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Severe complications of imported schistosomiasis, Spain: A retrospective observational study
Journal Pre-proof Severe complications of imported schistosomiasis, Spain: A retrospective observational study Joaquín Salas-Coronas, José Vázquez-Villegas, Ana B. Lozano-Serrano, Manuel J. Soriano-Pérez, Isabel Cabeza-Barrera, M Teresa Cabezas-Fernández, Antonio Villarejo-Ordóñez, José Carlos Sánchez-Sánchez, José Ignacio Abad Vivas-Pérez, Salvador Vázquez Blanc, Matilde Palanca Jiménez, José A. Cuenca-Gómez PII:
S1477-8939(19)30212-1
DOI:
https://doi.org/10.1016/j.tmaid.2019.101508
Reference:
TMAID 101508
To appear in:
Travel Medicine and Infectious Disease
Received Date: 27 February 2019 Revised Date:
20 October 2019
Accepted Date: 31 October 2019
Please cite this article as: Salas-Coronas Joaquí, Vázquez-Villegas José, Lozano-Serrano AB, Soriano-Pérez MJ, Cabeza-Barrera I, Cabezas-Fernández MT, Villarejo-Ordóñez A, Sánchez-Sánchez JoséCarlos, Abad Vivas-Pérez JoséIgnacio, Blanc SalvadorVá, Jiménez MP, Cuenca-Gómez JoséA, Severe complications of imported schistosomiasis, Spain: A retrospective observational study, Travel Medicine and Infectious Disease (2019), doi: https://doi.org/10.1016/j.tmaid.2019.101508. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Author contributions Joaquín
Salas-Coronas:
Conceptualization,
Methodology,
Formal
Analysis,
Investigation, Data Curation, Writing – Original Draft, Writing – Review& Editing, Visualization, Supervision, Project Administration. José Vázquez-Villegas: Conceptualization, Investigation, Data Curation, Writing – Original Draft, Writing – Review& Editing, Visualization. Ana B. Lozano-Serrano: Conceptualization, Investigation, Writing – Original Draft, Writing – Review& Editing, Visualization. Manuel J Soriano-Pérez: Investigation, Data Curation, Writing – Review& Editing. Isabel Cabeza-Barrera: Investigation, Data Curation, Writing – Review& Editing. Mª Teresa Cabezas-Fernández: Methodology, Investigation, Data Curation, Writing – Review& Editing. Antonio Villarejo-Ordóñez: Investigation, Data Curation, Writing – Review& Editing. José Carlos Sánchez-Sánchez: Investigation, Data Curation, Writing – Review& Editing. José Ignacio Abad Vivas-Pérez: Investigation, Data Curation, Writing – Review& Editing. Salvador Vázquez Blanc: Investigation, Data Curation, Writing – Review& Editing. Matilde Palanca Jiménez: Investigation, Data Curation, Writing – Review& Editing. José A. Cuenca-Gómez: Investigation, Data Curation, Writing – Review& Editing.
The present version of this paper has met the approval of all authors and they accept full responsibility for the content. The authors declare that this manuscript has not been simultaneously submitted for publication in any other journal, nor have the findings been partially disclosed in any other publication.
Title: Severe complications of imported schistosomiasis, Spain: a retrospective observational study Authors: Joaquín Salas-Coronasa,*, José Vázquez-Villegasb, Ana B. Lozano-Serranoa, Manuel J. Soriano-Péreza, Isabel Cabeza-Barreraa, Mª Teresa Cabezas-Fernándeza, Antonio Villarejo-Ordóñeza, José Carlos Sánchez-Sáncheza, José Ignacio Abad Vivas-Pérezc, Salvador Vázquez Blancc, Matilde Palanca Jiméneza, José A. Cuenca-Gómeza.
a
Tropical Medicine Unit, Hospital del Poniente, Ctra. de Almerimar, 31, 04700, El
Ejido (Almería), Spain. b
Tropical Medicine Unit, Distrito Sanitario Poniente de Almería, Calle Jesús de
Perceval, 22, 04700 El Ejido (Almería), Spain. c
Department of Urology, Hospital del Poniente, Ctra. de Almerimar, 31, 04700, El
Ejido (Almería), Spain.
* Corresponding author: Joaquín Salas-Coronas. Tropical Medicine Unit, Hospital del Poniente, Ctra. de Almerimar, 31, 04700, El Ejido (Almería), Spain. E-mail address: [email protected]
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ABSTRACT Background: Chronic schistosomiasis silently leads to severe organ-specific disorders, such as hydroureter, bladder cancer or portal hypertension in around 10% of infected people in endemic zones. However, in non-endemic areas, information on schistosomiasis' severe complications and their actual prevalence is scarce because diagnosis is usually reached when such complications are well established. Methods: Retrospective observational study of data obtained from a screening protocol designed for sub-Saharan migrants including search for stool parasites and schistosoma serology. After screening 3,090 sub-Saharans, 326 (10.5%) confirmed cases of schistosomiasis were found, based on detection of ova in feces, urine or in biopsy samples. Another 830 patients (26.9%) were diagnosed of probable schistosomiasis (positive serology and/or suggestive imaging findings). Results: Only patients with confirmed schistosomiasis were included in the final analysis. Among them, 13 (4%) presented severe complications at the time of diagnosis. Depending on the location, they account for 5% of patients with hepatointestinal schistosomiasis and 3.5% of patients with urogenital infection. Conclusions: Targeted systematic screening could reduce the prevalence of severe complications by enabling early diagnosis and treatment. Having indigenous transmission been demonstrated in southern Europe, prevention of future cases in nonendemic countries might be another sound reason supporting such screening. Keywords: Schistosoma, schistosomiasis, infectious imported diseases, migrants, screening, complications.
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1. Introduction Human schistosomiasis is a disease caused by trematode parasites of the genus Schistosoma. It is estimated that at least 230 million people worldwide are infected, 90% of them in sub-Saharan Africa, and that it causes around 300,000 deaths annually [1,2]. Schistosoma haematobium and Schistosoma mansoni are the predominant species and responsible for urogenital and hepatointestinal schistosomiasis respectively [1]. In endemic regions, the most prevalent form of disease is chronic schistosomiasis, resulting from repeated exposure to parasite cercariae. In many cases the disease may be unnoticed or just cause mild nonspecific symptoms [3], but in some patients, chronic tissue inflammation induced by the parasites' eggs, will lead to severe complications such as obstructive uropathy with hydronephrosis or squamous-cell carcinoma of the bladder in the case of S. haematobium, and liver fibrosis with portal hypertension and esophageal varices in the case of S. mansoni. It is estimated that approximately 10% of patients will develop severe complications [4]. The significant migratory flow of recent years from African countries to Europe has lead to an increase in the number of patients diagnosed with schistosomiasis in nonendemic regions [5-10]. This fact is behind the recommendation for the use of serological screening in new migrants coming from endemic countries recently issued by European health authorities [11]. However, the actual prevalence of severe complications of the disease in these regions is not well known, since most of the times the diagnosis is made only in those cases already presenting with specific complications [8] or publications just report single cases [12-14]. The objective of this study is to know the real prevalence of severe complications of the disease in a European area where there is a significant immigrant
3
population coming from schistosomiasis highly endemic regions, and where the screening for imported diseases in Primary and Specialized Care is well established.
2. Material and methods A retrospective observational study was conducted based on the data obtained after the systematic application of an imported disease screening protocol in immigrant of sub-Saharan origen assisted at the Tropical Medicine Unit of the Poniente hospital (El Ejido, Almeria, Spain) from October 2004 to February 2018. The Poniente area is an administrative area located in Southeast Spain holding a population close to 300,000 inhabitants with an immigrant share of 21%, many of them coming from sub-Saharan countries to work in horticultural greenhouses. In Primary Care, the screening protocol consists in a series of laboratory tests aimed to screen for imported and cosmopolitan diseases. The tests are usually offered the first time immigrants contact public health care system, no matter the reason they consult for. The screening protocol includes: blood count, liver and renal function tests, syphilis, HIV, HBV and HCV serologies, tuberculin skin test and search for stool parasites (three concentrated stool samples using Ritchie's method) and urine parasites (one concentrated urine sample [10 cc]). Migrant patients are referred to the hospital Tropical Medicine Clinic whenever an imported disease is either suspected or diagnosed. The hospital's protocol comprises medical history, epidemiological data, complete physical examination, and several additional tests: Strongyloides and Schistosoma serologies, and Knott and/or saponin tests for microfilariae. Chest and abdominal X-rays are routinely performed too. If any other specific disease is suspected (e.g., onchocerciasis, malaria, etc.), further proper diagnostic procedures are performed.
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Abdominal ultrasound is performed when schistosomiasis is suspected or diagnosed and whenever otherwise indicated (e.g., viral hepatitis). The following imaging findings are considered as suggestive of schistosomiasis: liver periportal thickening with or without cirrhosis, portal hypertension with spleen enlargement, urinary bladder wall thickening or other suggestive findings (calcifications or small parietal vegetations), abnormalities in the urinary tract (ureter dilatation or hydronephrosis), and lesions compatible with liver or bladder cancer [5,15]. Serum samples are evaluated for the detection of antibodies against Schistosoma spp. by qualitative determination of IgG-class antibodies against Schistosoma mansoni by means of an enzyme immunoassay (NovaLisa TM), indirect haemagglutination test for serum bilharzia antibodies (Fumouze Diagnostics, Levallois-Perret, France), or rapid test SCHISTOSOMA ICT IgG-IgM® (LDBIO Diagnostics), depending on the availability of each technique at the time. 2.1 Definitions Probable schistosomiasis: Positive serology and / or imaging findings compatible with schistosomiasis (see definition above) but without detection of ova. Confirmed schistosomiasis: Patients with detection of ova of Schistosoma in feces, urine or in biopsy samples obtained from different tissues. Severe complications: Severe complications for urogenital schistosomiasis are defined such as obstructive uropathy with hydronephrosis with or without renal dysfunction and or carcinoma of the bladder. For hepatointestinal schistosomiasis, liver fibrosis with portal hypertension with or without esophageal varices. We have also considered severe complications all cases with severe repercussions on the individual's health derived
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from the migration of the parasite or its ova to ectopic locations such as the CNS or other organs. 2.2 Statistical analysis A descriptive statistical analysis was conducted including the 326 patients diagnosed with confirmed schistosomiasis. Quantitative variables were expressed as means and interquartile ranges. Qualitative variables were described as frequencies and percentages. 2.3 Ethics Statement Samples were obtained at the Tropical Medicine Unit of Poniente Hospital (El Ejido, Almeria, Spain) for diagnosis purposes as part of the standard protocolized care of sub-Saharan patients attended at such unit. Anonymized data were collected retrospectively. This study has been approved by the Ethics Committee of the Coordinating Site (protocol Schis-01-UMT-2018).
3. Results Out of a total of 3,090 sub-Saharan patients attended during the study period, 326 (10.5%) were diagnosed with confirmed schistosomiasis based on the detection of ova in feces, urine or in biopsy samples obtained from different tissues. In parallel with a significant rise of migration in Spain, most of the diagnoses were made between 2008 and 2011, with a mean of 50 cases per year. Another 830 patients (26.9%) were diagnosed with probable schistosomiasis (positive serology and / or imaging findings compatible with schistosomiasis) and were
6
not included in the global analysis. Most of them had a positive serology (n=816; 98,3%) and mainly came from Mali (n=295), Senegal (n=219) and Guinea Bissau (n=73). In 48 of them, abdominal X-ray showed calcifications on the urinary bladder wall, and 37 presented ultrasound-imaging findings suggestive of schistosomiasis (irregularity, thickening and / or calcification of the bladder wall). All of them were treated with praziquantel at standard doses. General characteristics of patients with confirmed schistosomiasis are shown in Table 1.
Total patients N= 326 Age (years) Mean (range)
27.3 (11-52)
Gender (Number, %) • Male • Female
306 (93.9%) 20 (6.1%)
Time living in Spain (months) (1)
39.6 ± 36.7 (1-288)
Country of origin (Number, %) Mali Senegal Mauritania Equatorial Guinea Ghana Guinea-Conakry Guinea Bissau Gambia Burkina Faso Nigeria Ivory Coast Sierra Leona
164 (50.3%) 74 (22.7%) 24 (7.4%) 12 (3.7%) 11 (3.4%) 10 (3.1%) 10 (3.1%) 9 (2.8%) 5 (1.5%) 3 (0.9%) 3 (0.9%) 1 (0.3%)
Administrative status (Number, %) Undocumented- irregular Documented- regular Not indicated
236 (72.4%) 88 (27%) 2 (0.6%)
Analytical results Hemoglobin levels (gr/dL) (1) Presence of eosinophilia (≥450 Eo / mm3) • Mild (<1000 Eo / mm3) • Moderate (1,000-3,000 Eo / mm3) • Severe (> 3,000 Eo / mm3) - IgE levels (IU/L) (1) - Hematuria (321/326; 98.5%) - Positive Schistosoma serology (308/326; 94.5%) • Urogenital schistosomiasis (N=215) • Hepatointestinal schistosomiasis (N=90) • Mixed (N=3) Schistosoma species, N (%) S. haematobium S. mansoni S. intercalatum
14.75±1.52 (9.4-19.4) 186 (57.1%) 139 45 2 2,783.6±2499 (4-36,333) 123 (38.3%) 217 (70.5%) 138 (64.2%) 77 (85.6%) 2 (66.7%) 196 (60.1%) 65 (19.9%) 8 (2.5%)
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-
S. haematobium + S. mansoni S. haematobium+ S mansoni+ S. intercalatum Schistosoma spp. • Bladder biopsy • Intestinal biopsy (2) • Other biopsy (3)
Clinical manifestations, N (%) Genito-urinary (including hematuria) Abdominal pain Radiological findings Bladder calcifications in Rx of abdomen (309/326; 94.8%) Abnormal ultrasound (4) (282/326; 86.5%) • Wall bladder thickening • Parietal bladder nodes or focal thickening • Ureter dilatation or hydronephrosis • Calcifications • Lesions compatible with bladder cancer • Liver periportal thickening • Portal hypertension with spleen enlargement Coinfections, N. Helminths Hookworms Ascaris lumbricoides Trichuris trichiura Taenia spp. Hymenolepis nana Dicrocoelium dendriticum Strongyloides stercolaris Mansonella perstans Protozoa Entamoeba hystolitica / dispar Giardia lamblia Blastocystis hominis Cryptosporidium parvum Non-pathogenic amoebae (5) Plasmodium falciparum Transmissible diseases Chronic hepatitis B Chronic hepatitis C HIV Tuberculosis Syphilis
2 (0.6%) 1 (0.3%) 54 (16.6%) 29 23 2 102 (31.3%) 93 (28.5%) 56 (18.1%) 104 (36.9%) 20 (7.1%) 48 (17%) 6 (2.1%) 21(7.4%) 3 (1.1%) 5 (1.8%) 4 (1.4%)
30 (9.2%) 1 (0.3%) 6 (1.8%) 1 (0.3%) 2 (0.6%) 9 (2.8%) 35 (10.7%) 18 (5.5%) 28 (8.6%) 16 (4.9%) 55 (16.9%) 2 (0.6%) 74 (22.7%) 14 (4.3%) 83 (25.5%) 3 (0.9%) 2 (0.6%) 13 (4%) 38 (11.7%)
Table 1. Epidemiological, clinical, analytical and radiological results of patients included in the study. Variables: N/N (%): Number of analized patients /Number of total patients (%). (1) Mean ± std. deviation (range). (2) Rectal or appendicular biopsy. (3) Testicular biopsy. (4) Bladder abnormalities: diffuse or focal wall thickening, nodular lesions or ureterohydronephrosis. Liver abnormalities: characteristic periportal fibrosis with or without portal hypertension. (5) Entamoeba coli, Endolimax nana. Abbreviations: HIV: Human Immunodeficiency Virus.
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Mean age was 27.3 years and 93.9% were male. The main country of origin was Mali (50.3%). Most patients, 242 (74.2%), were referred from Primary Care. Mean length of stay in Spain was 39.6 ± 36.7 months. Patients were mostly asymptomatic (55.8%). Main reported symptoms were genitourinary (31.3%), including hematuria, and abdominal pain (28.5%). Two hundred and twenty-seven patients (69.6%) presented genitourinary schistosomiasis, 95 (29.1%) hepatointestinal schistosomiasis and 4 (1.2%) both of them. The isolated species were S. haematobium (N = 196), S. mansoni (N = 65 cases), and S. intercalatum (N = 8). Three patients presented coinfections of different Schistosoma species. In 54 cases the diagnosis was made by means of biopsies obtained from different tissues (Schistosoma spp.). Laboratory tests showed eosinophilia (≥450 Eo / mm3) in 57.1% of patients. Schistosoma serology was positive in 70.1% of the cases, reaching 85.6% in hepatointestinal cases but only 64.2% in those with urogenital schistosomiasis. Thirteen (4%) of the patients with confirmed schistosomiasis and 1 with probable schistosomiasis presented severe complications at the time of diagnosis (Table 2). For all but one, patient number 1, serological tests for Schistosoma were positive. Table 2. Characteristics of patients suffering from schistosomiasis' severe complications
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Patient number
Age (years)
Gender
Time living in Spain (months)
Country of origin
Eosinophils (Eo/mm3)
Schistosome species
Other associated infections
Imaging findings
Diagnosis Chronic liver disease with portal hypertension. Esophageal varices grade 3 Bilateral ureterohydronephrosis
1
18
Male
36
Mali
63
S. mansoni
Hepatomegaly. Periportal fibrosis with portal hypertension. Splenomegaly of 18 cm.
2
31
Male
84
Senegal
450
Schistosoma spp. in bladder biopsy
Bilateral ureterohydronephrosis Entire urinary bladder wall calcification. Large bladder nodule of 5 cm. with grade 3 bilateral hydronephrosis
3
4
5
6
7
8
9
10
Bilateral lithiasis at the ureterovesical junction. Bilateral ureterohydronephrosis grade 4
Squamous-cell carcinoma of the bladder. Bilateral ureterohydronephrosis grade 3 Bilateral renal lithiasis with ureterohydronephrosis
S. haematobium
Entire urinary bladder wall calcification. Bladder nodule of 7.7 x 3.5 cm.
Squamous-cell carcinoma of the bladder
137
Schistosoma spp. in testicular biopsy
Testicular necrosis with hydrocele
Guinea Conakry
520
S. mansoni
Periportal fibrosis with portal hypertension. Splenomegaly
Mali
480
S. haematobium
Syphilis, Strongyloides stercoralis
Entire urinary bladder wall calcification. Bilateral ureterohydronephrosis grade 4
Chronic hepatitis B
Chronic hepatopathy with periportal fibrosis
Hookworms, Strongyloides stercoralis.
Periportal fibrosis with cirrhosis signs and portal hypertension
33
Male
44
Senegal
290
S. haematobium
23
Male
9
Mali
620
Schistosoma spp. in bladder biopsy
37
Male
142
Mali
637
26
Male
45
Mali
23
Female
15
32
Male
66
28
Male
53
Mali
230
Schistosoma spp. in rectal biopsy
30
Male
32
Mali
1,277
S. mansoni
Chronic hepatitis B
Ischemic testicular necrosis due to vascular obstruction by schistosomes Chronic liver disease with portal hypertension Bilateral ureterohydronephrosis. Chronic renal failure on hemodialysis Chronic liver disease due to coinfection by S. mansoni and hepatitis B Chronic liver disease with portal hypertension. Esophageal varices grade 3
Outcome On follow-up. Variceal ligation program
Underwent surgery with resolution of ureterohydronephrosis Came back to home country before surgery. Lost to follow-up Surgical treatment and recovery of renal function Radical cystectomy with ileal conduit (Bricker) and pelvic lymphadenectomy. Death due to metastatic disease Testicular removal and cure
On follow-up. Fibrosis improvement Death because of sepsis
Improvement after treatment. Lost to follow-up after moving to another city. Lost to follow-up
10
11
12
13
14
30
Male
108
Mali
80
S. haematobium
Pleural tuberculosis. P. falciparum
Urinary bladder wall calcification. Bladder wall enlargement with left ureterohydronephrosis grade 2.
Unilateral ureterohydronephrosis
46
Male
288
Guinea Bissau
450
Schistosoma spp. in bladder biopsy
Chronic hepatitis B. Blastocystis hominis
Bladder nodule.
Urothelial tumor
Hepatomegaly. Periportal fibrosis with portal hypertension.
Chronic liver disease with portal hypertension. Esophageal varices grade 1.
Right ureterohydronephrosis.
Unilateral ureterohydronephrosis
26
Male
40
Mali
985
S. mansoni
30
Male
108
Mali
20
Probable schistosomiasis
Chronic hepatitis B. Plasmodium falciparum
Lost to follow-up
Surgical treatment and cure
On follow-up. Improvement of liver disease.
End of follow-up after resolution of the ureterohydronephrosis with medical treatment
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Among patients with severe complications, five had hepatointestinal schistosomiasis and presented with chronic liver disease and portal hypertension, three of them also accompanied by esophageal varices. The other nine patients had urogenital schistosomiasis: 5 presented with ureterohydronephrosis (3 bilateral and 2 unilateral, one of them with terminal renal failure requiring hemodialysis), 2 with squamous cell carcinoma of the bladder (one of them with bilateral hydronephrosis), 1 with urothelial tumor, and finally, 1 patient presented with testicular ischemic necrosis (Image C).
Image. Image A: Big mass (arrow) within urinary bladder –squamous cell carcinomawith calcification of the entire bladder wall. Image B: Urinary bladder tumor (arrow )
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obstructing right ureter and causing ureterohydronefrosis (arrow). Image C: Heterogeneous left testicle, with microcalcifications, diminished vascularization and hydrocele (arrow). Image D: Liver cirrhosis with advanced fibrosis in a patient with liver disease due to S. mansoni infection.
Discussion Approximately 4% of patients with confirmed schistosomiasis in the subSaharan immigrant population presented severe complications at the time of diagnosis. Depending on the location, they account for 5% of patients with hepatointestinal schistosomiasis and 3.5% of patients with the urogenital form. Figures reported in the literature for schistosomiasis severe complications are very different. Due to the great heterogeneity of the studies, the actual prevalence of severe forms remains mostly unknown. There are some studies with large series of patients after screening for schistosomiasis in migrant populations, but severe complications are barely described or not mentioned at all [3,5,9]. On the contrary, in those series of patients from centers where there is no such systematic screening and diagnosis relays on symptomatic patients, prevalence of severe forms exceeds 20% [8,16]. Some other studies include individuals diagnosed with schistosomiasis based exclusively on the positivity of serological techniques [3], or do not consider comorbidities that can also lead to severe hepatointestinal pathology (e.g. viral hepatitis). Roca et al [6], in a study with 200 immigrants diagnosed with intestinal schistosomiasis by S. mansoni, did found a prevalence of hepatosplenic involvement of 4.5%, very similar to ours (5%). It is worth stressing the high proportion of patients with schistosomiasis that also harboured chronic viral hepatitis. Nevertheless, only one patient in our series presented
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with severe liver disease. Two recent studies conducted in Europe [17,18] find that liver fibrosis and the risk of severe liver disease are not significantly increased in patients coinfected both with Schistosoma and HBV compared to those only infected by HBV. It has been suggested that these results may be due to the studies being carried out in nonendemic areas, where subjects have low parasitological burden, the most common species in these studies being S. haematobium, and fibrosis being measured by indirect tests, as liver biopsy and elastography were not included in the usual clinical practice at the time. Given that between 40%-60% of patients with chronic schistosomiasis are asymptomatic, as shown by our study and other large series of patients [3,5], it seems evident that systematic screening of the disease in people from endemic areas, regardless of the presence or absence of symptoms, may reveal a high number of cases. Furthermore, as urogenital schistosomiasis favors HIV transmission [19], treatment of schistosomiasis could help to limit the spreading of HIV in those populations with a high prevalence. Finally, diagnosis and treatment at earlier stages can improve the prognosis of long-term infected patients by preventing the development of severe complications. This could, in addition, be a cost-saving strategy as these complications may need expensive therapies, such as hemodialysis or kidney transplantation, among others [8]. Among all cases of schistosomiasis with severe complications described in our series, only one occurred in the group of patients with probable schistosomiasis. This could be related to several facts. First of all, to the fact that the parasitological burden in these patients with probable schistosomiasis may be low, with no detectable ova in faeces and urine, and thus, the potential to develop complications is diminished. Secondly, to the limitations of the serological tests, that do not distinguish between past 14
and active infections and that can react to other helminthic infections due to crossreactivity, and whose sensibility and specific highly varies depending on the kind of test used [20,21]. This last question rises the argument about the convenience of recommending parasitological direct studies, along with serological screening, to all those patients coming from endemic regions. On the other hand, systematic screening might constitute a useful tool to prevent further autochthonous transmission in Europe, as such indigenous transmission has recently been demonstrated in Corsica [22]. The presence of the intermediate host for S. haematobium, Bulinus truncatus, in several countries in southern Europe, including the area where our study was conducted [23], should awaken health authorities' awareness about schistosomiasis being no longer an imported disease but capable of affecting indigenous population in the future. The limitations of our study are derived from its very own design, that is, a retrospective and single-center study. Besides, given that in schistosomiasis screening in Primary Care does not include serology, asymptomatic patients without eosinophilia may be not diagnosed. In contrast, the strengths of the study rely on the fact that a systematic screening of the main imported diseases is carried out at a community level, which is the recommended strategy [11], and that a second complementary screening, using serological methods, is implemented at the specialized hospital clinic. Therefore, we believe that is hardly likely to miss those patients with high parasitological burden or with schistosomiasis-related complications. Chronic schistosomiasis can also produce, although much more infrequently, pulmonary hypertension, glomerulonephritis or neurological involvement [1,24], although we have not found such cases in our series.
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5. Conclusions Severe complications are not infrequent in patients with confirmed schistosomiasis, with a prevalence around 4%-5% of cases in non-endemic areas. New studies are needed to assess whether early diagnosis through systematic screening of people at risk could significantly reduce this number, avoiding cost overruns to health systems and preventing the expansion of the disease in non-endemic regions. In the event that an adequate screening strategy were not possible, empirical treatment with praziquantel for people from endemic regions could be a reasonable alternative.
Conflicts of interest The authors declare no conflict of interest.
Acknowledgments This study has been conducted within the activities developed by the research group PAIDI CTS 582 of the regional Ministry of Gender, Health and Social Policy of the Government of Andalusia, RICET (Cooperative Research Network on Tropical Diseases, co-financing FEDER, RD16 / 0027/0013) and CEMyRI (Center for the Study of Migration and Intercultural Relations) of the University of Almeria (Spain). This work was supported by projects RD16/0027/0013 and FIS PI16/00520 (grants numbers).
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al. Lung Involvement in Chronic Schistosomiasis with Bladder Squamous Cell Carcinoma. Emerg Infect Dis. 2018;24:2375-2378. [14]
Srougi V, Gallucci FP, Mattedi RL, Srougi M. Carcinosarcoma of the
bladder following local schistosomiasis infection. BMJ Case Rep. 2017; Mar 21. pii: bcr2016218642. doi: 10.1136/bcr-2016-218642. [15]
Salas-Coronas J, Vázquez-Villegas J, Villarejo-Ordóñez A, Sánchez-
Sánchez JC, Espada-Chavarría J, Soriano-Pérez MJ, et al. Radiological findings in patients with imported schistosomiasis Enferm Infecc Microbiol Clin. 2013;31(4):205-9
18
[16]
Barrio Muñoz M, García Rojo D, González Sala JL, Prats López J.
Urinary schistosomiasis: description of 8 cases. Med Clin (Barc). 2013; 140: 476-7. [17]
Cuenca-Gómez JÁ, Salas-Coronas J, Lozano-Serrano AB, Vázquez-
Villegas J, Soriano-Pérez MJ, Estévez-Escobar M, et al. Hepatitis B and Schistosoma co-infection in a non-endemic area. Eur J Clin Microbiol Infect Dis. 2016; 35:1487-93. [18]
Marchese V, Beltrame A, Angheben A, Marocco S, Gaeta GB, Bisoffi Z.
The impact of schistosomiasis co-infection in the presentation of viral hepatitis B in migrants: An observational study in non-endemic area. Travel Med Infect Dis. 2019; 23:101467 [19]
von Braun A, Trawinski H, Wendt S, Lübbert C. Schistosoma and Other
Relevant Helminth Infections in HIV-Positive Individuals-an Overview. Trop Med Infect Dis. 2019; 12: 4(2). [20]
Kinkel HF, Dittrich S, Bäumer B, Weitzel T. Evaluation of eight
serological tests for diagnosis of imported schistosomiasis. Clin Vaccine Immunol. 2012; 19:948-53 [21]
Beltrame A, Guerriero M, Angheben A, Gobbi F, Requena-Mendez A,
Zammarchi L, et al. Accuracy of parasitological and immunological tests for the screening of human schistosomiasis in immigrants and refugees from African countries: An approach with Latent Class Analysis.PLoS Negl Trop Dis. 2017; 11(6):e0005593. [22]
Ramalli L, Mulero S, Noël H, Chiappini JD, Vincent J, Barré-Cardi H, et
al. Persistence of schistosomal transmission linked to the Cavu river in southern Corsica since 2013. Euro Surveill. 2018; 23.
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[23]
Martínez-Ortí A, Bargues MD, Mas-Coma S. Dos nuevas localizaciones
para España de Bulinus trucatus (Audouin, 1827) (Gastropoda, Planorbidae), hospedador intermediario de Schistosomiasis urinaria. Arxious de Miscel-lània Zoològica. 2015;13:25-31. [24]
Thakur K, Zunt J. Neurologic parasitic infections in immigrants and
travelers. Semin Neurol. 2011; 31: 231-44.
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Data Statement: Data are available upon request to bona fide researchers. Data were collected routinely from patients at the UMT, and approval for access to these data can be granted on a case-by-case basis by the Ethical Review Board. This process is designed to protect patient confidentiality, which might be compromised if data were publically available. Request to access data should be made to the corresponding author Dr. Salas by mentioning the study title. Email: [email protected]
S1477-8939(19)30212-1
DOI:
https://doi.org/10.1016/j.tmaid.2019.101508
Reference:
TMAID 101508
To appear in:
Travel Medicine and Infectious Disease
Received Date: 27 February 2019 Revised Date:
20 October 2019
Accepted Date: 31 October 2019
Please cite this article as: Salas-Coronas Joaquí, Vázquez-Villegas José, Lozano-Serrano AB, Soriano-Pérez MJ, Cabeza-Barrera I, Cabezas-Fernández MT, Villarejo-Ordóñez A, Sánchez-Sánchez JoséCarlos, Abad Vivas-Pérez JoséIgnacio, Blanc SalvadorVá, Jiménez MP, Cuenca-Gómez JoséA, Severe complications of imported schistosomiasis, Spain: A retrospective observational study, Travel Medicine and Infectious Disease (2019), doi: https://doi.org/10.1016/j.tmaid.2019.101508. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Author contributions Joaquín
Salas-Coronas:
Conceptualization,
Methodology,
Formal
Analysis,
Investigation, Data Curation, Writing – Original Draft, Writing – Review& Editing, Visualization, Supervision, Project Administration. José Vázquez-Villegas: Conceptualization, Investigation, Data Curation, Writing – Original Draft, Writing – Review& Editing, Visualization. Ana B. Lozano-Serrano: Conceptualization, Investigation, Writing – Original Draft, Writing – Review& Editing, Visualization. Manuel J Soriano-Pérez: Investigation, Data Curation, Writing – Review& Editing. Isabel Cabeza-Barrera: Investigation, Data Curation, Writing – Review& Editing. Mª Teresa Cabezas-Fernández: Methodology, Investigation, Data Curation, Writing – Review& Editing. Antonio Villarejo-Ordóñez: Investigation, Data Curation, Writing – Review& Editing. José Carlos Sánchez-Sánchez: Investigation, Data Curation, Writing – Review& Editing. José Ignacio Abad Vivas-Pérez: Investigation, Data Curation, Writing – Review& Editing. Salvador Vázquez Blanc: Investigation, Data Curation, Writing – Review& Editing. Matilde Palanca Jiménez: Investigation, Data Curation, Writing – Review& Editing. José A. Cuenca-Gómez: Investigation, Data Curation, Writing – Review& Editing.
The present version of this paper has met the approval of all authors and they accept full responsibility for the content. The authors declare that this manuscript has not been simultaneously submitted for publication in any other journal, nor have the findings been partially disclosed in any other publication.
Title: Severe complications of imported schistosomiasis, Spain: a retrospective observational study Authors: Joaquín Salas-Coronasa,*, José Vázquez-Villegasb, Ana B. Lozano-Serranoa, Manuel J. Soriano-Péreza, Isabel Cabeza-Barreraa, Mª Teresa Cabezas-Fernándeza, Antonio Villarejo-Ordóñeza, José Carlos Sánchez-Sáncheza, José Ignacio Abad Vivas-Pérezc, Salvador Vázquez Blancc, Matilde Palanca Jiméneza, José A. Cuenca-Gómeza.
a
Tropical Medicine Unit, Hospital del Poniente, Ctra. de Almerimar, 31, 04700, El
Ejido (Almería), Spain. b
Tropical Medicine Unit, Distrito Sanitario Poniente de Almería, Calle Jesús de
Perceval, 22, 04700 El Ejido (Almería), Spain. c
Department of Urology, Hospital del Poniente, Ctra. de Almerimar, 31, 04700, El
Ejido (Almería), Spain.
* Corresponding author: Joaquín Salas-Coronas. Tropical Medicine Unit, Hospital del Poniente, Ctra. de Almerimar, 31, 04700, El Ejido (Almería), Spain. E-mail address: [email protected]
1
ABSTRACT Background: Chronic schistosomiasis silently leads to severe organ-specific disorders, such as hydroureter, bladder cancer or portal hypertension in around 10% of infected people in endemic zones. However, in non-endemic areas, information on schistosomiasis' severe complications and their actual prevalence is scarce because diagnosis is usually reached when such complications are well established. Methods: Retrospective observational study of data obtained from a screening protocol designed for sub-Saharan migrants including search for stool parasites and schistosoma serology. After screening 3,090 sub-Saharans, 326 (10.5%) confirmed cases of schistosomiasis were found, based on detection of ova in feces, urine or in biopsy samples. Another 830 patients (26.9%) were diagnosed of probable schistosomiasis (positive serology and/or suggestive imaging findings). Results: Only patients with confirmed schistosomiasis were included in the final analysis. Among them, 13 (4%) presented severe complications at the time of diagnosis. Depending on the location, they account for 5% of patients with hepatointestinal schistosomiasis and 3.5% of patients with urogenital infection. Conclusions: Targeted systematic screening could reduce the prevalence of severe complications by enabling early diagnosis and treatment. Having indigenous transmission been demonstrated in southern Europe, prevention of future cases in nonendemic countries might be another sound reason supporting such screening. Keywords: Schistosoma, schistosomiasis, infectious imported diseases, migrants, screening, complications.
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1. Introduction Human schistosomiasis is a disease caused by trematode parasites of the genus Schistosoma. It is estimated that at least 230 million people worldwide are infected, 90% of them in sub-Saharan Africa, and that it causes around 300,000 deaths annually [1,2]. Schistosoma haematobium and Schistosoma mansoni are the predominant species and responsible for urogenital and hepatointestinal schistosomiasis respectively [1]. In endemic regions, the most prevalent form of disease is chronic schistosomiasis, resulting from repeated exposure to parasite cercariae. In many cases the disease may be unnoticed or just cause mild nonspecific symptoms [3], but in some patients, chronic tissue inflammation induced by the parasites' eggs, will lead to severe complications such as obstructive uropathy with hydronephrosis or squamous-cell carcinoma of the bladder in the case of S. haematobium, and liver fibrosis with portal hypertension and esophageal varices in the case of S. mansoni. It is estimated that approximately 10% of patients will develop severe complications [4]. The significant migratory flow of recent years from African countries to Europe has lead to an increase in the number of patients diagnosed with schistosomiasis in nonendemic regions [5-10]. This fact is behind the recommendation for the use of serological screening in new migrants coming from endemic countries recently issued by European health authorities [11]. However, the actual prevalence of severe complications of the disease in these regions is not well known, since most of the times the diagnosis is made only in those cases already presenting with specific complications [8] or publications just report single cases [12-14]. The objective of this study is to know the real prevalence of severe complications of the disease in a European area where there is a significant immigrant
3
population coming from schistosomiasis highly endemic regions, and where the screening for imported diseases in Primary and Specialized Care is well established.
2. Material and methods A retrospective observational study was conducted based on the data obtained after the systematic application of an imported disease screening protocol in immigrant of sub-Saharan origen assisted at the Tropical Medicine Unit of the Poniente hospital (El Ejido, Almeria, Spain) from October 2004 to February 2018. The Poniente area is an administrative area located in Southeast Spain holding a population close to 300,000 inhabitants with an immigrant share of 21%, many of them coming from sub-Saharan countries to work in horticultural greenhouses. In Primary Care, the screening protocol consists in a series of laboratory tests aimed to screen for imported and cosmopolitan diseases. The tests are usually offered the first time immigrants contact public health care system, no matter the reason they consult for. The screening protocol includes: blood count, liver and renal function tests, syphilis, HIV, HBV and HCV serologies, tuberculin skin test and search for stool parasites (three concentrated stool samples using Ritchie's method) and urine parasites (one concentrated urine sample [10 cc]). Migrant patients are referred to the hospital Tropical Medicine Clinic whenever an imported disease is either suspected or diagnosed. The hospital's protocol comprises medical history, epidemiological data, complete physical examination, and several additional tests: Strongyloides and Schistosoma serologies, and Knott and/or saponin tests for microfilariae. Chest and abdominal X-rays are routinely performed too. If any other specific disease is suspected (e.g., onchocerciasis, malaria, etc.), further proper diagnostic procedures are performed.
4
Abdominal ultrasound is performed when schistosomiasis is suspected or diagnosed and whenever otherwise indicated (e.g., viral hepatitis). The following imaging findings are considered as suggestive of schistosomiasis: liver periportal thickening with or without cirrhosis, portal hypertension with spleen enlargement, urinary bladder wall thickening or other suggestive findings (calcifications or small parietal vegetations), abnormalities in the urinary tract (ureter dilatation or hydronephrosis), and lesions compatible with liver or bladder cancer [5,15]. Serum samples are evaluated for the detection of antibodies against Schistosoma spp. by qualitative determination of IgG-class antibodies against Schistosoma mansoni by means of an enzyme immunoassay (NovaLisa TM), indirect haemagglutination test for serum bilharzia antibodies (Fumouze Diagnostics, Levallois-Perret, France), or rapid test SCHISTOSOMA ICT IgG-IgM® (LDBIO Diagnostics), depending on the availability of each technique at the time. 2.1 Definitions Probable schistosomiasis: Positive serology and / or imaging findings compatible with schistosomiasis (see definition above) but without detection of ova. Confirmed schistosomiasis: Patients with detection of ova of Schistosoma in feces, urine or in biopsy samples obtained from different tissues. Severe complications: Severe complications for urogenital schistosomiasis are defined such as obstructive uropathy with hydronephrosis with or without renal dysfunction and or carcinoma of the bladder. For hepatointestinal schistosomiasis, liver fibrosis with portal hypertension with or without esophageal varices. We have also considered severe complications all cases with severe repercussions on the individual's health derived
5
from the migration of the parasite or its ova to ectopic locations such as the CNS or other organs. 2.2 Statistical analysis A descriptive statistical analysis was conducted including the 326 patients diagnosed with confirmed schistosomiasis. Quantitative variables were expressed as means and interquartile ranges. Qualitative variables were described as frequencies and percentages. 2.3 Ethics Statement Samples were obtained at the Tropical Medicine Unit of Poniente Hospital (El Ejido, Almeria, Spain) for diagnosis purposes as part of the standard protocolized care of sub-Saharan patients attended at such unit. Anonymized data were collected retrospectively. This study has been approved by the Ethics Committee of the Coordinating Site (protocol Schis-01-UMT-2018).
3. Results Out of a total of 3,090 sub-Saharan patients attended during the study period, 326 (10.5%) were diagnosed with confirmed schistosomiasis based on the detection of ova in feces, urine or in biopsy samples obtained from different tissues. In parallel with a significant rise of migration in Spain, most of the diagnoses were made between 2008 and 2011, with a mean of 50 cases per year. Another 830 patients (26.9%) were diagnosed with probable schistosomiasis (positive serology and / or imaging findings compatible with schistosomiasis) and were
6
not included in the global analysis. Most of them had a positive serology (n=816; 98,3%) and mainly came from Mali (n=295), Senegal (n=219) and Guinea Bissau (n=73). In 48 of them, abdominal X-ray showed calcifications on the urinary bladder wall, and 37 presented ultrasound-imaging findings suggestive of schistosomiasis (irregularity, thickening and / or calcification of the bladder wall). All of them were treated with praziquantel at standard doses. General characteristics of patients with confirmed schistosomiasis are shown in Table 1.
Total patients N= 326 Age (years) Mean (range)
27.3 (11-52)
Gender (Number, %) • Male • Female
306 (93.9%) 20 (6.1%)
Time living in Spain (months) (1)
39.6 ± 36.7 (1-288)
Country of origin (Number, %) Mali Senegal Mauritania Equatorial Guinea Ghana Guinea-Conakry Guinea Bissau Gambia Burkina Faso Nigeria Ivory Coast Sierra Leona
164 (50.3%) 74 (22.7%) 24 (7.4%) 12 (3.7%) 11 (3.4%) 10 (3.1%) 10 (3.1%) 9 (2.8%) 5 (1.5%) 3 (0.9%) 3 (0.9%) 1 (0.3%)
Administrative status (Number, %) Undocumented- irregular Documented- regular Not indicated
236 (72.4%) 88 (27%) 2 (0.6%)
Analytical results Hemoglobin levels (gr/dL) (1) Presence of eosinophilia (≥450 Eo / mm3) • Mild (<1000 Eo / mm3) • Moderate (1,000-3,000 Eo / mm3) • Severe (> 3,000 Eo / mm3) - IgE levels (IU/L) (1) - Hematuria (321/326; 98.5%) - Positive Schistosoma serology (308/326; 94.5%) • Urogenital schistosomiasis (N=215) • Hepatointestinal schistosomiasis (N=90) • Mixed (N=3) Schistosoma species, N (%) S. haematobium S. mansoni S. intercalatum
14.75±1.52 (9.4-19.4) 186 (57.1%) 139 45 2 2,783.6±2499 (4-36,333) 123 (38.3%) 217 (70.5%) 138 (64.2%) 77 (85.6%) 2 (66.7%) 196 (60.1%) 65 (19.9%) 8 (2.5%)
7
-
S. haematobium + S. mansoni S. haematobium+ S mansoni+ S. intercalatum Schistosoma spp. • Bladder biopsy • Intestinal biopsy (2) • Other biopsy (3)
Clinical manifestations, N (%) Genito-urinary (including hematuria) Abdominal pain Radiological findings Bladder calcifications in Rx of abdomen (309/326; 94.8%) Abnormal ultrasound (4) (282/326; 86.5%) • Wall bladder thickening • Parietal bladder nodes or focal thickening • Ureter dilatation or hydronephrosis • Calcifications • Lesions compatible with bladder cancer • Liver periportal thickening • Portal hypertension with spleen enlargement Coinfections, N. Helminths Hookworms Ascaris lumbricoides Trichuris trichiura Taenia spp. Hymenolepis nana Dicrocoelium dendriticum Strongyloides stercolaris Mansonella perstans Protozoa Entamoeba hystolitica / dispar Giardia lamblia Blastocystis hominis Cryptosporidium parvum Non-pathogenic amoebae (5) Plasmodium falciparum Transmissible diseases Chronic hepatitis B Chronic hepatitis C HIV Tuberculosis Syphilis
2 (0.6%) 1 (0.3%) 54 (16.6%) 29 23 2 102 (31.3%) 93 (28.5%) 56 (18.1%) 104 (36.9%) 20 (7.1%) 48 (17%) 6 (2.1%) 21(7.4%) 3 (1.1%) 5 (1.8%) 4 (1.4%)
30 (9.2%) 1 (0.3%) 6 (1.8%) 1 (0.3%) 2 (0.6%) 9 (2.8%) 35 (10.7%) 18 (5.5%) 28 (8.6%) 16 (4.9%) 55 (16.9%) 2 (0.6%) 74 (22.7%) 14 (4.3%) 83 (25.5%) 3 (0.9%) 2 (0.6%) 13 (4%) 38 (11.7%)
Table 1. Epidemiological, clinical, analytical and radiological results of patients included in the study. Variables: N/N (%): Number of analized patients /Number of total patients (%). (1) Mean ± std. deviation (range). (2) Rectal or appendicular biopsy. (3) Testicular biopsy. (4) Bladder abnormalities: diffuse or focal wall thickening, nodular lesions or ureterohydronephrosis. Liver abnormalities: characteristic periportal fibrosis with or without portal hypertension. (5) Entamoeba coli, Endolimax nana. Abbreviations: HIV: Human Immunodeficiency Virus.
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Mean age was 27.3 years and 93.9% were male. The main country of origin was Mali (50.3%). Most patients, 242 (74.2%), were referred from Primary Care. Mean length of stay in Spain was 39.6 ± 36.7 months. Patients were mostly asymptomatic (55.8%). Main reported symptoms were genitourinary (31.3%), including hematuria, and abdominal pain (28.5%). Two hundred and twenty-seven patients (69.6%) presented genitourinary schistosomiasis, 95 (29.1%) hepatointestinal schistosomiasis and 4 (1.2%) both of them. The isolated species were S. haematobium (N = 196), S. mansoni (N = 65 cases), and S. intercalatum (N = 8). Three patients presented coinfections of different Schistosoma species. In 54 cases the diagnosis was made by means of biopsies obtained from different tissues (Schistosoma spp.). Laboratory tests showed eosinophilia (≥450 Eo / mm3) in 57.1% of patients. Schistosoma serology was positive in 70.1% of the cases, reaching 85.6% in hepatointestinal cases but only 64.2% in those with urogenital schistosomiasis. Thirteen (4%) of the patients with confirmed schistosomiasis and 1 with probable schistosomiasis presented severe complications at the time of diagnosis (Table 2). For all but one, patient number 1, serological tests for Schistosoma were positive. Table 2. Characteristics of patients suffering from schistosomiasis' severe complications
9
Patient number
Age (years)
Gender
Time living in Spain (months)
Country of origin
Eosinophils (Eo/mm3)
Schistosome species
Other associated infections
Imaging findings
Diagnosis Chronic liver disease with portal hypertension. Esophageal varices grade 3 Bilateral ureterohydronephrosis
1
18
Male
36
Mali
63
S. mansoni
Hepatomegaly. Periportal fibrosis with portal hypertension. Splenomegaly of 18 cm.
2
31
Male
84
Senegal
450
Schistosoma spp. in bladder biopsy
Bilateral ureterohydronephrosis Entire urinary bladder wall calcification. Large bladder nodule of 5 cm. with grade 3 bilateral hydronephrosis
3
4
5
6
7
8
9
10
Bilateral lithiasis at the ureterovesical junction. Bilateral ureterohydronephrosis grade 4
Squamous-cell carcinoma of the bladder. Bilateral ureterohydronephrosis grade 3 Bilateral renal lithiasis with ureterohydronephrosis
S. haematobium
Entire urinary bladder wall calcification. Bladder nodule of 7.7 x 3.5 cm.
Squamous-cell carcinoma of the bladder
137
Schistosoma spp. in testicular biopsy
Testicular necrosis with hydrocele
Guinea Conakry
520
S. mansoni
Periportal fibrosis with portal hypertension. Splenomegaly
Mali
480
S. haematobium
Syphilis, Strongyloides stercoralis
Entire urinary bladder wall calcification. Bilateral ureterohydronephrosis grade 4
Chronic hepatitis B
Chronic hepatopathy with periportal fibrosis
Hookworms, Strongyloides stercoralis.
Periportal fibrosis with cirrhosis signs and portal hypertension
33
Male
44
Senegal
290
S. haematobium
23
Male
9
Mali
620
Schistosoma spp. in bladder biopsy
37
Male
142
Mali
637
26
Male
45
Mali
23
Female
15
32
Male
66
28
Male
53
Mali
230
Schistosoma spp. in rectal biopsy
30
Male
32
Mali
1,277
S. mansoni
Chronic hepatitis B
Ischemic testicular necrosis due to vascular obstruction by schistosomes Chronic liver disease with portal hypertension Bilateral ureterohydronephrosis. Chronic renal failure on hemodialysis Chronic liver disease due to coinfection by S. mansoni and hepatitis B Chronic liver disease with portal hypertension. Esophageal varices grade 3
Outcome On follow-up. Variceal ligation program
Underwent surgery with resolution of ureterohydronephrosis Came back to home country before surgery. Lost to follow-up Surgical treatment and recovery of renal function Radical cystectomy with ileal conduit (Bricker) and pelvic lymphadenectomy. Death due to metastatic disease Testicular removal and cure
On follow-up. Fibrosis improvement Death because of sepsis
Improvement after treatment. Lost to follow-up after moving to another city. Lost to follow-up
10
11
12
13
14
30
Male
108
Mali
80
S. haematobium
Pleural tuberculosis. P. falciparum
Urinary bladder wall calcification. Bladder wall enlargement with left ureterohydronephrosis grade 2.
Unilateral ureterohydronephrosis
46
Male
288
Guinea Bissau
450
Schistosoma spp. in bladder biopsy
Chronic hepatitis B. Blastocystis hominis
Bladder nodule.
Urothelial tumor
Hepatomegaly. Periportal fibrosis with portal hypertension.
Chronic liver disease with portal hypertension. Esophageal varices grade 1.
Right ureterohydronephrosis.
Unilateral ureterohydronephrosis
26
Male
40
Mali
985
S. mansoni
30
Male
108
Mali
20
Probable schistosomiasis
Chronic hepatitis B. Plasmodium falciparum
Lost to follow-up
Surgical treatment and cure
On follow-up. Improvement of liver disease.
End of follow-up after resolution of the ureterohydronephrosis with medical treatment
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Among patients with severe complications, five had hepatointestinal schistosomiasis and presented with chronic liver disease and portal hypertension, three of them also accompanied by esophageal varices. The other nine patients had urogenital schistosomiasis: 5 presented with ureterohydronephrosis (3 bilateral and 2 unilateral, one of them with terminal renal failure requiring hemodialysis), 2 with squamous cell carcinoma of the bladder (one of them with bilateral hydronephrosis), 1 with urothelial tumor, and finally, 1 patient presented with testicular ischemic necrosis (Image C).
Image. Image A: Big mass (arrow) within urinary bladder –squamous cell carcinomawith calcification of the entire bladder wall. Image B: Urinary bladder tumor (arrow )
12
obstructing right ureter and causing ureterohydronefrosis (arrow). Image C: Heterogeneous left testicle, with microcalcifications, diminished vascularization and hydrocele (arrow). Image D: Liver cirrhosis with advanced fibrosis in a patient with liver disease due to S. mansoni infection.
Discussion Approximately 4% of patients with confirmed schistosomiasis in the subSaharan immigrant population presented severe complications at the time of diagnosis. Depending on the location, they account for 5% of patients with hepatointestinal schistosomiasis and 3.5% of patients with the urogenital form. Figures reported in the literature for schistosomiasis severe complications are very different. Due to the great heterogeneity of the studies, the actual prevalence of severe forms remains mostly unknown. There are some studies with large series of patients after screening for schistosomiasis in migrant populations, but severe complications are barely described or not mentioned at all [3,5,9]. On the contrary, in those series of patients from centers where there is no such systematic screening and diagnosis relays on symptomatic patients, prevalence of severe forms exceeds 20% [8,16]. Some other studies include individuals diagnosed with schistosomiasis based exclusively on the positivity of serological techniques [3], or do not consider comorbidities that can also lead to severe hepatointestinal pathology (e.g. viral hepatitis). Roca et al [6], in a study with 200 immigrants diagnosed with intestinal schistosomiasis by S. mansoni, did found a prevalence of hepatosplenic involvement of 4.5%, very similar to ours (5%). It is worth stressing the high proportion of patients with schistosomiasis that also harboured chronic viral hepatitis. Nevertheless, only one patient in our series presented
13
with severe liver disease. Two recent studies conducted in Europe [17,18] find that liver fibrosis and the risk of severe liver disease are not significantly increased in patients coinfected both with Schistosoma and HBV compared to those only infected by HBV. It has been suggested that these results may be due to the studies being carried out in nonendemic areas, where subjects have low parasitological burden, the most common species in these studies being S. haematobium, and fibrosis being measured by indirect tests, as liver biopsy and elastography were not included in the usual clinical practice at the time. Given that between 40%-60% of patients with chronic schistosomiasis are asymptomatic, as shown by our study and other large series of patients [3,5], it seems evident that systematic screening of the disease in people from endemic areas, regardless of the presence or absence of symptoms, may reveal a high number of cases. Furthermore, as urogenital schistosomiasis favors HIV transmission [19], treatment of schistosomiasis could help to limit the spreading of HIV in those populations with a high prevalence. Finally, diagnosis and treatment at earlier stages can improve the prognosis of long-term infected patients by preventing the development of severe complications. This could, in addition, be a cost-saving strategy as these complications may need expensive therapies, such as hemodialysis or kidney transplantation, among others [8]. Among all cases of schistosomiasis with severe complications described in our series, only one occurred in the group of patients with probable schistosomiasis. This could be related to several facts. First of all, to the fact that the parasitological burden in these patients with probable schistosomiasis may be low, with no detectable ova in faeces and urine, and thus, the potential to develop complications is diminished. Secondly, to the limitations of the serological tests, that do not distinguish between past 14
and active infections and that can react to other helminthic infections due to crossreactivity, and whose sensibility and specific highly varies depending on the kind of test used [20,21]. This last question rises the argument about the convenience of recommending parasitological direct studies, along with serological screening, to all those patients coming from endemic regions. On the other hand, systematic screening might constitute a useful tool to prevent further autochthonous transmission in Europe, as such indigenous transmission has recently been demonstrated in Corsica [22]. The presence of the intermediate host for S. haematobium, Bulinus truncatus, in several countries in southern Europe, including the area where our study was conducted [23], should awaken health authorities' awareness about schistosomiasis being no longer an imported disease but capable of affecting indigenous population in the future. The limitations of our study are derived from its very own design, that is, a retrospective and single-center study. Besides, given that in schistosomiasis screening in Primary Care does not include serology, asymptomatic patients without eosinophilia may be not diagnosed. In contrast, the strengths of the study rely on the fact that a systematic screening of the main imported diseases is carried out at a community level, which is the recommended strategy [11], and that a second complementary screening, using serological methods, is implemented at the specialized hospital clinic. Therefore, we believe that is hardly likely to miss those patients with high parasitological burden or with schistosomiasis-related complications. Chronic schistosomiasis can also produce, although much more infrequently, pulmonary hypertension, glomerulonephritis or neurological involvement [1,24], although we have not found such cases in our series.
15
5. Conclusions Severe complications are not infrequent in patients with confirmed schistosomiasis, with a prevalence around 4%-5% of cases in non-endemic areas. New studies are needed to assess whether early diagnosis through systematic screening of people at risk could significantly reduce this number, avoiding cost overruns to health systems and preventing the expansion of the disease in non-endemic regions. In the event that an adequate screening strategy were not possible, empirical treatment with praziquantel for people from endemic regions could be a reasonable alternative.
Conflicts of interest The authors declare no conflict of interest.
Acknowledgments This study has been conducted within the activities developed by the research group PAIDI CTS 582 of the regional Ministry of Gender, Health and Social Policy of the Government of Andalusia, RICET (Cooperative Research Network on Tropical Diseases, co-financing FEDER, RD16 / 0027/0013) and CEMyRI (Center for the Study of Migration and Intercultural Relations) of the University of Almeria (Spain). This work was supported by projects RD16/0027/0013 and FIS PI16/00520 (grants numbers).
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Data Statement: Data are available upon request to bona fide researchers. Data were collected routinely from patients at the UMT, and approval for access to these data can be granted on a case-by-case basis by the Ethical Review Board. This process is designed to protect patient confidentiality, which might be compromised if data were publically available. Request to access data should be made to the corresponding author Dr. Salas by mentioning the study title. Email: [email protected]