We assessed morbidity due to Opisthorchis viverrini and Schistosoma mekongi infections in 243 individuals in Lao People's Democratic Republic. Morbidity was associated with O. viverrini infection intensity. Coinfection with S. mekongi resulted in excess risk of liver fibrosis and left liver lobe enlargement. The high public health impact of opisthorchiasis warrants contro

Akkhavong, Kongsap

Hatz, Christoph

Odermatt, Peter

Rasphone, Oroth

Sayasone, Somphou

Tanner, Marcel

Utzinger, Jürg

Vanmany, Monely

Vounatsou, Penelope

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B R I E F R E P O R TSevere Morbidity Due toOpisthorchis viverrini andSchistosoma mekongi Infection inLao People’s Democratic RepublicSomphou Sayasone,1,3,5 Oroth Rasphone,2 Monely Vanmany,1Penelope Vounatsou,3,5 Jürg Utzinger,3,5 Marcel Tanner,3,5Kongsap Akkhavong,1 Christoph Hatz,4,5,6 and Peter Odermatt3,51National Institute of Public Health, and 2Department of Radiology, MahosotHospital, Vientiane, Lao PDR; 3Departments of Epidemiology and Public Health,Basel, 4Medical Services and Diagnostic, Swiss Tropical and Public HealthInstitute, Basel, 5University of Basel, and 6Institute of Social and PreventiveMedicine, University of Zurich, SwitzerlandWe assessed morbidity due to Opisthorchis viverrini andSchistosoma mekongi infections in 243 individuals in LaoPeople’s Democratic Republic. Morbidity was associatedwith O. viverrini infection intensity. Coinfection with S.mekongi resulted in excess risk of liver ﬁbrosis and left liverlobe enlargement. The high public health impact of opis-thorchiasis warrants control.Food-borne trematodiasis is of public health importance inSoutheast Asia [1]. More than 8 million people are parasitizedby the liver ﬂuke Opisthorchis viverrini, and an estimated76 000 individuals have severe clinical manifestation, causinga global burden of 70 000 disability-adjusted life-years [2].Opisthorchis viverrini infection is associated with hepatobiliarymorbidity, such as hepatomegaly, jaundice, cholecystitis, chol-angitis, and cholangiocarcinoma, a fatal bile duct cancer [3].In Lao People’s Democratic Republic (PDR), >70% of theresident population lives in areas where the prevalence of O.viverrini exceeds 5%, and almost 2 million people are infected[4]. The highest prevalence rates occur in central-southern LaoPDR [5]. However, detailed information on intestinal and hep-atobiliary morbidity due to O. viverrini infection is lacking.Furthermore, the effect of coinfection with the blood ﬂukeSchistosoma mekongi, endemic in the southern Champasackprovince [6], has never been assessed.Opisthorchis viverrini is acquired by consumption of insufﬁ-ciently cooked ﬁsh dishes. The adult parasite lives and repro-duces in bile ducts. In contrast, S. mekongi cercariae penetratehuman skin when exposed to infested water. The adult para-site reproduces in the portal vein. Both parasites lead to hepa-tobiliary pathologies. The most widely used diagnosticapproach is the detection of parasite eggs in stool. The objec-tive of this study was to assess the severity of morbidity associ-ated with O. viverrini and concurrent S. mekongi infection inadults in Lao PDR.METHODSEthics StatementThe study was approved by the Ethics Committee of Basel,Switzerland, and the National Ethics Committee, Vientiane,Lao PDR. Written informed consent was obtained from allparticipants. Head of households signed for minors (aged <18years). People infected with O. viverrini and/or S. mekongiwere treated with praziquantel (40 mg/kg, single oral dose).Soil-transmitted helminth infections were treated with alben-dazole (400 mg, single oral dose) [7]. Antispasmodic treat-ment and oral rehydration were provided to purged patientswith abdominal pain and diarrhea.Field and Laboratory ProceduresCross-sectional surveys were carried out in hospitals and vil-lages. Hospital investigations were done at the infectiousdisease ward of Mahosot (largest hospital in the capital city ofVientiane) and Savannakhet provincial hospital (referral hos-pital for central provinces of Lao PDR) in September–October2005. Village surveys were conducted in O. viverrini–endemicareas in June 2006 (Champhone district, Savannakhet prov-ince; and Saravane district, Saravane province), inO. viverrini–S. mekongi coendemic areas (Mounlapamok andKhong districts, Champasack province), and in an area whereneither ﬂuke infection is present (Paksong district, Champa-sack province) between March and May 2006.Hospital patients and villagers (aged ≥15 years) who sub-mitted a stool sample for parasitological examination, whichrevealed the presence of O. viverrini–like eggs, were selectedand invited to participate in the study. Three stool specimenscollected over a period of 5 days were subjected to theReceived 14 January 2012; accepted 24 May 2012; electronically published 5 June 2012.Correspondence: Peter Odermatt, PhD, MPH, Department of Epidemiology and PublicHealth, Swiss Tropical and Public Health Institute, PO Box, CH-4002 Basel, Switzerland(peter.odermatt@unibas.ch).Clinical Infectious Diseases 2012;55(6):e54–e7© The Author 2012. Published by Oxford University Press on behalf of the Infectious DiseasesSociety of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/cis528e54 • CID 2012:55 (15 September) • BRIEF REPORTKato-Katz method (single 41.7-mg-thick smear per specimen)[8]. Helminth eggs were enumerated under a microscope andrecorded for each species separately.The number of O. viverrini ﬂukes was quantiﬁed by purga-tion. Study participants were treated with praziquantel (40mg/kg) after dinner. Albendazole (400 mg) was added if thepatient was coinfected with soil-transmitted helminths. Thefollowing morning a purgative (45 mL of monosodium-sulphate solution, Swiff, Berlin Pharmaceutical Industry Co,Ltd, Berlin, Germany) was administered. All stools producedwithin 24 hours (usually 6–8 bowel movements) were collect-ed and quantitatively examined for adult O. viverrini worms(length 5.5–9.5 mm, width 0.7–1.6 mm).Morbidity data were obtained from each participant by in-terview (ie, right upper quadrant [RUQ] pain and abdominaldiscomfort [ADC]) and by physical examination (ie, hepato-megaly, jaundice, splenomegaly, and RUQ pain at palpation),conducted by a general physician. Examining the level of leftliver lobe (hepatomegaly) and of spleen was done in the stand-ing position from xiphoid to liver or spleen edge. Additionally,an experienced radiologist performed an abdominal ultraso-nography in all enrolled persons to assess left liver lobe en-largement measuring from cranial to the caudal margin,destruction surrounding intrahepatic bile duct (periductal ﬁ-brosis), common bile duct dilatation (CBD), and intrahepaticbile duct dilatation (IHBD). The radiologist was unaware ofstool examination results.Statistical AnalysisData were double-entered in EpiData (www.epidata.ch) andanalyzed using Stata software (version 10.1). Data were sum-marized using proportions (categorical variables) and arith-metic mean (worm counts). Negative binomial regression wasused to calculate the intensity rate ratio (IRR) and to associateadult worms counts with the clinical indicators (presence orabsence). Multivariate logistic regressions were used tocompare clinical outcomes of noninfected individuals withcategories of infected individuals. Left liver lobe size was clas-siﬁed into normal (size ≤2 SD) and enlarged (size >2 SD)using height-adjusted measures from a Chinese reference pop-ulation [9]. A P value of <.05 was considered statisticallysigniﬁcant.RESULTSTwo hundred forty-three individuals were enrolled: 15 fromhospitals, 80 from O. viverrini–endemic areas, 49 fromO. viverrini–S. mekongi coendemic areas, and 99 from an areawhere neither parasite is endemic (uninfected). One hundredtwenty-three participants (50.6%) had an O. viverrini infec-tion, whereas 21 individuals (8.6%) were concurrently infectedwith O. viverrini and S. mekongi. All individuals with S.mekongi infections were restricted to the Kong and Mounlapa-mok districts, and they were all coinfected with O. viverrini.There were 117 females (48.2%); median age was 38 years(range, 15–81 years).Most participants reported ADC (65.8%), whereas one-third reported RUQ pain (13.6%). Upon physical examination,jaundice was diagnosed in 9 patients (3.7%). Ultrasono-graphy revealed CBD (4.1%), any liver ﬁbrosis (10.7%), andgallbladder stones (7.3%). IHBD was diagnosed in 3 patients(1.2%).Opisthorchis viverrini infection intensity was signiﬁcantlyhigher in males than in females (IRR, 1.9; 95% conﬁdence in-terval [CI], 1.1–3.5) and increased with age (IRR, 1.2; 95% CI,1.1–1.5). Positive associations were observed between morbidi-ty and O. viverrini infection intensity, the latter quantiﬁed bythe number of adult O. viverrini worms after purging(Table 1). Patients with RUQ pain (IRR, 2.6; 95% CI, 1.1–6.3),ADC (IRR, 2.7; 95% CI, 1.4–5.2), and jaundice (IRR, 2.3; 95%CI, 1.1–5.9) had an almost 3 times higher O. viverrini wormburden than those without. Hepatobiliary pathology was posi-tively associated with O. viverrini infection intensity. Thestrongest association was found in patients with IHBD (IRR,12.9; 95% CI, 5.2–20.2).Association between morbidity and O. viverrini infection(infected vs noninfected) and coinfection with S. mekongishowed strong associations but distinctly different patterns.Whereas patients with a single O. viverrini infection had ahighly increased risk for RUQ pain (odds ratio [OR], 3.6; 95%CI, 1.5–8.3) and ADC (OR, 6.3; 95% CI, 3.4–11.5) comparedwith their noninfected counterparts, patients coinfected withO. viverrini and S. mekongi had an increased risk for liver pa-thology. Compared with the uninfected control group, theyhad an almost 12-fold (OR, 11.7; 95% CI, 4.3–31.7) and 14-fold (OR, 13.6; 95% CI, 3.9–47.7) higher risk for liver ﬁbrosisand left liver lobe enlargement, respectively.DISCUSSIONThis report highlights the severe intestinal and hepatobiliarymorbidity that may be associated with O. viverrini andS. mekongi coinfection. We investigated patients from differentsettings of central and southern Lao PDR and found severemorbidity associated with O. viverrini single infection andwith O. viverrini–S. mekongi coinfection. Strikingly, the O. vi-verrini worm burden, as determined after purging, is stronglyassociated with self-reported morbidity and with clinical andultrasound investigations. Purging is the only direct method ofworm burden assessment, but this procedure is rarely per-formed [10]. Hence, this investigation provides new evidencethat O. viverrini infection causes substantial morbidity in LaoBRIEF REPORT • CID 2012:55 (15 September) • e55PDR. The widespread distribution of this liver ﬂuke in LaoPDR and in northeastern Thailand and adjacent countries ofSoutheast Asia, and the high morbidity it causes, calls for con-certed action [3, 5, 11, 12].Ultrasonographic examinations revealed that individualswith concurrent infections with O. viverrini and S. mekongiwere frequently diagnosed with liver ﬁbrosis and hepatomega-ly. However, the liver ﬁbrosis frequency reported (10.7%) wasconsiderably lower than in the endemic area in northeastThailand (23.6%) [13]. Schistosoma mekongi can cause liver (eg,advanced liver ﬁbrosis and portal hypertension) and spleenmorbidity [6]. The current study included 1 group of patientscoinfected with S. mekongi and O. viverrini. Our ﬁndingssuggest that concurrent infection with both ﬂukes aggravatesmorbidity, compared with single infection, supporting earlierreports suggesting that multiple helminth infections, even atlow-intensity levels, may elicit important morbidity [14].In future research, it will be crucial to compare the currentﬁndings with a patient group infected with S. mekongi alone.Other infection factors related to hepatic morbidity, such asviral hepatitis, might have contributed to morbidity, and thisneeds further scientiﬁc inquiry.We adhered to a rigorous diagnostic approach. Study partic-ipants had multiple stool samples examined with the quantita-tive Kato-Katz technique, supplemented with purging todetermine the worm burden. Usually, the number of eggsfound in the stools is taken as proxy for the number of adultparasites. Purging allows direct counting of adult O. viverriniworms and enables differential diagnosis with intestinal ﬂukeinfections, also prevalent in Lao PDR. We showed thatTable 1. Prevalence and Association of Morbidity With Opisthorchis viverrini Infection Intensity (Mean Worm Burden) and InfectionStatus (O. viverrini Infection and Coinfection Between O. viverrini and Schistosoma mekongi) Among Study Participants (N = 243)IndicatorMeasurementsPrevalence(N = 243) % (No.)Intensity of Infection AssociationP ValueNo. of Adult O. viverrini Flukesin Stool (N = 243) No. Infection(n = 99)O. viverriniInfection(n = 123)O. viverrini–S. mekongi Coinfection(n = 21)Mean IRR (95% CI) P ValueOR (95%CI) OR (95% CI) OR (95% CI)Self-report morbidityRight upper quadrant painNo 86.4 (210) 87 1.0 1.0 1.0 1.0Yes 13.6 (33) 225 2.6 (1.1–6.3) .022 0.2 (.1–.6) 3.6 (1.5–8.3) 1.1 (.3–3.8) .002Abdominal discomfortNo 34.2 (83) 50 1.0 1.0 1.0 1.0Yes 65.8 (160) 135 2.7 (1.4–5.2) .004 0.2 (.1–.4) 6.3 (3.4–11.5) 0.5 (.2–1.3) <.001Physical examinationJaundiceNo 96.3 (234) 103 1.0Yes 3.7 (9) 235 2.3 (1.1–5.9) .011 NA NA NA NAUltrasound examinationIntrahepatic bile duct dilationNo 98.8 (240) 92 1.0Yes 1.2 (3) 1188 12.9 (5.2–20.2) .003 NA NA NA NACommon bile duct dilationNo 95.9 (233) 94 1.0Yes 4.1 (10) 383 4.1 (1.1–19.1) .026 NA NA NA NAPeriductal liver fibrosisNo 89.3 (217) 87 1.0 1.0 1.0Yes 10.7 (26) 265 3.1 (1.1–8.2) .012 0.2 (.1–.6) 0.9 (.4–2.2) 11.7 (4.3–31.7) <.001Size of left liver lobeNormal ≤2 SD 53.5 (130) 140 1.0 1.0 1.00 1.0Enlarged >2 SD 46.5 (113) 67 0.5 (.3–.9) .023 0.3 (.1–.5) 1.7 (.9–2.8) 13.6 (3.9–47.7) <.001P values were obtained from the likelihood ratio test.Abbreviations: CI, confidence interval; IRR, intensity rate ratio calculated from negative binomial regression model; NA, not applicable; OR, odds ratio obtainedfrom logistic regression model; SD, standard deviation.e56 • CID 2012:55 (15 September) • BRIEF REPORTsubstantial hepatobiliary pathologies are induced by O. viverriniinfection in Lao PDR; it is therefore conceivable that morbidi-ty attributable to O. viverrini is currently underestimated [2].Community-based investigations, including the assessment ofprecursors of cholangiocarcinoma, are warranted. In particu-lar, S. mekongi–induced morbidity is of importance and needsurgent attention and public health action.NotesAcknowledgments. We are grateful for the participation of the patientsand communities and for the support of the curative and preventivehealth authorities of the various locations. We thank Isabelle Grilli for ex-amining stool samples; the facilitators from Research Institute for TropicalMedicine; and the World Health Organization, Western Paciﬁc Ofﬁce,Manila, Philippines, for their support on the data analysis during a scien-tiﬁc writing workshop.Financial support. This work was supported by the Swiss NationalScience Foundation, the Swiss Agency for Development and Cooperation(project number NF3270B0-110020), and The Bill & Melinda Gates Foun-dation (to M. T.)Potential conﬂicts of interest. J. U. is an editor for PLoS NeglectedTropical Diseases. M. T. is a board member of the Drugs for NeglectedDiseases Initiative and UBS-Optimus Foundation, and a member of thescientiﬁc advisory board for the Novartis Institute for Tropical Diseases.All other authors report no potential conﬂicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConﬂicts of Interest. Conﬂicts that the editors consider relevant to thecontent of the manuscript have been disclosed.References1. Keiser J, Utzinger J. Food-borne trematodiases. Clin Microbiol Rev2009; 22:466–83.2. Fürst T, Keiser J, Utzinger J. Global burden of human food-bornetrematodiasis: a systematic review and meta-analysis. Lancet Infect Dis2012; 12:210–21.3. Sripa B, Kaewkes S, Intapan PM, et al. Food-borne trematodiases inSoutheast Asia: epidemiology, pathology, clinical manifestation andcontrol. Adv Parasitol 2010; 72:305–50.4. World Health Organization. Report of the WHO expert consultationon foodborne trematode infections and taeniasis/cysticercosis. 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Severe Morbidity Due to Opisthorchis viverrini and Schistosoma mekongi Infection in Lao People's Democratic Republic

Severe Morbidity Due to Opisthorchis viverrini and Schistosoma mekongi Infection in Lao People's Democratic Republic

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