International Health Advance Access published May 20, 2015

The interrelation between intestinal parasites and latent tuberculosis infections among newly resettled refugees in Texas Amy R. Boarda,* and Sumihiro Suzukib a

ORIGINAL ARTICLE

Int Health doi:10.1093/inthealth/ihv033

University of North Texas Health Science Center, School of Public Health, Department of Public Health Education, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA; bUniversity of North Texas Health Science Center, School of Public Health, Department of Biostatistics and Epidemiology, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA

Received 18 January 2015; revised 6 March 2015; accepted 2 April 2015 Background: Previous research has documented that parasite infection may increase vulnerability to TB among certain at risk populations. The purpose of this study was to identify whether an association exists between latent tuberculosis infection (LTBI) and intestinal parasite infection among newly resettled refugees in Texas while controlling for additional effects of region of origin, age and sex. Methods: Data for all refugees screened for both TB and intestinal parasites between January 2010 and midOctober 2013 were obtained from the Texas Refugee Health Screening Program and were analyzed using logistic regression. Results: A total of 9860 refugees were included. In multivariable logistic regression analysis, pathogenic and nonpathogenic intestinal parasite infections yielded statistically significant reduced odds of LTBI. However, when individual parasite species were analyzed, hookworm infection indicated statistically significant increased odds of LTBI (OR 1.674, CI 1.126–2.488). Discussion: A positive association exists between hookworm infection and LTBI in newly arrived refugees to Texas. More research is needed to assess the nature and extent of these associations. Keywords: Hookworm, Intestinal parasites, Latent tuberculosis, Refugees, Texas, USA

Introduction Although much international focus has been placed on the prevention and treatment of TB, it continues to remain a significant public health threat. It is the second leading cause of death due to infectious diseases worldwide, claiming 1.4 million lives each year.1 Approximately one-third of the world’s population is infected with TB,2 and it is estimated that 5–10% of all untreated, infected individuals will develop active TB disease.3 For many years, researchers have worked to identify illnesses that may cause decreased immunity and heightened sensitivity to TB. Much attention has surrounded HIV, with other chronic illnesses such as diabetes mellitus receiving additional research focus. However, far less emphasis has been placed on another, more common source of potential immune system vulnerability globally: intestinal parasites. Intestinal parasites are most prevalent in developing nations, where unclean water sources and improper sanitation infrastructure encourage transmission.4 They pose a significant threat to proper nutrition, growth and development of children and the overall health and wellbeing of the individual.4 In recent years, studies have demonstrated that parasite infection may also

increase vulnerability to TB due to an increase in Th2 and/or regulatory T cell (Treg) immune responses, which are generally stimulated by parasitic infection, and a corresponding depressed Th1 immune response, the critical mechanism for containing bacteria infections.5–9 Poverty, crowded living conditions, and migration are key risk factors for both TB and intestinal parasite infection.6,10 Therefore, one population particularly vulnerable to TB/parasite coinfection is refugees. Refugees are individuals forced to flee their countries of origin due to persecution based on religion, race or ethnic identity, or political opinion.11 They are often confined for years in crowded, unsanitary conditions in rural camps or urban slums where they become highly vulnerable to communicable diseases and infections.12 There are an estimated 10.4 million refugees worldwide,13 and approximately 60 000–70 000 are resettled in the USA annually.14 According to the Centers for Disease Control and Prevention’s (CDC) guidelines, all newly arrived refugees must be screened for TB and other illnesses upon arrival to the USA.15 Most refugees are presumptively treated overseas for intestinal parasites; those who are not may either be given presumptive treatment during their initial health screening or be screened using stool ova and

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*Corresponding author: Tel: +1 817 735 2000; Fax: +1 817 735 2619; E-mail: [email protected]

A. R. Board and S. Suzuki

Materials and methods The data utilized for this study were obtained from the Texas Refugee Health Screening Program within the Texas Department of State Health Services. The data set comprised de-identified individual screening results for all arriving refugees seen at one of the seven Texas refugee health clinics located in Abilene, Amarillo, Austin, Dallas, Fort Worth, Houston, and San Antonio between January 2010 and mid-October 2013. All Texas refugee health clinics are required to report individual refugee health outcomes utilizing the Electronic System for the Health Assessment of Refugees (eSHARE) (http://www.dshs. state.tx.us/idcu/health/refugee_health/reporting/). The eSHARE document includes basic demographic data, domestic vaccination records, and health screening outcomes. For this study, only variables collected from eSHARE that were related to TB and intestinal parasite infection were pulled for analysis. Although refugee health clinics also serve asylees, Cuban entrants and parolees, Special Immigrant Visa holders and international victims of trafficking, only refugees were included in this analysis. Refugees are unique from other eligible groups because of their prolonged exposure to various health risk factors in refugee camps or crowded urban environments. Therefore, only individuals with refugee status were included.

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Only refugees who were screened for both TB and intestinal parasites were included in the study. During the timeframe studied, less than half of refugees seen in the clinics were screened for intestinal parasites and thus only these individuals were included in the analysis. HIV positive individuals were also excluded due to the well-documented increased vulnerability HIV confers on infection with TB.10 The primary outcome was LTBI status, as measured by a positive or negative tuberculin skin test (TST) or QuantiFERON®-TB Gold In-Tube (QFT) screening test. TST products are manufactured in the form of Tubersol® by Sanofi Pasteur Limited (Swiftwater, PA, USA) and Aplisol® by JHP Pharmaceuticals, LLC (Parsippany, NJ, USA). The QFT is manufactured by Qiagen, Inc. (Valencia, CA, USA). Both the TST and QFT are commonly used screening tests for infection with Mycobacterium tuberculosis. In keeping with CDC guidelines,15 positive TST was indicated as an induration of greater than 10 mm, while a negative TST result was a reading of 10 mm or less. Only the outcome values of positive or negative for the TST were utilized, rather than individual induration readings. Results from QFT tests were reported through eSHARE as positive, negative or indeterminate. Those with indeterminate QFT results (21 individuals) were excluded. In our sample, 7914 refugees received the TST while 2923 received the QFT. Of these, 978 received both tests. Individuals who tested positive on either the TST or QFT were considered to have LTBI for the purposes of this study. The primary factor of interest was the presence of pathogenic intestinal parasites, as measured by stool ova and parasite analysis and/or serology screening tests. Stool screening tests are commonly used to identify presence of intestinal parasites. Two to three stool samples were collected from each refugee patient and were analyzed by fecal microscopy using ova and parasite techniques. Each of the seven screening clinics contracted with a local parasitology lab or the state parasitology lab to perform the stool examinations using standard operating procedures. Findings were then recorded using the eSHARE document. Serology screening tests are also occasionally used to detect schistosomiasis and strongyloidiasis and were first implemented in screening clinics halfway through the timeframe of our study sample. Refugees were classified as positive for serology screening result or at least one pathogenic parasite species in stool, positive for non-pathogenic parasites, positive for both types of parasites, or negative for any parasite. Controlling variables included age, gender, and region of origin. All three variables have been documented to affect LTBI, parasite infection, or coinfection rates in previous studies.4,19 Statistical analysis was performed using SPSS Version 20 (IBM, Armonk, NY, USA). Logistic regression was used to investigate the association between LTBI and intestinal parasite infection. This study was approved by the University’s institutional review board.

Results A total of 9860 refugees were included in the sample. Of these, 33.0% (3249/9860) were positive for LTBI, while 25.3% (2494/ 9860) were positive for pathogenic parasites. An additional 29.3% (2889/9860) of refugees screened positive for non-pathogenic parasites. Common non-pathogenic species among immigrant

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parasite examination and serology tests, where applicable.16 However, treatment is only provided immediately before departure, despite the fact that refugees receive ongoing exposure to parasites throughout their time in the camp environment. While parasite treatment prior to departure may effectively eliminate current pathogenic organisms, it may come several years too late to have reduced immune system vulnerability to ongoing exposure and infection with TB. Presence of latent TB infection (LTBI) and parasite infections have both been documented separately in high levels among newly arriving refugees, with rates of LTBI and pathogenic parasites as high as 64% and 40%, respectively.17 Despite these high prevalence rates and the vulnerability to TB that parasite infection may confer, there is limited research on this topic. Previous studies of TB/parasite coinfection have focused on other at-risk populations.5–9 To our knowledge, no large-scale examination of coinfection among refugees has yet been explored. In addition, prior research has focused on the relationship between parasite infection and active TB disease8 and the efficacy of the BCG vaccine,6,7 with LTBI only recently receiving more attention.5,9,18 Therefore, further research is needed to assess whether an association exists between parasite infection and LTBI among refugees, the magnitude of association, and to examine variables that have been documented to show variability in coinfection rates: country of origin, age, and gender.4,19 The purpose of this study was to identify whether an association exists between LTBI and intestinal parasite infection among newly resettled refugees in Texas while controlling for additional effects of region of origin, age, and sex. Texas is currently the number one resettlement state, receiving 10% of the nation’s arrivals.14 Enhancing the overall understanding of intestinal parasite infection as a risk factor for LTBI among refugees carries important policy implications for refugee health providers both domestically and internationally.

1346 (30.1) 930 (20.8) 1154 (25.8) 796 (17.8) 251 (5.6) 181 (31.9) 43 (7.6) 89 (15.7) 206 (36.3) 48 (8.5) 666 (23.1) 356 (12.3) 735 (25.4) 827 (28.6) 305 (10.6) 639 (33.2) 291 (15.1) 375 (19.5) 492 (25.5) 130 (6.7) 1158 (35.6) 680 (20.9) 556 (17.1) 771 (23.7) 84 (2.6) 2832 (28.7) 1620 (16.4) 2353 (23.9) 2321 (23.5) 734 (7.4)

1674 (25.3) 940 (14.2) 1797 (27.2) 1550 (23.4) 650 (9.8)

2458 (54.9) 2019 (45.1) 313 (55.2) 254 (44.8) 1534 (53.1) 1355 (46.9) 1044 (54.2) 883 (45.8) 1934 (59.5) 1315 (40.5) 5349 (54.2) 4511 (45.8)

3415 (51.7) 3196 (48.3)

1448 (32.3) 1558 (34.8) 900 (20.1) 289 (6.5) 282 (6.3) 250 (44.1) 198 (34.9) 90 (15.9) 21 (3.7) 8 (1.4) 784 (27.1) 1197 (41.4) 564 (19.5) 179 (6.2) 165 (5.7) 804 (41.7) 707 (36.7) 257 (13.3) 82 (4.3) 77 (4.0) 2698 (40.8) 2230 (33.7) 993 (15.0) 363 (5.5) 327 (4.9) 588 (18.1) 1430 (44.0) 818 (25.2) 208 (6.4) 205 (6.3)

6611 3249 9860

3286 (33.3) 3660 (37.1) 1811 (18.4) 571 (5.8) 532 (5.4)

Age 0–17 (median: 8) 18–34 (median: 26) 35–49 (median: 40) 50–59 (median: 54) 60–105 (median: 66) Gender Male Female Region of origin Southeast Asia South Asia Middle East Sub-Saharan Africa Other

Both pathogenic and nonpathogenic parasites found n (%) 567 Non-pathogenic parasites found n (%) 2889 n (%)

LTBI positive n (%)

LTBI negative n (%)

Pathogenic parasites found n (%) 1927 Total

The purpose of this study was to identify whether an association exists between LTBI and intestinal parasite infections while controlling for additional effects of age, gender and region of origin. Reduced odds of LTBI were observed among individuals infected

Table 1. Frequency of LTBI and parasitic infections by age, gender and region of origin

Discussion

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populations include Entameoba hartmanni, Entamoeba coli, Entameoeba polecki, Entamoeba dispar, Entamoeba moshkovskii, Endolimax nana, Iodameoba butschlii, Chilomastix mesnili, and Trichomonas hominis.20 Specific non-pathogenic parasite results are typically not reported using eSHARE, therefore, prevalence rates in our sample could not be determined. Individuals aged 18–34, males, and arrivals from Southeast Asia had the highest prevalence of LTBI. Individuals aged 0–17, males, and arrivals from Southeast Asia had the highest prevalence of pathogenic parasite infection (Table 1). The results of multivariable logistic regression that included parasite screening result, controlling for age, gender and region of origin, is shown in Table 2. Interestingly, in this analysis, infection with non-pathogenic parasites, pathogenic parasites, and both types of parasites all yielded statistically significant reduced odds of LTBI. This was contrary to our original hypothesis. Therefore, we extended our analysis by examining individual parasite species. Individual parasites were examined using logistic regression to identify both odds of LTBI infection and eosinophilia, measured as greater than or equal to 400 cells/mL (Table 3). Eosinophil production is a marker of an increased Th2 immune response,7 which is one immune mechanism that may lead to increased vulnerability to LTBI. The most common types of parasite infections were protozoan, including Giardia, Dientamoeba, and amoebiasis. Helminth infections included Ascaris, Trichuris, Clonorchis, and hookworm. Among individual parasites, only hookworm yielded statistically significant increased odds of LTBI (OR 1.674, CI 1.126–2.488). Other parasitic infections did not yield statistically significant results or, in the case of Ascaris, Trichuris, Giardia and Amoebiasis, had statistically significant decreased odds of LTBI (Table 3). With regard to eosinophilia, helminths had the highest statistically significant increased odds. Protozoa results ranged from no statistical significance (Dientamoeba and Amoebiasis), to slightly increased odds of eosinophilia (Giardia), to reduced odds of eosinophilia (other protozoan parasites). Logistic regression analysis for burden of parasite infection was also performed. Reduced odds of LTBI were found for those infected with two or three different parasites compared to those who had no parasite infection (OR 0.749, CI 0.611–0.919 and OR 0.409, CI 0.241–0.693, respectively), while no significant relationship was found for the small sample size infected with four different parasites (OR 1.096, CI 0.262–4.590). In addition, separate analysis was conducted by type of test used to determine LTBI (TST or QFT). Both analyses yielded reduced odds of LTBI for individuals with non-pathogenic parasite infections (TST OR 0.624, CI 0.557–0.698; QFT OR 0.814, CI 0.679–0.975) and individuals with both types of parasite infections (TST OR 0.374, CI 0.286–0.488; QFT OR 0.649, CI 0.475–0.886). Analysis of pathogenic parasite infections by only TST results yielded significant reduced odds of LTBI (OR 0.514, CI 0.455–0.581), while analysis by only IGRA results yielded no significant relationship (OR 1.264, CI 0.959– 1.666).

No parasites found n (%) 4477

International Health

A. R. Board and S. Suzuki

with pathogenic parasites, contrary to our hypothesis. However, when individual parasites were examined, we found that varying associations existed between specific parasite species, their effects on the host’s immune response (as measured by

Table 2. Association between age, gender, region of origin and latent tuberculosis infection (LTBI) 95% CI

Ref. 0.665 0.631 0.457

Ref. (0.597–0.740) (0.558–0.714) (0.367–0.570)

Ref. 3.047 4.249 3.187 3.681

Ref. (2.717–3.417) (3.713–4.862) (2.601–3.904) (2.985–4.538)

1.353 Ref.

(1.236–1.481) Ref.

6.142 5.642 2.296 4.868 Ref.

(4.800–7.859) (4.374–7.277) (1.786–2.952) (3.789–6.255) Ref.

Ref: reference group. All odds ratios were statistically significant at p

The interrelation between intestinal parasites and latent TB infections among newly resettled refugees in Texas.

Previous research has documented that parasite infection may increase vulnerability to TB among certain at risk populations. The purpose of this study...
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