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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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More recently, it has been recognized that there are other important diseases and medical conditions affecting refugees, which can cause considerable morbidity and can pose sizable public health risks. To address these issues, the Centers for Disease Control and Prevention (CDC) has developed a strategy of enhanced refugee health assessments. This strategy uses a population-specific approach to screening and treatment of diseases among resettling refugee groups; it aims to improve the health of individuals within the refugee population, and protect the health of the public in the United States. Initial application of the strategy among African refugees has focused on parasitic diseases, including malaria and intestinal parasites.5
Management of malaria in resettling refugees can pose many challenges. In the United States and other countries not endemic for this disease, malaria is rarely seen and expertise in diagnosis and management is often limited, leading to delays in diagnosis or administration of inappropriate therapy.6 In addition, there may be limited availability of appropriate antimalarial drugs. Antimalarial drug resistance is widespread and treatment with the most effective therapies, although usually available abroad, may not be available in the United States as a result of federal licensing regulations and poorly stocked pharmacies. Finally, costs associated with the management of malaria in the United States are typically far greater than those associated with diagnosis and treatment in the country of origin or refuge.
In addition to individual malaria case management and treatment concerns, resettlement of refugees from malaria-endemic regions into the United States carries the potential for local transmission of malaria through the introduction of malaria parasites into the local mosquito population. Anopheles species mosquitoes are present in 49 of 50 states (excluding Hawaii) in the United States, and the introduction of a large number of gametocytemic individuals could, given appropriate climatic conditions, lead to local transmission of malaria. Such transmission has been documented and attributed to individuals coming from malaria-endemic regions.7–11
Many of the concerns outlined above were realized in 1992 when a group of 402 Montagnard refugees were rapidly resettled from Vietnam to North Carolina; no formalized overseas malaria screening and treatment program was implemented. A number of cases of malaria were identified among refugees within one month of arrival in the United States, and the burden of malaria diagnosis and case management overwhelmed the capacities of local and state health departments. Subsequently, comprehensive post-arrival screening showed a malaria prevalence of 58%, and mass treatment with halofantrine was implemented.12 This screening and treatment effort required extensive mobilization of local, state, and federal resources and was conducted at the cost of significant unplanned outlay of time, money, and other resources, including the hiring of additional staff.13 Following this experience, recommendations were made to include malaria screening and treatment as a component of overseas health assessments of refugee groups from malaria-endemic regions headed to the United States.13 Two general approaches for malaria management among refugee populations have been used; screening and targeted treatment, and mass presumptive treatment (with selective screening of population subsets).5,14
In April 2002, the U.S. government accepted another group of Montagnard refugees for urgent resettlement. An enhanced refugee health assessment program, including pre-departure malaria screening and targeted treatment, mass (presumptive) treatment of intestinal parasites, and age-appropriate vaccination was implemented by CDC and the International Organization for Migration (IOM) in Phnom Penh, Cambodia. This report outlines the methodology and results of the pre-departure malaria screening and treatment strategy, discusses the usefulness, accuracy, and appropriateness of diagnostic options in this setting, and comments on the utility of various alternative malaria screening and treatment strategies.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Malaria screening and treatment strategy. The malaria screening and treatment strategy and other enhanced health assessment activities were conducted in parallel with the mandatory U.S. health assessments and administrative procedures in Phnom Penh. Refugees were screened for malaria irrespective of symptoms and previous medical history. Informed written consent to conduct malaria screening was obtained from each adult refugee and from parents or guardians of minors prior to initiation of screening. Refugees were aware that the results of the malaria screening would not affect their approval for resettlement in the United States. This research was conducted in compliance with all applicable federal regulations governing the protection of human subjects research.
A malaria team from CDC, consisting of an expert microscopist and medical epidemiologist, trained four local Khmer medical doctors in blood sample collection by finger stick, in the use of the rapid diagnostic test (RDT), in interpretation of RDT results, and in preparation of blood smears and filter papers specimens.
Refugees were screened in groups of three by two teams of two doctors: one performed the finger stick and prepared the blood smear and filter paper specimen, while the other performed the RDT. The RDT results were available within 20–25 minutes. No active symptom history was obtained during the malaria-screening process. However, medical history was obtained during the routine pre-departure medical screening conducted by the IOM. The CDC team reviewed RDTs throughout the day to ensure accurate interpretation of RDT results.
Blood smears corresponding to positive and indeterminate RDTs were stained and read in the field by the expert microscopist to confirm presence of parasitemia and identify species. Blood smears corresponding to the negative RDTs were also stained and read if there was clinical suspicion of malaria.
Refugees were treated if they had a positive RDT result, an indeterminate RDT result with a positive smear, or a negative RDT result and a clinical suspicion of malaria confirmed by microscopy. Treatment consisted of a combination of artesunate and mefloquine (as per the Cambodian national treatment policy) or with quinine (in the case of pregnancy or allergy to artesunate or mefloquine).
Rapid diagnostic tests. The OptiMAL-IT® (DiaMed AG, Cressier s/Morat, Switzerland) test was the RDT chosen for screening. This RDT uses a dipstick coated in monoclonal antibodies against the metabolic enzyme parasite lactate de-hydrogenase (pLDH) produced by viable malaria parasites. Plasmodium falciparum and non-falciparum infections are distinguished by the antigenic differences among the pLDH isoforms.
The RDT was performed according to the manufacturer’s instructions. The test has three diagnostic regions. The appearance of a band at the P region, which contains the monoclonal antibody against the pLDH antigen common to all species of Plasmodium, indicates the presence of malaria parasites. The presence of a second band at the Pf region containing monoclonal antibody specific to pLDH antigen from P. falciparum indicates the presence of P. falciparum. A band in the control region should be present on all tests to indicate a valid test.
Results were considered positive if the control band and the P band were present (indicating pure non-falciparum infection), or if the control, P, and Pf band were present (indicating either a pure P. falciparum infection or a mixed infection). Results were considered indeterminate if any of the following occurred: no control band, only one band at the Pf region, or blood did not clear from the test strip after 10 minutes in the wash well. Results were considered negative if there was a control band and no other bands on the test strip.
Microscopic examination. Thick and thin smears were prepared at the time of finger stick blood collection. Smears were stained with 2% Giemsa prepared with filtered water and phosphate buffer (pH 7.2) and examined under 1,000x magnification for the presence of malaria parasites. Smears were considered negative if no parasites were seen after counting 200 oil-immersion fields on the thick smear. Parasite densities were calculated with reference to the white blood cell (WBC) count (assumed to be 8,000 WBC/µL).
Upon the return of CDC staff to Atlanta, a quality control assessment and RDT evaluation was performed. Microscopy was performed on smears corresponding to all positive and indeterminate RDT results and a randomly selected 10% sample of negative RDT results. The microscopists were blinded to the RDT results. Where there was discordance between the first and second microscopists, a third expert microscopist read the smear. Final smear results were determined by the concordance of two of the three readers.
Analysis by polymerase chain reaction (PCR). Blood samples were collected on IsoCode® STIX (Schleicher and Schuell, Keene, NH). The samples were air-dried and stored and transported at room temperature with a desiccant pillow. The DNA was extracted by boiling, and the supernatant was used to detect and speciate Plasmodium in a nested PCR assay.15 Small modifications were made to this method to improve detection of P. ovale. The PCR analysis was performed on all filter paper specimens corresponding to the RDT positive and indeterminate results and the random sample of negative results.
Statistical analysis. Categorical variables were analyzed using frequency distributions. Since microscopy is still considered the gold standard for malaria diagnosis and was the next best alternative in this setting (the PCR, although more sensitive, is currently regarded as a research tool only), RDT results were classified as true positives, false positives, true negatives, and false negatives compared with microscopy. Since only a random sample (10%) of blood smears corresponding to the negative RDT results were read, calculations of sensitivity, specificity, and positive and negative predictive values are based on results of this sub-sample.
United States post-arrival malaria strategy. Upon arrival in the United States, therapy with a 14-day course of primaquine to prevent relapse from P. vivax or P. ovale was planned for all non-pregnant refugees with normal levels of glucose-6-phosphate dehydrogenase irrespective of their pre-departure screening result.
A passive fever surveillance system to track malaria infections among the refugees was instituted by the receiving health authorities. Physicians evaluating refugees with fever were encouraged to consider malaria as a differential diagnosis and to prepare blood smears.
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RESULTS |
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shows the demographic characteristics of the Montagnard group. The population consisted of 906 Montagnard refugees, all of whom consented to malaria screening. The majority (76.1%) were young men (median age = 26 years, range = < 1–90 years). Seventy-one (7.7%) refugees were less than five years old and 22 (15.8%) of the women (12–50 years old) were pregnant.
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Malaria screening results.
Table 2 summarizes the malaria screening results from RDT, microscopy, and PCR tests, by Plasmodium species. We screened 902 (99.6%) of 906 refugees with RDTs. Approximately 80 refugees per day were screened for malaria. Of the four we were unable to screen with RDTs, two had microscopy alone, while another two received no screening because they were hospitalized for illnesses other than malaria during the screening period.
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Among those with a positive RDT result, nine (75%) were considered positive by microscopy performed in Cambodia (field microscopy). A species was identified in only two (22.2%) of these microscopically positive specimens (one P. falciparum and one P. vivax). Among the indeterminate RDT results, five (17.9%) were considered positive by field microscopy, with no species able to be determined.
Microscopic review of smears upon return to CDC in Atlanta (final microscopy) showed the following: of the 12 positive RDT results, two (16.7%) were positive by microscopy (one P. falciparum and one P. vivax), and of the 28 indeterminate RDT results, one (3.6%) was positive (no species identified) by microscopy. All three positive smears were of very low density (500–4,000 parasites/µL).
Among the blood smears corresponding to the 10% random sample of negative RDT results (n = 86), none were considered positive by microscopy. Baseline characteristics of this 10% sample did not differ from the Montagnard group as a whole.
Results of the PCR. The PCR analysis of the filter paper specimens corresponding to the positive RDT results confirmed only two positive results: one P. vivax, and one mixed infection with P. falciparum and P. vivax. There were no PCR-positive specimens among the indeterminate RDT results or the sample of negative RDT results.
Treatment. Eighteen (2.0%) of the screened refugees were treated with antimalarials: 12 with RDT-positive results, five with RDT-indeterminate results with positive or suspicious smear results by microscopy in the field, and one RDT-negative but symptomatic refugee with a suspicious smear result by microscopy.* Seventeen refugees received the combination of artesunate and mefloquine, while one received quinine.
Performance of the RDT.
Table 3 shows sensitivity, specificity, positive predictive value, and negative predictive value of the RDT compared with microscopy in the field and final microscopy in Atlanta (excluding and including the indeterminate results as positive).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Screening showed a malaria prevalence of 1.3% by RDT (< 1% confirmed by expert microscopy) among this recent group of Montagnard refugees. This prevalence differs substantially from that observed in the 1992 Montagnard group (58.1% by microscopy).13 This difference in pre-departure prevalence might be explained by a number of factors. First, there was a substantial difference in the length of time spent by each group in the temporary UNHCR camps prior to resettlement in the United States. The 2002 group described in this paper lived in temporary camps for approximately one year, while the 1992 group were resettled after only one month in such camps. The UNHCR-administered camps typically make available regular medical care and encourage refugees to seek medical advice as needed. This is likely to have resulted in timely diagnosis and treatment of malaria during encampment. In addition, personal protective measures (such as insecticide-treated nets) are usually provided in the camps. A second factor might be the change in malaria epidemiology of the region over the interim decade. Regional data suggest that malaria transmission has decreased over the past 10 years.16 In 2000, malaria incidence per 1,000 population in Cambodia and Vietnam were 5.33 and 0.97, respectively, compared with 10.37 and 2.01 in 1992.17,18 This change in epidemiology in combination with different times in camp and pre-departure medical experience is likely to explain the very low prevalence of malaria observed among this group of refugees compared with a similar group a decade earlier.
The RDTs were chosen for diagnostic screening because they are reported to be sensitive, require minimal training, are easy to use and interpret, results are rapidly available, and the tests are relatively robust.19–21 This specific RDT was chosen because it can distinguish between acute infections with P. falciparum and non-falciparum species (thought to be important given the malaria epidemiology in Vietnam and Cambodia) and is less likely to give false-positive results associated with persistent antigen post-treatment (compared with histidine rich protein-2 antigen tests).19
Our experience, although not a formal evaluation, demonstrated that health staff with no prior experience with RDTs could perform and interpret the results with minimal training. It was possible for each trained health worker to perform multiple tests at a time, thus minimizing waiting times and maximizing the number of refugees screened each day. We were able to screen up to 130 refugees on some days. Microscopy in this setting was unlikely to have been as efficient or as accurate given the large number of smears, particularly with many negative and low-density smears.
Although a small sample size was used, the RDT demonstrated good sensitivity. Interestingly, despite RDTs having a reputation of poor performance at low-density parasitemias (< 100 parasites/µL),19 and with experience suggesting such parasitemias were to be expected among this refugee group,13 the quality control assessment and informal evaluation of the RDT described in this report showed no missed malaria cases (false-negatives) in a randomly selected sub-sample. Notwithstanding, fever surveillance should remain an important activity after arrival in the United States. In addition, although the RDTs used in this setting correctly identified all refugees with malaria, less than optimal specificity was noted, leading to over-diagnosis (false-positives). These false positive results may have been the result of persistent circulating antigen, although this is unlikely given that pLDH is only produced by viable parasites. Such false-positive results have been reported elsewhere.22,23 Possible explanations include visualization of the monoclonal antibody strip when test strip is dampened (shadow line) or as a result of non-specific binding of the antibody to the capture lines. The possibility of the tests being affected by the humidity or other realistic field conditions needs to be further explored.
In terms of predictive ability, because of the false-positive results in this setting, we found a low overall positive predictive value for the test. In contrast, review of a 10% random sample of smear corresponding to the negative RDT results demonstrated an overall negative predictive value (ability of a negative test result to exclude malaria) of 100% for the test.
From an operational perspective, the indeterminate RDT results were of concern. These RDT results all demonstrated sub-optimal wicking of blood during the first buffer phase of the test and inadequate clearing of the blood from the test strip during the second phase. Subsequently, it was not possible to determine whether these test results were positive or negative because the positive band area on the test strip was obscured. This phenomenon was likely to have been related to the environmental conditions in which the test was being performed, including the high temperature and humidity. Little information is available pertaining to the stability of RDTs in conditions of extremes of temperature during transport, storage, or use. These concerns have been highlighted by others as possible explanations for poor performance seen with RDT use in some programmatic settings.22,24 The lack of quality control and quality assurance measures during the manufacture of RDTs has also raised concerns regarding inter-batch reproducibility and optimal performance of RDT kits.20,23 Manufacturers recommend the optimal temperature for storage and use as between 3°C and 30°C. Such conditions are often exceeded in tropical countries where these tests are likely to be used programmatically.
For indeterminate RDT results, corresponding blood smears were evaluated by microscopy in the field to determine the need for treatment. If microscopy had not been available in the field, reasonable alternatives would have been to consider refugees with indeterminate RDT results as parasitemic and treat appropriately, or to repeat the RDT, hoping to avoid any immediate environmental factors contributing to the poor wicking, and treat based on this repeat result.
In summary, our report highlights the importance of incorporating a pre-departure malaria screening and treatment strategy into enhanced health assessments for refugees resettling from malaria-endemic to non-malaria endemic areas. Despite the issues discussed and the need for further study of RDT characteristics and performance, our experience demonstrates that RDTs were useful screening tools in this urgent field situation, allowing for rapid, efficient, timely malaria screening and targeted treatment, with only limited available local expertise and supplies. Although some over-diagnosis and treatment occurred, the primary goals of reducing malaria morbidity and mortality and preventing importation of malaria into the United States were achieved. After one year since resettlement in United States, no refugees from this group have been diagnosed with malaria post-arrival.
Ultimately, further evaluation is needed to determine the most appropriate interventions in other refugee settings, including comprehensive analysis of the cost effectiveness of alternative malaria strategies (both mass and targeted screening and treatment options). Determination of the appropriate strategy for each setting should consider local malaria epidemiology (including species prevalence and status of drug resistance), availability and characteristics of diagnostic tests, extent of resources and personnel, availability and feasibility of effective antimalarial treatment, and the available time frame. With increasingly expensive antimalarials, and decreasing diagnostic costs, screening of refugees followed by targeted treatment may prove to be more cost effective than mass treatment in a number of settings, even when the malaria prevalence is relatively high among such groups.
Finally, in addition to pre-departure strategies, post-arrival strategies such as fever surveillance should continue to be used to detect recrudescent, relapsing, or missed cases. Anti-relapse therapy may be administered on a targeted or mass scale, again depending on regional malaria epidemiology and available resources.
Received June 10, 2004. Accepted for publication December 9, 2004.
Acknowledgments: We are very grateful to the local staff and staff of the IOM office in Phnom Penh for their assistance with the implementation of this screening and treatment program. At the CDC, Division of Parasitic Diseases laboratory We thank J. Pieniazek, Maniphet V. Xayavong, Stephanie P. Johnston, and Susanne P. Wahlquist (Division of Parasitic Diseases, CDC) for their assistance with specimen evaluation and technical support.
Financial support: This malaria strategy was supported by CDC and the International Organization for Migration.
Disclaimer: Use of trade names and commercial sources is for identification only and does not imply endorsement by CDC or the U.S. Department of Health and Human Services.
Disclosure: None of the authors has any conflicts of interest.
Authors’ addresses: Louise M. Causer, John R. MacArthur, and Peter B. Bloland, Malaria Branch, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway, NE, Atlanta, GA 30341, Telephone: 770-488-7755, Fax: 770-488-4206. Henry S. Bishop, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Mailstop F-36, 4770 Buford Highway, NE, Atlanta, GA 30341, Telephone: 770-488-4474, Fax: 770-488-3115. Donald J. Sharp, Elaine W. Flagg, J. Jina Shah, Susan A. Maloney, and Martin S. Cetron, Division of Global Migration and Quarantine, Centers for Disease Control and Prevention, Mailstop E-03, Executive Park 57, Atlanta, GA 30333, Telephone: 404-498-1600, Fax: 404-498-1633. Jaime F. Calderon and, Vincent Keane, International Organization for Migration, No 46, Street 310, Chamcar Mon, PO Box 435, Phnom Penh, Cambodia, Telephone: 855-23-216-532, Fax: 855-23-216-423.
Reprint requests: Louise M.Causer, Malaria Branch, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway, Atlanta, GA 30341, Telephone: 770-488 7782, Fax: 770-488 4206, E-mail: lsc6{at}cdc.gov.
* Field microscopy results called suspicious were considered to be positive for the purpose of prescribing treatment in this setting. 
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REFERENCES |
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This article has been cited by other articles:
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  W. M. Stauffer, M. Weinberg, R. D. Newman, L. M. Causer, M. J. Hamel, L. Slutsker, and M. S. Cetron Pre-departure and Post-arrival Management of P. falciparum Malaria in Refugees Relocating from Sub-Saharan Africa to the United States Am J Trop Med Hyg, August 1, 2008; 79(2): 141 - 146. [Abstract] [Full Text] [PDF]
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J. J. Shah, S. A. Maloney, Y. Liu, E. W. Flagg, S. P. Johnston, S. A. Young, R. Weston, S. Merritt, P. P. Wilkins, V. Keane, et al. Evaluation of the Impact of Overseas Pre-departure Treatment for Infection with Intestinal Parasites among Montagnard Refugees Migrating from Cambodia to North Carolina Am J Trop Med Hyg, May 1, 2008; 78(5): 754 - 759. [Abstract] [Full Text] [PDF]
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