Presumptive Treatment of P. falciparum Malaria in Refugees Relocating from Sub-Saharan Africa to the United States

Background

Each year, refugee arrivals to the United States varies from less than 35,000 to more than 100,000. The proportion of newly arriving refugees originating from Africa increased from 9% in 1998 to 39% in 2005 [1]. Since 2005, African refugee arrivals have accounted for 30%–40% of all new arrivals annually [1]. Because of high prevalence, potential virulence, and dynamic epidemiology, malaria has emerged as a disease of particular concern in refugees. Malaria has historically plagued displaced populations in endemic areas, and this situation continues in many refugee settings [2, 3]. When refugees lack access to host country health programs, they may be at risk for many diseases, including malaria and other parasitic infections.

Although global malaria incidence has declined over the past 10 years, an estimated 219 million new cases of malaria occurred worldwide in 2017, with 92% of them in Africa [4]. The acute clinical consequences of infection and disease are most severe in persons who have no malaria immunity (also called tolerance); as a result, in highly endemic areas, young children account for most malaria deaths. Although five species of malaria routinely infect humans, the burden and consequences of Plasmodium falciparum predominate. Among those with no immunity, P. falciparum infection may lead to severe morbidity or mortality within hours of onset of symptoms. In contrast, in highly endemic (hyperendemic or holoendemic) areas, most individuals have acquired tolerance (“partial immunity”) to infection, and may have few or no symptoms. Areas with high endemicity are most common in West and Central Africa and in geographically discrete areas of East Africa. P. malariae and the relapsing species of human malaria, P. vivax and P. ovale, also occur in sub-Saharan Africa but cause severe disease or death less often than P. falciparum.

Other areas, such as Central Asia, South Asia, Southeast Asia, and parts of Latin America and the Caribbean, have varying levels of malaria transmission, rarely reaching hyperendemic or holoendemic levels. These areas also have varying ratios of P. falciparum and non-falciparum malaria; many have a higher proportion of non-falciparum malaria (specifically P. vivax) than falciparum malaria. Additionally, P. knowlesi is found in Southeast Asia and may cause severe morbidity and mortality.

Malaria was endemic in most of the continental United States and much of Europe into the 20th century. Most of the continental United States has Anopheles mosquitoes (particularly An. quadrimaculatus and An. freeborni), which are competent vectors of malaria under favorable conditions. Local US vector-borne transmission has resulted in more than 150 locally transmitted cases and more than 60 limited outbreaks in the United States over the past 50 years [5, 6]. In addition, more than 2,000 cases of malaria are reported annually in the United States, with most cases occurring in returned travelers [7]. Local transmission of malaria within the United States has never been associated with newly arriving refugees.

History of Pre-departure Presumptive Malaria Therapy in US-bound Refugees

Refugees may arrive in North America with asymptomatic or subclinical malaria infection [3, 8, 9]. Some refugees who have subclinical infection will develop disease after arrival, while others will clear the infection without developing disease [10]. Lack of knowledge of malaria among healthcare professionals in the United States frequently leads to delay in diagnosis and inappropriate treatment [11, 12]. This lack of familiarity has been associated with fatal outcomes [12]. In addition, malaria may interfere with a refugee’s successful integration into a host community by creating issues such as physical incapacity, added financial stresses, and social stigma.

Refugees from sub-Saharan Africa may have subclinical P. falciparum malaria, which may persist for months after arrival, although it is unusual to develop signs or symptoms of disease more than 3 months after arrival. As refugees may have circulating parasites in the blood that could be transmitted by a competent mosquito, there is a theoretical concern that this could lead to an autochthonous transmission. However, to date, no transmission has been traced to a newly arrived refugee.

Data collected from 1997 to 1999 showed that 60% of Liberian refugees, arriving from four primary countries of asylum in holoendemic West Africa, were parasitemic 4 weeks after arrival [13]. Of untreated refugees arriving in Canada from an area of lower transmission in Tanzania, 18% had evidence of infection up to 3 months after arrival [8]. In the late 1990s, concerns about the high prevalence of Plasmodium infection in refugees from sub-Saharan Africa led CDC to recommend that all refugees departing for the United States from malaria-endemic areas in sub-Saharan Africa receive presumptive therapy for malaria. These recommendations were issued in May 1999 to organizations and clinicians performing pre-departure examinations and management (“panel physicians”). The treatment recommended at that time was a presumptive course of sulfadoxine-pyrimethamine (SP, Fansidar^TM).

Following implementation of presumptive therapy, imported cases dropped dramatically in a high-risk West African cohort of refugees arriving in Minnesota, with the incidence decreasing from more than 8% to nearly zero between 1996 and 2005 [10]. An evaluation found substantial cost savings for host communities and estimated that the presumptive treatment program was cost-effective when the rate of clinical malaria exceeded 1.5% in departing populations. This analysis estimated that among West African refugees, 12 refugees needed to be treated to prevent one case of clinical malaria [10].

However, by 2000, it was noted that SP treatment of malaria in Africa was becoming increasingly ineffective because of rising resistance. Among 103 newly arrived Liberian refugees who were treated with SP before resettlement in Minnesota, 8.7% were found to have subclinical P. falciparum at 4 weeks after arrival [9]. In 2006, the World Health Organization (WHO) changed its recommendation for the treatment of choice for clinical malaria in Africa from SP to artemisinin-based combination therapy (ACT) [14]. CDC subsequently revised its domestic refugee malaria guidance to correspond with the WHO recommendations because of concerns for persistent malaria in refugees arriving in the United States.

However, for many reasons, including global artemisinin shortages, the US Refugee Admissions Program continued to use SP for pre-departure treatment. In spring 2007, additional cases of clinical malaria were reported to CDC in Burundian refugees arriving from Tanzania. In May 2007, active surveillance started in Tanzania, and pre-departure ACT was initiated (artemether-lumefantrine [Coartem™]). Between May 2007 and February 2008, more than 6,100 African refugees were processed in Tanzania and resettled in the United States, some of whom were presumptively treated with SP, while others received ACT. Thirty-nine malaria cases were detected among those resettled, with 82% of cases resulting in hospitalization and 10% having severe manifestations. Of those with severe manifestations, 27% had a parasitemia level exceeding 5%. Most importantly, disease incidence in the SP group was 15.5/1,000, while those who received ACT had an incidence of 1.3/1,000 [15]. Since 2008, presumptive ACT has been used to prevent P. falciparum malaria cases in sub-Saharan African refugees resettling to the United States.

Recommendations for Pre-departure Presumptive and Directed Treatment for P. falciparum Infection for Refugees from sub-Saharan Africa

The currently recommended ACT regimen is artemether-lumefantrine because it is widely available as a fixed-combination tablet, including in most refugee camps, has a wide therapeutic window, has a minimal adverse event profile, and is consistent with most national guidelines for treating clinical malaria. Pre-departure presumptive malaria therapy must be administered and documented as directly observed therapy, and the refugee must carry this documentation. To be considered valid, the presumptive therapy must be completed no sooner than 5 days before departure.

Historically, special populations, including pregnant women, infants weighing less than 5 kg, and lactating women who were breastfeeding infants under 5 kg, did not receive presumptive pre-departure treatment. In 2015, WHO revised its guidance, stating that the use of artemether-lumefantrine is safe for pregnant women during their second and third trimesters, and for lactating women regardless of the infant’s weight [16]. Thus, CDC revised its pre-departure presumptive guidance to include these groups [17]. Asymptomatic infants weighing less than 5 kg and women in their first trimester of pregnancy will not be offered presumptive treatment, and should only receive directed treatment after diagnostic testing identifies malaria parasitemia. Testing will be performed with blood smear microscopy and/or rapid diagnostic tests (RDT) with a kit agreed upon in consultation with CDC’s Division of Global Migration Health. Microscopy and RDT have limited sensitivity and do not rule out malaria [9]. Therefore, any refugee who develops clinical signs or symptoms of malaria should receive further evaluation, regardless of screening test results. Refugees who have signs or symptoms of clinical malaria before departure should be evaluated and treated according to the host country’s national guidelines.

Recommendations for Post-arrival Presumptive and Directed Treatment for Refugees from sub-Saharan Africa

Clinicians conducting the domestic medical screening should consider the following recommendations for newly arrived refugees:

• Refugees who have received pre-departure treatment with a recommended antimalarial drug or drug combination do not need further evaluation or treatment for malaria unless they have signs or symptoms of disease.
• Subclinical P. falciparum malaria may be present in those from hyperendemic and holoendemic regions of sub-Saharan Africa. Subclinical infection is usually seen in adults and older children who have semi-immunity, however it may also be present in infants and young children. Clinical disease due to P. falciparum, when it occurs, generally manifests within 3 months of arrival. If a refugee has been living in a non-endemic region for more than 3 months, P. falciparum malaria is unlikely, although any symptomatic refugee should be tested.
• It is recommended that refugees (including children weighing at least 5 kg) originating in sub-Saharan Africa who have not received pre-departure therapy with a recommended regimen either receive presumptive treatment on arrival (preferred) or have laboratory screening to detect Plasmodium infection if seen within 3 months of arrival.
• For refugees from sub-Saharan Africa with contraindications to presumptive treatment, testing should be performed if seen within 3 months of arrival, including women in their first trimester of pregnancy and infants weighing less than 5 kg.
• Refugees from areas other than sub-Saharan Africa who are asymptomatic do not need routine presumptive treatment or testing, unless under specific instructions by CDC.
• Refugees from regions endemic for malaria who present with signs or symptoms of malaria should be promptly evaluated and treated as indicated.

Post-arrival Presumptive Antimalarial Treatment

When presumptive treatment for malaria is deemed necessary, atovaquone-proguanil (Malarone™) and artemether-lumefantrine are the medications of choice in the United States. Atovaquone-proguanil and artemether-lumefantrine are effective treatments for P. falciparum malaria as well as P. malariae and the blood stages of P. vivax and P. ovale (Table 1). In addition, there is little parasite resistance to these medications, the treatment regimens are short, and they are well tolerated with few adverse effects. All other available oral medications have higher rates of adverse effects (e.g., mefloquine) or more complex dosing regimens of combination medications (e.g., quinine plus a second agent) and are therefore of limited use for presumptive treatment. Certain populations should not receive presumptive malaria regimens, including ACT or atovaquone-proguanil. They include pregnant women in their first trimester, infants weighing less than 5 kg, and those with a known allergy or hypersensitivity to these medications. Additional information on the treatment of malaria can be found on the CDC Malaria website.

Medical and Laboratory Screening after Arrival

An alternative to presumptive treatment is to test newly arriving sub-Saharan African refugees for malaria infection. However, diagnosis of asymptomatic or subclinical malaria infection can be difficult due to laboratory test limitations. Screening with laboratory testing can also present challenges to clinics due to the logistics of obtaining blood smears at the appropriate time intervals or sending samples out for PCR testing. Therefore, local determination of feasible testing modalities must be considered. Polymerase chain reaction (PCR) is the most sensitive test and is the preferred method to test for asymptomatic or subclinical malaria, when available, and is helpful in species determination [18, 19]. If PCR is not available, blood smears (3 separate blood films taken at 12- to 24-hour intervals) should be examined, as the next most sensitive option. Although this test has excellent sensitivity for P. falciparum in symptomatic patients, it is less sensitive in the diagnosis of asymptomatic or subclinical infection for P. falciparum in newly arrived refugees [9]. RDT has an even lower sensitivity than blood smears and should only be used in conjunction with blood smears. Regardless of testing modality or presumptive treatment, all refugees should be advised to seek healthcare if they develop any signs or symptoms of disease, as no presumptive treatment or diagnostic test is 100% effective for all malaria species.

Some hematologic or physical examination findings in screening of asymptomatic individuals, such as thrombocytopenia or splenomegaly, are associated with malaria in individuals from highly endemic areas [13]. Malaria should be considered in the differential diagnosis of refugees with these clinical signs, even when lacking other common symptoms such as fever. High rates of splenomegaly have been observed in Congolese refugees, and CDC has issued specific guidance for this population [20, 21].

Refugees from Other Regions

Refugees arriving from Southeast Asia, South Asia, Central Asia, and all areas in the Western Hemisphere generally come from areas with low or no malaria transmission. In contrast to refugees from sub-Saharan Africa, it is rare for persons from these areas to have asymptomatic or subclinical P. falciparum malaria infection. In these refugee populations, the risks and cost of post-arrival presumptive treatment outweigh the potential benefits. Furthermore, routine laboratory screening (given challenges with sensitivity and predictive value in low prevalence populations, cost, and test availability) is not indicated unless signs or symptoms of disease are present. Therefore, CDC does not currently recommend routine presumptive treatment or routine laboratory screening for malaria in groups of refugees from areas outside sub-Saharan Africa, unless additional guidance is provided. However, any refugee from an endemic area with signs or symptoms of malaria should receive diagnostic testing for Plasmodium and treatment for confirmed infections.

Strategies to Prevent Non-falciparum Malaria in Newly Arriving Refugees

Non-falciparum malaria (caused by P. vivax, P. ovale, or P. malariae) is less often associated with severe illness or death. Two species, P. vivax and P. ovale, may form a parasite life stage (hypnozoite) that lies dormant in the liver for months to years before re-emerging to cause blood stage infection and clinical disease. Primaquine and tafenoquine are the only Food and Drug Administration-approved medications in the United States with the ability to treat hypnozoites. Therapy is complicated by the need to test glucose-6-phosphate dehydrogenase (G6PD) enzyme levels before treating with primaquine or tafenoquine, because of the potential risk of life-threatening hemolytic anemia in G6PD-deficient individuals. CDC does not recommend routine presumptive treatment for P. vivax or P. ovale with primaquine or tafenoquine. Routine laboratory testing for non-falciparum malaria in asymptomatic individuals is also not recommended. Current testing modalities (i.e., blood film, RDT, and PCR) are unreliable in detecting subclinical or asymptomatic infection.

P. malariae also may cause persistent infections, although it has no dormant liver stage. Infected individuals are frequently asymptomatic, although they may develop clinical malaria leading to complications, including nephrotic syndrome. Because this organism is not common and is thought to respond to currently recommended presumptive therapy for P. falciparum, there are no additional recommendations for P. malariae infection.

Tables

Table 1. Dosing of antimalarials for presumptive or directed treatment of P. falciparum malaria in sub-Saharan African refugees after arrival in the United States

Presumptive Therapies

^*Should be taken with foods rich in fat, such as milk. If vomiting occurs within 1 hour after taking the medicine, another dose should be taken.

NOTE: More specific guidance, including information on directed therapy alternatives and how to access CDC’s Malaria Hotline for clinical consultation, can be found at the CDC Malaria website.

Table 2: Relative sensitivity of malaria testing modalities