In 1999, the U.S. Centers for Disease Control and Prevention (CDC) recommended pre-departure presumptive sulfadoxine-pyrimethamine (SP) for P. falciparum malaria for all U.S.-bound refugees from sub-Saharan Africa. This recommendation was implemented by the International Organization for Migration (IOM) who performed the pre-departure medical assessment for U.S.-bound refugees within 72 hours of departure. As regional resistance to SP intensified, CDC issued revised recommendations in 2005 that called for artemisinin-based combination therapy to replace SP treatment. This recommendation was not implemented at that time because of drug cost and availability.

Twenty-eight cases were detected among 1,805 refugees in the SP group, and all 28 had received SP. Nineteen (68%) cases were in refugees < 15 years of age (median age = 9.5 years, range = 3–71 years) and 15 (54%) were male. In the partially supervised AL group, nine cases were identified among 2,773 refugees; eight (89%) were cases were in refugees < 15 years of age and 4 (44%) were male. All eight pediatric patients had received partially supervised AL, and one pregnant adult did not receive any pre-departure treatment. In the fully supervised AL group, two cases, one in a person < 15 years of age, were detected among 1,581 refugees, and both persons had received fully supervised AL. Disease incidence was significantly higher among refugees in the SP group compared to the combined AL groups (RR = 6.2, 95% CI = 3.1–12.4) after adjusting for age; incidence was also higher among children < 5 years of age (RR = 2.2, 95% CI = 0.9–5.4, P = 0.09) and 5–14 years of age (RR = 3.1, 95% CI = 1.5–6.5) when compared with adults ≥ 15 years of age after adjusting for treatment group. Adjusted disease incidence did not differ significantly between the partially and fully supervised AL groups (RR = 2.6, 95% CI = 0.5–11.9, P = 0.2).

Median time to symptom onset after arrival did not differ by treatment group (median = 4 days, first and third quartiles = 10 and 17 days, range = 3–46 days). Thirty-two (82%) persons required hospitalization, and four (10%) had severe manifestations, including impaired consciousness, respiratory distress, anemia, hypoglycemia, and acidosis. Among 32 hospitalized persons, 26 (81%) were hospitalized for ≥ 2 days (median = 3 days, range = 1–12 days). Among 33 persons with known parasite densities, 9 (27%) had parasitemias > 5% (range = < 0.1–18%). No cases resulted in deaths.

Among 1,805 at-risk refugees who received pre-departure SP, 66 (4%) were ineligible for presumptive re-treatment with atovaquone-proguanil (AP), including 28 persons treated for symptomatic P. falciparum malaria, two treated for symptomatic non-P. falciparum malaria, 24 pregnant women, and 13 lactating women. Among the remaining 1,738 eligible candidates, 1,434 (83%) received re-treatment. No subsequent malaria cases were detected. The remaining 304 eligible refugees did not receive presumptive re-treatment because some jurisdictions elected to screen everyone and treat only those who were parasitemic.

Because P. falciparum resistance to SP is high in Tanzania,^4,5 the apparent failure of this regimen is not unexpected and highlights the impact of failing to provide effective presumptive treatment. Artemether-lumefantrine, the first fixed-dose artemisinin-based combination therapy pre-qualified and recommended by the World Health Organization,⁶ has high cure rates.^7,8 However, the six-dose AL regimen is complicated, requiring doses twice a day for three days, preferably with a fatty snack to promote lumefantrine absorption.^9,10 Because of the complexity of delivering a fully supervised regimen in a refugee camp situation, initially, only three doses were supervised. Thus, cases observed in the partially supervised AL group may have been caused by subtherapeutic dosing after poor patient compliance or poor absorption. Furthermore, because neither AL nor SP has an effect on hepatic schizonts, these therapies may not be curative for all patients who were infected near the time of treatment. Although the risk of imported malaria among U.S.-bound refugees can be reduced, complete elimination of imported cases is not achievable with the present strategy, even when effective drugs are administered under ideal circumstances.

Our analysis also confirms that controlling P. falciparum infections and preventing disease among U.S.-bound refugees is an appropriate priority for refugee populations emigrating from areas to which malaria is highly endemic. Plasmodium falciparum malaria causes considerable morbidity among refugees. In this series, 70% of persons required hospitalization ≥ 48 hours, and 10% experienced severe manifestations. In general, post-arrival care may not be optimal because refugees are often unable to access medical care for a myriad of reasons (e.g., language, cultural, logistical, and other barriers to care in an unfamiliar system), which may lead to delays in care,^11–14 and U.S. clinicians may have little experience with malaria, which delays diagnosis and impedes appropriate management.¹⁵

Imported malaria may create a substantial strain on the receiving communities, health care systems, and public health agencies. For example, in our series, hospitalization costs alone averaged approximately $5,000 per case, and domestic re-treatment costs (drug plus personnel time) for refugees who received SP and were re-treated with AP exceeded $220,000 (Bagga S and others, unpublished data). Others have shown that effective pre-departure presumptive antimalarial therapy produces a cost-savings when the prevalence of clinical malaria infection in the resettlement group exceeds 1%.¹⁶ Furthermore, imported infections present the potential for autochthonous transmission.^17,18 Competent anopheline mosquito vectors are found throughout the lower 48 states,¹⁹ and in the past decade, local transmission has been documented in five states.²⁰ However, no instances of local transmission in the United States have been linked to refugee resettlement. Finally, 8–60% of refugees from areas to which malaria is highly endemic have detectable P. falciparum parasitemias more than four weeks after resettlement in North America.^21–23 Because no widely available testing modality is sensitive enough to reliably detect persons with subclinical infection at the time of arrival medical screening,^22,23 alternatives to mass presumptive treatment of the control of subclinical infections are few.

This evaluation has several limitations. First, because our investigation was not a randomized controlled trial, causation cannot be demonstrated. Therefore, only temporal associations between the presumptive treatment regimen and incidence of imported malaria are reported. Second, case-finding may have missed refugees who did not seek care for malaria symptoms, particularly those in the SP group who arrived before active case-finding was initiated. In addition, most refugees who had received SP before departure were presumptively re-treated with AP after arrival. Both of these factors would have contributed to under-reporting the true incidence of malaria in the SP group, which would have under-estimated the impact of pre-departure therapy. Missed cases in this group would have increased the differences observed. Third, although camp surveillance systems in Tanzania indicate that the intensity of malaria transmission remained high throughout the observation period, there was no other data available to verify that on-going malaria in the area during the study period remained stable through the study period. Lastly, our findings were in refugees from camps located in a specific geographic location and may not be generalizable to other groups of immigrants or refugees.