the Centers for Disease Control and Prevention (CDC), with approximately 80 from Maryland and 7 from the District of Columbia. The incidence rate of malaria in the United States stands at 0.4 cases per 100,000.1 Travelers to endemic areas who are visiting friends and relatives (VFR) are known to be less likely to take proper preventive measures,2 and those going to sub-Saharan Africa have an increased relative risk of >200 compared to other travelers to other regions.3–5 Although nationwide reviews remain lacking, recent publications from single centers or several in a given metropolitan region have begun to provide a more complete picture of the current experience with pediatric malaria in the United States.6–10 Common trends are travel to visit friends and relatives among West African immigrant families and low rates of both prophylaxis usage and adherence. There is limited information on the economic impacts of this disease in the United States.11 The last published review of pediatric malaria at Children's National Medical Center (CNMC) in Washington, DC reported 64 inpatient cases diagnosed between 1983 and 1992, most having been acquired in Africa.12 This study reviews inpatient and outpatient cases diagnosed at CNMC over an 8-year period from 1999 to 2006 and contextualizes that with the national burden of pediatric malaria, including both disease severity and cost, by reviewing inpatient malaria cases in the Pediatric Health Information System (PHIS), containing data from a nationwide network of children's hospitals, including CNMC, from January 2003 to June 2008. By correlating these results with publicly available census records, a pattern of risk emerges that can be used by health planners to guide and target prevention strategies.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclaimer
  7. Declaration of Interests
  8. References

CNMC Review

CNMC is a 280-bed, multidisciplinary center serving the District of Columbia and surrounding metropolitan area. Cases were identified by searching the CNMC clinical laboratory database for all results between January 1, 1999 and December 31, 2006 for thick and thin blood smears or malaria percent parasitemia smears. All case files with positive samples were included in the study. Electronic medical records of patient encounters, progress notes, and laboratory results were retrospectively reviewed for pertinent epidemiological and clinical data.

Statistical analysis included descriptive analysis of patient demographics and basic clinical parameters. Patients were stratified at the time of presentation into either severe or non-severe cases using criteria established by the CDC.13 Chi-square with Yates correction and one-way ANOVA tests were utilized to assess the relationships between demographic and clinical data. These data were compared against US Census Bureau datasets from the 2000 US Census for socioeconomic indicators to include the zip code-based population density of people stating sub-Saharan African ethnicity.14 ArcGIS Geographic Information System (GIS) software (ESRI, Redlands, CA) was utilized to map the overlay of malaria cases with the distribution and density of sub-Saharan African ethnic groups.

Nationwide Review

The PHIS hospitals, of which CNMC is a member, are 40 of the largest children's hospitals in America representing 17 of the 20 major metropolitan regions. PHIS is a detailed comparative database that gives participating hospitals an opportunity to assess epidemiology trends, resource utilization, and other data that can be used to assess performance and outcomes.15 Cases were obtained from the PHIS database, using a query of ICD-9 codes 0.840-0.849 for primary diagnoses of malaria listed for inpatients treated at PHIS hospitals between January 2003 and June 2008. De-identified patient data included demographics, location, type of malaria, procedures performed, hospital charges, and All Patient Refined Diagnosis Related Groups (APR-DRG) severity index. The APR-DRG severity index is an automated scoring derived from standardized clinical parameters (3M Health Information Systems), and provides a unified method of comparing severity across institutions but does not necessarily correlate with the specific diagnostic criteria of severe malaria by CDC criteria. Using total admissions to PHIS hospitals as the denominators, cumulative incidences (CI) were generated for the PHIS hospitals across the United States in aggregate, each region, and at CNMC. Chi-square and t-tests were used for comparisons. Logistic regression was used to compare CI and generate odds ratios. Multivariate analysis of variance was employed to ascertain mean hospital charges.

This research study was reviewed and approved by the CNMC institutional review board and the PHIS.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclaimer
  7. Declaration of Interests
  8. References

CNMC Case Review 1999–2006

Ninety-eight cases (inpatient and outpatient) of malaria were treated at CNMC during the study period, and detailed case records were available in 93. Sixty-two percent (n = 61) of patients were admitted to the hospital and 31% of that group (n = 19) were treated in the intensive care unit for severe malaria. Patient epidemiology and clinical parameters are reported in Table 1. Time until diagnosis, by malaria species, in terms of time in the United States and number of days sick prior to diagnosis is reported in Table 2. Forty-six percent (n = 45) of patients were long-term U.S. residents who visited friends or relatives in their country of origin, 37% (n = 36) were recent immigrants, and travel purpose status was not recorded in 17% of cases. GIS mapping of these cases relative to sub-Saharan population density is shown in Figure 1. The vast majority of cases originated with an exposure in sub-Saharan Africa (95%). Seventy-nine cases (85%) were exposed in West Africa, with Nigeria the most common country of exposure, 37% of all cases. The peak incidence was in August. Ninety case files commented on prophylaxis use. Prophylaxis was not used by 70% of patients and either an ineffective regimen or an improperly used “effective” regimen was reported in 24%. Only 6% of cases reported proper adherence to an effective regimen. The use of nets and repellents was not consistently documented in the medical records, so no conclusions can be made regarding these prevention strategies. Pre-diagnosis treatment with antimalarial medications, or with medications having partial activity against Plasmodium species (such as azithromycin) occurred in 31% of patients. One patient, with travel to Africa, was empirically prescribed chloroquine by a U.S. physician to treat a suspected Plasmodium falciparum infection, three patients were taking azithromycin for presumptive respiratory tract infections, and the remaining patients were either empirically self-treating with medications purchased off the shelf in Africa, or were prescribed antimalarials by a physician in Africa. Chloroquine and sulfadoxine pyramethamine were most common.

Table 1.  Clinical features of inpatient and outpatient cases at Children's National Medical Center (CNMC) 1999–2006*
  1. WBC = white blood cell count ×103/mm3; Hgb = hemoglobin %; PLT = platelet count ×103/mm3; AST = aspartate aminotransferase U/L; ALT = alanine aminotransferase U/L, glucose mg/dL.

  2. *Includes five family clusters and one patient admitted twice in different years.

  3. Five patients >25% peak parasitemia.

Mean age (range)9.6 years (0.6–18.6)
Race, n (%) 
 Black92 (94)
 Hispanic5 (5)
 South Asian1 (1)
Male gender, n (%)53 (54)
Initial diagnosis other than malaria, n (%)17 total patients
 Respiratory tract infection7 (41)
 Viral syndrome4 (24)
 Malaria considered but smears neg.3 (18)
 Sickle cell crisis2 (12)
 Neutropenic fever (oncology patient)1 (6)
Previous diagnosis of malaria34 (35)
Admission status, n (%) 
 Outpatient37 (38)
 Ward42 (43)
 Intensive care unit19 (19)
Bed days, mean ± SD 
 Total hospital3.4 ± 3.3, Max. 22
 Intensive care unit2.4 ± 1.3, Max. 7
Percent parasitemia, mean ± SD (95% CI) 
 Initial3.8 ± 7.5 (2.2–5.4), Max. 42.4
 Peak5.3 ± 8.9 (3.2–7.3), Max. 45
WBC, initial, mean ± SD (95% CI)7.3 ± 3.2 (6.6–8.2)
HgB, mean ± SD (95% CI) 
 Initial11.2 ± 3.7 (10.4–11.9), Min. 5.4
 Nadir9.2 ± 2.1 (8.7–9.7), Min. 4.4
PLT, mean ± SD (95% CI) 
 Initial135 ± 90 (116–153) Min. 23
 Nadir98 ± 75 (80–115), Min. 15
AST, initial, mean ± SD (95% CI)62 ± 68 (44–79), Max. 443
ALT, initial, mean ± SD (95% CI)46 ± 38 (35–55), Max. 184
Glucose, mean ± SD (95% CI) 
 Initial102 ± 21 (97–107), Min. 50
Nadir89 ± 15 (84–93), Min. 60
Bacteremia within 48 h of admission (n = 2)Non-typhi Salmonella sp. Staphylococcus aureus
Table 2.  Time in days until presentation, inpatient and outpatient cases at Children's National Medical Center (CNMC) 1999–2006
 Plasmodium falciparumPlasmodium malariaePlasmodium vivaxNot reported/unidentifiedMixed (P. falciparum + Plasmodium ovale)
  1. Mean ± SD (95% CI).

 N = 76N = 7N = 3N = 11N = 1
Time in the United States until diagnosis15 ± 23 (9.9–20.7), Max. 164118 ± 102 (23–210), Max. 317119 ± 97 (122–361), Max. 19953 ± 52 (6-107), Max. 16911 days
 (N = 72)(N = 7)(N = 3)(N = 8)
Days symptomatic before diagnosis and treatment5 ± 5.4 (3.8–6.4), Max. 303 ± 2.3 (1.2–5.4), Max. 76 ± 4.9 (5–18.5), Max. 125 ± 4.7 (1–9.0), Max. 14
image

Figure 1. Place of residence of pediatric malaria cases treated at Children's National Medical Center 1999–2006.

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There were no deaths in the study population. One patient experienced cardiac arrest but survived. Another patient (newly arrived from a Liberian refugee camp) had a sibling that died at home 1 week before presenting; details of that out-of-hospital death were not available. Malaria was accurately diagnosed on the day of initial presentation for 82% of the 92 patients for whom this information was available for review. At least three patients who were given their first treatment dose in the emergency department and then managed as outpatients were subsequently admitted after clinically worsening following failed attempts to fill their prescriptions at local pharmacies. Two patients were treated with exchange transfusions. Clinical and epidemiological analysis of the CNMC cohort did not find statistically significant indices of risk such as age, gender, purpose of travel, or pre-treatment with antimalarial medications for accurately predicting who, at the time of presentation, was at risk of severe malaria or to require hospitalization.

National PHIS Hospitals

A total of 306 inpatient cases for which malaria was the primary diagnosis were obtained from the PHIS database. Epidemiology and clinical findings from the PHIS hospitals compared to CNMC PHIS data during the same time period is summarized in Table 3. The CI for the entire dataset was 1.2 per 10,000 patient admissions [95% CI 1.1–1.3]. Of the 306 inpatient cases, 67% (n = 205) were of black race. Plasmodium falciparum infection was seen in 52% (n = 160) of patients, and 39% had an unspecified species. Unspecified species may reflect coding variation in the database as opposed to the actual diagnosis and clinical management. Patients of black race comprised three-quarters of all P. falciparum cases (n = 119, 74%); however, all other races combined experienced the greatest number of non-P. falciparum infections (n = 22, 79%). As was seen at CNMC, the peak of malaria cases occurred in the summer months of July, August, and September, with a lower, secondary peak of malaria occurring in January. The hospital charges incurred by the 306 cases totaled US $5,360,951. Crude mean charges equaled $17,519 [95% CI $1,149–718,956; SD ± 46,346] with crude average daily charges equal to $4,247 [SD ± 2,459]. By malaria type, charges for P. falciparum were $19,138 [95% CI $10,152–28,124], for non-P. falciparum$14,636 [95% CI $5,360–23,912], and for unspecified species $16,008 [95% CI $10,365–21,652].

Table 3.  Pediatric inpatient malaria: Pediatric Health Information System (PHIS) database, January 2003 and June 2008
 PHISCNMC*NortheastSouthNorth CentralWest
  1. Unless indicated, results shown were not statistically different across sites in comparison to PHIS.

  2. *Children's National Medical Center (CNMC) data are also reflected in the PHIS aggregate and South region data columns.

Cases, n (%)30660 (20)48 (16)167 (55)59 (19)32 (10)
Incidence per 10,000 admissions (95% CI)1.2 (1.1–1.3)9 (6.7–11.3)1.3 (0.9–2.0)1.8 (1.5–2.0)0.8 (0.6–0.1)0.6 (0.4–0.8)
Incidence ratios versus PHIS (95% CI)7.6 (5.8–10.0)1.1 (0.8–1.5)1.5 (1.3–1.9)0.7 (0.5–0.9)0.5 (0.3–0.7)
  p < 0.0001nsp < 0.0001p = 0.03p < 0.0001
Age, mean ± SD (95% CI)8.2 ± 4.9 (7.6–8.7)7.9 ± 4.4 (6.9–9.1)7.8 ± 5.2 (6.3–9.3)8.3 ± 4.8 (7.6–9.1)7.6 ± 4.8 (6.3–8.8)8.8 ± 5.4 (6.9–10.8)
Male gender, n (%)168 (55)31 (52)27 (56)89 (53)35 (59)17 (53)
Black race, n (%)205 (67)48 (80)35 (73)124 (74)32 (54)14 (44)
  p < 0.0001nsp = 0.003p = 0.02p = 0.003
Length of stay, days mean ± SD (95% CI)3.5 ± 3.0 (3.1–3.8)3.4 ± 3.3 (2.6–4.2)3.8 ± 3.2 (2.9–4.8)3.5 ± 3.4 (3.0–4.1)3.3 ± 2.3 (2.7–3.9)2.7 ± 1.1 (2.3–3.1)
Species, n (%)      
  P. falciparum160 (52)34 (57)23 (48)90 (54)33 (56)14 (43)
 Non-falciparum28 (9)3 (5)4 (8)15 (9)2 (3)7 (22)
 Unspecified118 (39)23 (38)21 (44)62 (37)24 (41)11 (34)
APR-DRG severity index, n (%)      
 Minor143 (47)26 (43)22 (46)80 (47.9)29 (49)12 (37)
 Moderate102 (33)22 (37)14 (29)56 (33.5)16 (27)16 (5)
 Major45 (15)8 (13)7 (15)22 (13.2)12 (20)4 (13)
 Extreme16 (5)4 (7)5 (10)9 (5.4)2 (3)0
Hospital charges, mean ± SD (95% CI)$17,519 ± 46,345 (12,306–22,732)$19,206 ± 34,341 (10,335–28,077)$18,270 ± 23,231 (11,525–25,016)$20,486 ± 60,883 (11,184–29,788)$12,202 ± 11,839 (9,117–15,288)$10,711 ± 7,283 (8,085–13,337)

CNMC PHIS Results

CNMC had a CI of nine malaria cases per 10,000 patients [95% CI 6.7–11.3], 7.6 times greater [95% CI 5.8–10.0, p < 0.0001] than that for all PHIS hospitals (1.2 per 10,000 patients [95% CI 1.0–1.3]). CNMC saw a total of 60 inpatients (19.6% of total PHIS cases) with a primary diagnosis of malaria, an average of 12 admissions per year, out of an average of 13,290 inpatients per year over the study period, or 15 per year if adjusted for the partial reporting of 2008. CNMC accounted for 21% ($1,152,379) of charges in the PHIS dataset. Mean charges were slightly higher than those for all PHIS hospitals, at $19,206 [95% CI $10,335–28,077]; however, multivariate analysis showed no significant difference in individual per patient hospital charges between CNMC and the other PHIS hospitals in aggregate.

PHIS Results by Census Region

The 39 hospitals reporting cases represent most metropolitan areas of the United States and were sorted by U.S. Census Bureau region variable [Northeast, South, North Central (Midwest), West] as designated by PHIS. The CI, APR-DRG severity index ratios, and mean hospital charges are summarized in Table 3. The South region experienced the highest burden [1.8 per 10,000 patients, 95% CI (1.5–2.0)] and the West the lowest [0.6 per 10,000; 95% CI (0.4–0.8)] of all four regions. The CI for the South region was 1.5 times greater (95% CI 1.3–1.9) than for all PHIS hospitals and 3.2 times greater (95% CI 2.2–4.7) than the West.

In the Northeast, South, and North Central regions, the majority of cases were of black race. Only in the West region did cases of all other races outnumber those of black race, 56% to 44%. The breakdown of malaria types was consistent between all regions, with the majority of cases having P. falciparum. In all four regions, the majority of cases were aged 9 years or younger and males outnumbered females. Mean hospital charges ranged from $10,711 in the West to $20,486 in the South.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclaimer
  7. Declaration of Interests
  8. References

The high burden of pediatric malaria cases in the Washington, DC region compared to similar pediatric medical centers around the country reflects its large population of African immigrants and demonstrates that improving the delivery and acceptance of preventive travel health care in this population is needed. The majority of patients in this series were long-term US residents who did not utilize recommended prevention methods. Empirical self-treatment by parents, both abroad and in the United States, with ineffective medications was common. GIS mapping of CNMC malaria cases demonstrates a correlation between numbers of cases and areas with large populations of individuals of sub-Saharan African ethnicity. This region extends in a narrow band along the northeastern border of Washington, DC and Maryland. The Washington, DC-metro area (comprising the District of Columbia and suburban regions of Maryland and Virginia) has the second largest proportion of African-born immigrants in the United States, with 159,928 (11.3%) of the total African-born population in the United States.16 Geographic clustering of malaria cases, in the absence of endemic disease, highlights the fact that both the origins and solution of this problem have sociocultural roots in health-seeking behaviors. The pattern that emerges reflects specific geographic risk areas, corresponding to immigrant residence patterns, in which public health education resources can and should be concentrated. This large at-risk population provides unique public health challenges and opportunities for targeted health interventions.

Several clinical lessons learned can also be drawn from this experience: (1) High-risk groups do not demonstrate recommended health care seeking behaviors. (2) Although children with uncomplicated disease can potentially be managed safely as outpatients. The high prevalence of partial immunity among patients in the CNMC cohort may affects our findings, so in a naÏve patient with falciparum malaria it is prudent to admit for at least 24 h, a position favored by recent CDC recommendations.13 If outpatient therapy is considered, next day follow-up and both availability and adherence to medication is required. As recognized by the three patients unable to fill prescriptions in the CNMC series, this may be difficult to guarantee. A follow-up study to this review demonstrated zip code level disparities in the availability of antimalarial medications based on income and ethnic makeup.17 Either a full course of treatment should be dispensed at the time of diagnosis, or the first dose administered at the time of diagnosis and then availability of medication at a local pharmacy be confirmed prior to departure from the clinic or emergency department. (3) Pediatric travelers with malaria typically present initially with normal leukocyte counts, hemoglobin levels, and blood glucose, but alterations in these values may evolve over time. Although not universally seen, mild to moderate thrombocytopenia and mild elevation in the aspartate aminotransferase (AST) are helpful indicators to suggest the diagnosis. (4) Co-morbid bacteremia in the traveler population occurs, but is not common, as opposed to reports from populations residing in endemic countries.18–21

Although information on travel history and purposes was not included in the PHIS dataset, the demographic breakdown and types of malaria diagnosed indicate a high probability that a majority of patients, especially those with P. falciparum, likely traveled to Africa, an observation supported by other patient registries.1,4,9,10 As of the 2000 US Census, the South was home to 307,324 African-born residents, 34.9% of the total African-born population, the highest of all four regions.22 Within the South region are two of the top four cities with the highest proportion of African-born immigrants: Washington, DC (second highest) and Atlanta, GA (third highest). The distribution of other immigrant groups may also explain why the West region had more cases of non-P. falciparum malaria than anywhere else. The West region is home to 45% of the total Asian-born population, and 40% of the total Latin American-born population.22 Given that the majority of malaria cases occur in VFR travelers, it is probable that a higher percentage of cases in the West region are acquiring malaria in Asia and South America which have lower incidence of malaria attributed to P. falciparum than in sub-Saharan Africa.23

The 306 cases contained within the PHIS dataset incurred a total of $5,360,951 in charges. Bloland and colleagues estimated the mean cost of hospitalization in the United States from 1988 to 1989 due to P. falciparum infection in a mixed adult-pediatric population to be $2,743.51.11 When these costs are adjusted to reflect 2008 monetary values, using the Bureau of Labor Statistics inflation calculator (www.bls.gov/data/inflation_calculator.htm) the predicted mean hospitalization cost is $4,764. However, the unadjusted mean hospital charges from this study were $17,519. Whether this represents differences in care related to adults versus children, regional differences in where medical care was delivered, or broader increases in the cost of health care is unclear.

This study provides for the first time a national picture of imported pediatric malaria in the United States, both as a whole, by US Census Bureau Region, and locally from hospital to community. The findings of this study highlight the clinical impact of malarial infections in children as well as the economic burden of pediatric malaria. Retrospective design is a limitation of this study resulting in incomplete data capture for some cases. Reliable clinical predictors for inpatient versus outpatient management of uncomplicated malaria cannot be distinguished with these results. Prospective studies of treatment among pediatric travelers are needed. Reliance on ICD-9 coding may not reflect actual clinical nationwide incidence by species. A prospective study of travelers to malaria-endemic countries may help evaluate the true incidence of malaria in children traveling abroad. Given the high prevalence of self-treatment seen in this study, we hypothesize that many cases never reach medical attention. Pediatricians and family practitioners should endeavor to provide appropriate “medical homes” for immigrant patients.24 Recent publications highlight this gap in medical care, but effective strategies proven to enhance health-seeking behavior and adherence with prevention strategies, including repellents, insecticide treated nets, and chemoprophylaxis, remain elusive.25–29 If this important health disparity is to be eliminated, both more research in this area, and focus on prevention from clinicians in the community is needed. Recognizing the unique medical risks of this patient population and proactively engaging parents on the need for proper pre-travel medical care may improve adherence to recommended interventions. In regions with high densities of immigrants, particularly those from sub-Saharan Africa, physicians must be aware of the risk of malaria in these patients, understand recommended prophylaxis and treatment regimens, and advocate for their appropriate use in the community.

Disclaimer

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclaimer
  7. Declaration of Interests
  8. References

The views expressed in this article are those of the authors and do not necessarily reflect the official policy of the Department of Defense or U.S. Government.

Declaration of Interests

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclaimer
  7. Declaration of Interests
  8. References

The authors state they have no conflicts of interest to declare.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclaimer
  7. Declaration of Interests
  8. References