Public Health in Practice 3 (2022) 100245 Contents lists available at ScienceDirect Public Health in Practice journal homepage: www.sciencedirect.com/journal/public-health-in-practice A simple new screening tool for diagnosing imported schistosomiasis Silvia Roure a, b, *, Olga Pérez-Quílez a, Xavier Vallès a, c, Lluís Valerio a, Gemma Fernández-Rivas d, Belén Rivaya d, Israel López-Muñoz a, Laura Soldevila a, b, Xavier Villanova a, Roger Paredes c, e, f, g, Maria-Lluïsa Pedro-Botet b, Sebastián Videla g, h, Bonaventura Clotet b, e, f, g a North Metropolitan International Health Program (PROSICS), Badalona, Spain b Infectious Diseases Department, Germans Trias i Pujol University Hospital, Universitat Autònoma de Barcelona, Badalona, Spain c Institut per la Recerca en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain d Microbiology Department, Germans Trias i Pujol University Hospital, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Badalona, Spain e AIDS Research Institute-IrsiCaixa Foundation, Germans Trias i Pujol University Hospital, Universitat Autònoma de Barcelona, Badalona, Spain f Fight AIDS Foundation, Germans Trias i Pujol University Hospital, Badalona, Spain g Universitat de Vic-Universitat Central de Catalunya, Vic, Spain h Clinical Research Support Unit, Clinical Pharmacology Department, Bellvitge University Hospital / Bellvitge Biomedical Research Institute (IDIBELL) / University of Barcelona, L’Hospitalet de Llobregat, Spain A R T I C L E I N F O A B S T R A C T Keywords: Objectives: We sought to test the sensitivity and feasibility of a Schistosoma infection screening process consisting Schistosomiasis of a scored patient consultation questionnaire and a serological diagnostic test. Screening Study design: Prospective cross-sectional study. Migrant population Methods: We collected from Schistosoma-exposed individuals a 14-point check list of clinical and laboratory data Imported disease related to Schistosoma infection, alongside a serological test to detect Schistosoma spp infection. A check list score was created and compared with the risk of infection and clinical recovery through an agreement analysis. Results: Two-hundred and fifty individuals were enrolled, of whom 220 (88%) were male and 30 (12%) female. The median age was 39 (range 18–78). One hundred-fifty (60%, 95% CI 54.9%–65.1%) had a check-list score ≥2. Serology test results were positive for 142 (56.8%, 95% CI 51.6%–62%). Chronic complications compatible with long-term Schistosoma infection were detected in 29 out of these 142 (20.4%, 95% CI 13.8%–27%).,. The median score value was 3, the area under the receiver operating characteristic (ROC) curve against serology results was 0.85 and the estimated intercept check-list questionnaire score value was 1.72 (95%, CI: 1.3–2.2). Participants with a positive serological test had a substantially higher check-list score (Cohen’s kappa coefficient: 0.62, 95% CI: 0.54–0.70). Ninety four percent patients empirically treated showed a subsequent improvement in clinical and laboratory parameters. Conclusions: A two-component process consisting of a scored patient consultation questionnaire followed by serological assay can be a suitable strategy for screening populations at high risk of schistosomiasis infection. Conflicts of interest the third most serious endemic tropical parasitic disease in the world, after malaria and amoebiasis. It affects over 258 million people in 78 The authors of this study have no conflicts of interest to declare. countries, most of them in sub-Saharan Africa, where 90% of cases occur, and causes an estimated 200,000 deaths annually [1]. Morbidity 1. Introduction and mortality attributable to advanced stages of the disease have been estimated at around 3.3 million disability-adjusted life-years [2,3]. Schistosomiasis, a water-borne human helminthiasis, is regarded as The disease is caused by worms of the Schistosoma genus, most * Corresponding author. North Metropolitan International Health Unit PROSICS. Infectious Diseases Department, Germans Trias i Pujol University Hospital, Carretera canyet s/n, 08916, Badalona, Spain. E-mail address: sroura.mn.ics@gencat.cat (S. Roure). https://doi.org/10.1016/j.puhip.2022.100245 Received 23 August 2021; Received in revised form 8 March 2022; Accepted 15 March 2022 Available online 18 March 2022 2666-5352/© 2022 The Authors. Published by Elsevier Ltd on behalf of The Royal Society for Public Health. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). S. Roure et al. Public Health in Practice 3 (2022) 100245 frequently Schistosoma mansoni and Schistosoma haematobium species, known prior history of schistosomiasis and a 14-item checklist to which use certain types of freshwater snails (Bulinus spp. for determine the presence or absence of the most commonly recognized S. haematobium and Biomphalaria spp. for S. mansoni) as intermediary signs and symptoms of previous or current Schistosoma infection [16], hosts from which the human-invasive cercaria form asymptomatically listed in Table 1 below. The checklist included retrospective data from penetrates exposed skin. Thereafter, Schistosoma flukes may remain clinical records of the patients, such eosinophil, creatinine, glomerular clinically silent for decades (30%–50% of cases) or cause relatively mild filtrate and transaminase counts. A score of 1 was awarded for every and non-specific symptoms before eventually evolving into severe and affirmative answer of each of the questions or clinically demonstrated irreparable organ damage such as fibrosis leading to portal hypertension presence of a symptom. (S. mansoni) or obstructive uropathy and hydronephrosis (S. haematobium), which in turn may lead to squamous cell carcinoma of 2.4. Serological assay the bladder [4]. Consequently, schistosomiasis should never be consid­ ered a benign asymptomatic infection [5]. A highly cost-effective, safe In parallel, a venous blood sample (5 mL) was collected and tested and well-tolerated short course treatment (praziquantel) is widely for Schistosoma spp. with the SCHISTO-96 test kit (Scimedx Corporation, available [6], and in areas with moderate to high transmission rates of Dover, USA). A spectrophotometer absorbance reading (450–620 nm) schistosomiasis, mass-preventive periodic chemotherapy among school greater than 0.3 optical density (OD) units was a regarded as a positive children has proved to be an effective control strategy [7,8]. result for Schistosoma infection. Direct examinations of biological samples (faeces or urine) are the gold standard for diagnosis, but show low sensitivity in non-endemic 2.5. Treatment protocol countries. Serological assay, the most widely available laboratory test, shows an 80% sensitivity [9,10]. Therefore, both direct and indirect Patients who had either a total check-list questionnaire score ≥2 or diagnostic methods show drawbacks. positive serological test results were treated with praziquantel in The prevalence of Schistosoma infection among migrants living in the accordance with standard protocols. Patients with one or more positive North Metropolitan Health District of Barcelona, Spain, is estimated to checklist items but negative serology were clinically rechecked and be high but remains largely underdiagnosed. The underlying reasons for treated with praziquantel if necessary, given the limited 80% sensitivity these underdiagnoses are the lack of infection suspicion due to the silent of the serological test9,10. nature of the infection until late-stage complications and the unavail­ Six months after treatment, patients were reassessed by means of ability of rapid screening tools at the primary care level, compounded by complete blood count and blood chemistry tests and abdominal ultra­ the steady increase in the number of migrants from schistosomiasis- sonography. Patients who presented eosinophilia also underwent endemic regions [11–14]. Strongyloides stercoralis serology testing and were treated according to The aim of this study was to assess the sensitivity of a screening the results. methodology consisting of a check-list questionnaire eliciting patient sociodemographic background information and identifying symptoms 2.6. Data management and statistical analysis and signs of Schistosoma infection, combined with a serological assay. If effective and feasible, such a relatively simple screening process could An electronic case report form was created ad hoc in Access® format help to increase the treatment coverage of this largely preventable life- and sociodemographic baseline data for each patient were introduced threatening disease in Europe. alongside data obtained from the sign and symptom questionnaire (see Table 1), serological results for schistosomiasis, presumptive Schisto­ 2. Methods soma species if any were identified based on clinical data, eosinophil count and comorbidities. Data was obtained from electronic clinical 2.1. Study population records (i.e. previous ultrasound study or laboratory results), and cur­ rent or past signs and symptoms referred by the patient at enrolment. The North Metropolitan International Health Unit serves a popula­ Qualitative variables were displayed as proportions with corre­ tion of approximately 1,300,000, of whom about 15% are immigrants sponding 95% Confidence Intervals (95% CI). Continuous variables from non-EU countries, most of them living in the northern crown of the were displayed as median and 25–75 Interquartile Range (IQR). For greater metropolitan area of Barcelona, Spain. The medical facilities run association analysis, the Chi-Square test was used to compare two by this service are publicly accessible and free of charge. qualitative variables and Student’s t-test was used for quantitative var­ iables after testing for normality (skewness and kurtosis tests) or their 2.2. Study design Table 1 This prospective cross-sectional study involved a sample from a Areas covered by signs and symptoms checklist for the diagnosis of cohort of sub-Saharan African migrants aged 18 or older who were schistosomiasis. attended at the Unit facilities for pre-travel health advice between June Laboratory criteria 2015 and February 2020. Those attended at the Unit who met inclusion Eosinophilia (>500 cells/μL or absolute count >8%) Yes = 1/No =0 criteria were randomly invited to participate in the study. However, any Transaminitis of unknown origin Yes = 1/No =0 candidates with known positive Schistosoma serology who reported Abnormal dipstick test result Yes = 1/No =0 previous treatment with praziquantel were excluded. Given that the Renal failure (creatinine >1.3 mg/mL) Yes = 1/No =0 Clinical criteria prevalence of infection is 24% among migrants from schistosomiasis- Adult or childhood haematuria Yes = 1/No =0 endemic countries who are now living in non-endemic countries [15], Dysuria Yes = 1/No =0 a sample size of 200 was estimated to be representative within the usual Recurring urinary tract infections Yes = 1/No =0 confidence parameters. Chronic abdominal pain Yes = 1/No =0 Rectal bleeding Yes = 1/No =0 Diarrhoea of unknown origin Yes = 1/No =0 2.3. Sign and symptom check-list questionnaire Chronic liver disease Yes = 1/No =0 Sterility Yes = 1/No =0 A clinician completed a detailed questionnaire for each participant Ictus/myelitis Yes = 1/No =0 which included questions to obtain basic sociodemographic information Image criteria Abnormal ultrasound findings (urogenital and/or hepatosplenic) Yes = 1/No = 0 including age, gender, country of origin, years of residence in the EU and 2 S. Roure et al. Public Health in Practice 3 (2022) 100245 non-parametric counterparts when necessary (Fisher test or Wilcoxon The median checklist score for signs and symptoms was 3 (IQR 2–5, test, respectively). To ascertain the sensitivity/specificity of the check- range 0–10). Chronic Abdominal pain (43.0%) and dysuria (22.0%) list questionnaire score against serology results, we performed a ROC were the most prevalent symptoms; with referred background of hae­ analysis. Area Under the Curve (AUC) and the intercept of plotted score maturia (35.3%) the most frequently cited sign. Among the serious values with the ROC curve were estimated. The estimated score inter­ comorbidities, chronic renal insufficiency (n = 37, 15.0% CI 10.8–20.1) cept was considered a cut-off and tested for sensitivity and specificity was the most frequent. Two participants (0.8%, CI 0.1–2.9) had previ­ against the outcome of interest (i.e. positive serology). ously undergone kidney transplantation and one (0.4%, CI 0.01–2.2) A p-value ≤ 0.05 was considered statistically significant. Data anal­ had suffered an ischemic cerebrovascular stroke. Overall, 142 (56.2%) ysis was carried out using R (R Core Team, Vienna, Austria, 2015) [17, had a positive serology test results. 18] and the Stata© 14.0 statistical package (Stata Corp., College Station, Based on organ involvement, suspected schistosomiasis infection was Texas, 2015). classified as urogenital (n = 58, 41%, 95% CI 32.2%–48.2%), intestinal and hepatosplenic (n = 26, 18%, 95% CI 11.4%–23.9%) or indetermi­ 3. Results nate (n = 58, 41%, 95% CI 33.1%–49.2%). Concomitant active Hepatitis B infection (HBsAg+) was detected in 3.1. Baseline patient characteristics and check-list questionnaire results 26 cases out of 136 tested (19.1%) and Strongyloides stercolaris infection was detected in 47 of the 129 tested (36.4%), of whom 25 (53.2%, p = Of a total of 2076 sub-Saharan African migrants who attended the 0.27) had a positive Schistosoma spp serology test. The presence of pre-travel service during the study period and met the inclusion criteria, Strongyloides infection was significantly associated with eosinophilia in 252 (12.1% of the eligible population) were randomly invited to blood tests (p < 0.001). Bivariate analysis showed that individuals with participate. Two of those invited declined to be included in the study Strongyloides infection tended to report higher eosinophilia than those (0.8%). The final study sample consisted of 250 individuals. The with schistosomiasis infection (mean 14.3% (SD 7.2) vs mean 9.2% (SD screening process as applied to the study sample is illustrated in the flow 6.73), p < 0.001). chart in Fig. 1 below. The top rows of Table 2 below show the participants’ baseline 3.2. Agreement and accuracy between checklist score and serological test characteristics. Briefly, 220 were males (88.0%) and the mean age was 39.5 years (SD = 9.8, range 18–78). The most frequent country of origin The AUC was 0.85 (see Fig. 2), and the intercept of the check-list was Senegal (n = 73, 29.6%). The subsequent rows show the results of questionnaire score value was estimated at 1.72 (95% CI 1.26–2.18). the results of the 14-item questionnaire-checklist for signs and symp­ Therefore, we set the cut-off score value at ≥2 for testing against toms of schistosomiasis, followed by data regarding coinfection by sensitivity and specificity. Considering this cut-off, we observed a hepatitis B or Strongyloides stercolaris. sensitivity of 87% (95% CI 81.5%–92.5%), and specificity of 75% (95% Fig. 1. Flow-chart of the screening and treatment procedure, showing number of participants ants at each step. 3 S. Roure et al. Public Health in Practice 3 (2022) 100245 Table 2 candidates for specific treatment for Schistosoma infection, of which 123 Results of schistosomiasis screening questionnaire, showing sociodemographic had a checklist score ≥2 and positive serology, 27 had a checklist score information, signs and symptoms of schistosomiasis identified and serological ≥2 and negative serology (after a clinical recheck), and 19 had a assay results for the 250 study participants (significant p-values in boldface). checklist score <2 and positive serology. Fifty-seven of these 169 (33%) [n (%)] N Total serology p- did not return to pick up the results of the screening procedure and thus positive negative value did not receive treatment. Overall, a total of 112 (45%) participants with n = 142 n = 108 presumptive Schistosoma infection successfully completed the treatment. Gender 249 219 127 92 (42.1) 0.4 Of these 112, 82 (73.2%) had a complete follow-up with laboratory and Male (88.0) (56.0) 15 (50.0) clinical final results. Female 30 15 Based on the baseline data at enrolment, after treatment, levels of (12.0) (50.0) transaminases normalized in 16 out of 17 cases (94%), eosinophilic Age (mean, SD) 250 39.5 38.5 40.8 0.05 count normalized in 32 out of 34 (94%) and symptoms improved in 30 (9.8) (8.7) (10.9) <10 years in the EU 170 63 43 20 0.5 out of 31 (96%). (37.4) (68.3) (31.83) Country of origin 245 4. Discussion Senegal 73 39 32(45.1) 0.6 Mali (29.6) (54.9.) 18(34.6) 0.2 Gambia 52 34 22(44.0) 0.8 Our results support the contention that a two-component screening Other (21.3) (65.4) 32(44.4) 0.5 strategy, a checklist-type questionnaire followed by a serological test, 50(20.2) 28 could be a valuable tool to detect active schistosomiasis, with any 72(29.1) (56.0) screened individual scoring ≥2 on the questionnaire for schistosomiasis 40 being offered treatment and those with score <2 and serology test (55.6) Laboratory criteria positive. Such a screening procedure would help to prevent chronic Eosinophiliaa 238 123 82 41 (40.2) 0.002 complications resulting from schistosomiasis among a growing at-risk (51.7) (60.3) population in Europe. The fact that almost 20% of serological positive Transaminitis of unknown 234 33 27 6 (18.2) 0.001 test had a score <2, supports the necessity of including the serological origin (14.1) (81.9) Abnormal dipstick test 101 35 28 7 (20.0) 0.2 test, which is considered the most effective screening test for detection result (34.7) (80.0) schistosomiasis in low-endemicity settings [19]. Otherwise, in support Chronic Renal failureb 246 37 26 11 (29.7) 0.08 of a stand-alone questionnaire-checklist methodology is that the (15.0) (70.3) questionnaire-based screening process may show higher specificity Clinical criteria regarding active infection than serological testing, which cannot Background of haematuria 247 88 71 16 (18.4) < (35.3) (81.6) 0.001 distinguish between current and past infection. This may be the case of Dysuria 250 55 43 12 (21.8) < this mentioned subgroup of patients with score <2 and positive sero­ (22.0) (78.2) 0.001 logical test. Furthermore, stand-alone use of a serology test could not be Recurring urinary tract 248 38 29 9 (23.7) 0.007 considered sufficient. Serological tests do have higher, but still limited infectionsc (15.3) (76.3) Chronic abdominal pain 249 107 77 29 (27.4) < sensitivity compared to conventional parasitological methods in sce­ (43.0) (72.6) 0.001 narios of scarce egg density samples or in non-endemic countries [9,14, Rectal bleeding 249 21 (8.4) 17 4 (19.1) 0.02 15,19]. In addition, available serological tests have sub-optimal speci­ (81.0) ficity, which may differ depending on Schistosoma species. Diarrhoea of unknown 249 27 21 3 (19.2) 0.009 Notwithstanding, we cannot rule out that a simple drug distribution origin (10.8) (80.8) Sterilityd 175 13 (7.4) 9 (69.2) 4 (30.8) 0.9 strategy using as unique criteria the background of coming from an Ictus/myelitis 248 1 (0.4) 1 (100) 0 (0.0) 0.6 endemic country, as set up elsewhere, may be the most cost-effective Schistosoma during 166 13 (7.8) 11 1 (8.3) 0.2 and efficient strategy [20]. This is supported by the estimated high childhood (91.7) prevalence of Schistosoma infection among this population and the in­ Image criteria Abnormal ultrasound 91 31 27 4 (12.9) 0.04 clusion of previous laboratory results in the questionnaire (eosinophil finding (urogenital and/ (34.1).4 (87.1) and transaminase blood count), which may not be available for most of or hepatosplenic) patients. Coinfections In this sense, it will be noted that the estimated prevalence of Hepatitis B (HBsAg+) 136 26 13 13 (50.0) 0.2 Schistosoma infection in our sample is higher than the previously re­ (19.1) (50.0) Strongyloides stercolaris 129 47 25 22 (46.8) 0.4 ported estimates of 24% in Europe [15] though our figures are in line (36.4) (53.2) with those obtained by Beltrame et al. based on a comparable population a of West African immigrants in Italy [13,14]. Even assuming the lower Eosinophilia (>500 cells/μL or absolute count >8%). b Renal insufficiency was defined as decreased estimated glomerular filtration estimate, considering that over 73,000 individuals from hyperendemic rate (<60 mL/min/1.73 m2) or elevated blood creatinine (>1.3 mg/mL). areas of sub-Saharan Africa are legally registered residents of Catalonia c Recurrent urinary tract infections were defined as >2 urinary tract infections [21], roughly 17,000 schistosomiasis-infected people could remain (urinalysis either by microscopy or by dipstick and/or urine culture with sus­ largely undiagnosed. Of note, these numbers are much higher than es­ ceptibility data) as recorded in the patient’s medical file. timates for other infectious diseases already included in systematic d Sterility was defined as inability of a couple to conceive after 12 months of screening programs such as those targeting the Zika virus or using regular intercourse without use of contraception. serological assays to detect Chagas disease among exposed pregnant women. CI 69.7%–82.1%), with a predictive positive value of 82% (95% CI Overall, the epidemiological data and our study results, strongly 75.7%–88.3%) and predictive negative value of 81% (95% CI 74.5%– supports that whether a systematic Schistosoma screening or a mass drug 87.5%) against serology positivity. distribution of high-risk populations is an urgent need among migrant populations in Europe, as screening programs applied in non-endemic 3.3. Clinical management countries are demonstrably able to reduce the morbidity and mortality attributable to this chronic disease [19,22,23]. This assertion is sup­ The screening process selected a total of 169 participants to be ported by the fact that 92% of our study-patients treated for previous 4 S. Roure et al. Public Health in Practice 3 (2022) 100245 Fig. 2. ROC curve and estimated AUC of checklist score against serology test results. analytical alterations (eosinophilia and/or transaminase elevation) and the generalizability of our results may therefore be questionable. showed a good response to treatment (i.e. resolution of these alter­ Secondly, we cannot rule out the presence of a selection bias among ations). This reinforces the idea that the observed alterations were individuals who agreed to participate in the study. Participants who actually mainly attributable to previously undetected schistosomiasis agreed to participate may have done so because they considered them­ infections. We should underscore that a substantial number of our pa­ selves to be high-risk. This may in turn have produced a certain over­ tients already have long-term complications of Schistosoma infection (i. estimation of Schistosoma prevalence in our results. Finally, it would be e. renal insufficiency) with more than 10 years of residence in Europe of interest to validate our results with further studies using a proper (60% of our study sample), which denotes a high rate of delayed control group and comparing the relative cost-benefit ratios of empirical diagnosis. and non-empirical treatment strategies when applied in non-endemic We would like to outline the underrepresentation of women in our countries. study sample (n = 12; 5%), which deserves a separate comment. Women In short, the prevalence of schistosomiasis infection and its compli­ account for 30% of non-EU individuals living in our study area, and the cations among sub-Saharan African immigrants living in non-endemic prevalence of Schistosoma infection is uniform across gender [24]. This countries may be largely underestimated. In order to determine the indicates that any test-and-treat strategy should be pro-active and true prevalence of what tends to be regarded as a “benign” tropical community-based with the goal of reaching underdiagnosed disease in these high-risk populations a two-component screening sub-Saharan women and other hard-to-reach high-risk populations. In approach such involving a questionnaire-checklist could prove quick to addition, our data suggest that women have specific signs and symp­ perform and effective at detecting schistosomiasis infection, besides the toms, like more urinary infections than men (26.7% (8/30) vs 13.8% consideration of unspecific drug distribution strategy, allowing rapid (30/217), p = 0.07), which suggests that any check-list questionnaire treatment to avoid chronic disease and complications. should be gender-adapted Women may also show more gynaecological-related symptomatology [25–27] (i.e. dyspareunia, pel­ Ethical approval vic pain, discharge and bleeding, sterility). Of note, given the high rates of lost of follow-up, a test and treat The study protocol was approved by the local IRB (ethics committee strategy is even most necessary [22]. Therefore, more sensible and of the Germans Trias i Pujol University Hospital) with the reference specific, feasible point-of-care screening methodologies should be number PI-17-136. developed. For instance, besides improving sensitivity and specificity of serological tests, an obvious way to improve the availability and Funding cost-effectiveness is to develop new devices that could be used as point-of-care tests, incorporating them at the primary care level [28,29]. This research did not receive any funding from agencies in the These new devices should overcome the mentioned limitation of lack public, commercial, or not-for-profit sectors. specificity towards past infection and variable specificity/sensitivity. The questionnaire may include proven biomarkers and prognostic fac­ Declaration of competing interests tors in the chronically infected population living in non-endemic countries and more gender orientated questions focused on female None to declare. genital manifestations. An adequate strategy could be the implementa­ tion of such screening programs in sexual and reproductive primary Declaration of competing interest health centres to improve the accessibility of women to the schistoso­ miasis screening programs. The authors of this study have no conflicts of interest to declare. Our study is subject to several limitations. First, the population studied here was taken from a very specific European metropolitan area, 5 S. Roure et al. Public Health in Practice 3 (2022) 100245 Acknowledgements [15] A. Asundi, A. Beliavsky, X. JianLiu, et al., Prevalence of strongyloidiasis and schistosomiasis among migrants: a systematic review and meta-analysis, Lancet Global Health 7 (2019) e236–248, https://doi.org/10.1016/S2214-109X(18) The authors wish to thank the study participants for their contribu­ 30490-X. tion to the research. [16] Schistosomiasis, WHO reports substantial treatment progress for school age children, 2016. 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