a comparative evaluation of three methods for diagnosis of

1
A Comparative Evaluation of Three Methods for Diagnosis of Visceral A Comparative Evaluation of Three Methods for Diagnosis of Visceral Leishmaniasis Leishmaniasis in Serbia in Serbia Leishmaniasis Leishmaniasis in Serbia in Serbia Zorica Zorica Dakić Dakić 1 , M. Pelemiš , M. Pelemiš 2,3 2,3 , G. Stevanović , G. Stevanović 2,3 2,3 , L. Lavadinović , L. Lavadinović 2,3 2,3 , J. Poluga J. Poluga 2,3 2,3 , B. Milošević , B. Milošević 2,3 2,3 , N. Indjić N. Indjić 4 , Zorica Zorica Dakić Dakić 1 , M. Pelemiš , M. Pelemiš 2,3 2,3 , G. Stevanović , G. Stevanović 2,3 2,3 , L. Lavadinović , L. Lavadinović 2,3 2,3 , J. Poluga J. Poluga 2,3 2,3 , B. Milošević , B. Milošević 2,3 2,3 , N. Indjić N. Indjić 4 , O. Dulović O. Dulović 2,3 2,3 , I. Ofori , I. Ofori-Belić Belić 1 , M. Pavlović M. Pavlović 2, 3 2, 3 Clinical Center of Serbia Clinical Center of Serbia 1 Parasitological Laboratory Parasitological Laboratory, Service of Microbiology , Service of Microbiology, Clinical Center of Serbia, Belgrade, Serbia , Clinical Center of Serbia, Belgrade, Serbia 2 Faculty of Medicine, Faculty of Medicine, University of Belgrade, University of Belgrade, Serbia; Serbia; 3 Clinic of Infectious and Tropical Diseases, Clinic of Infectious and Tropical Diseases, CCS, Belgrade, Serbia CCS, Belgrade, Serbia 4 Center of Preventive Medical Care, Belgrade, Serbia Center of Preventive Medical Care, Belgrade, Serbia Introduction Introduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945- 1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rare 1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rare autochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, with only one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosed each year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to the each year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to the Parasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL. Patients Patients and and methods methods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe, Patients Patients and and methods methods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe, England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL, were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from the an endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BM an endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BM smears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinical presentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who were tested by IHA and strip-test, without BM aspiration. tested by IHA and strip-test, without BM aspiration. Results Results VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and Tropical Diseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smears Diseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smears was successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL was confirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of 92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with each 92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with each other or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmed liver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA. Patient Patient Age Age Sex Sex Origin of Origin of Incubation Incubation Clinical presentation Clinical presentation Preexistent Preexistent IHA IHA Strip Strip-test test Dg by BM Dg by BM Patient Patient No No Age Age Sex Sex Origin of Origin of infections infections Incubation Incubation period period Clinical presentation Clinical presentation Preexistent Preexistent diseses diseses IHA IHA titer titer Strip Strip-test test result result Dg by BM Dg by BM smears smears 1 24 24 m south Serbia south Serbia 18 mo 18 mo Fever with sweating, weight loss, pancytopenia, Fever with sweating, weight loss, pancytopenia, no no 1:1024 1:1024 + positive 1x positive 1x 1 24 24 m south Serbia south Serbia 18 mo 18 mo hepatosplenomegaly hepatosplenomegaly no no positive 1x positive 1x numerous amastigotes numerous amastigotes 2 68 68 f Montenegro Montenegro sea sea-cost cost 3 mo 3 mo Fever, pancytopenia, hepatosplenomegaly Fever, pancytopenia, hepatosplenomegaly Sarcoidosis Sarcoidosis 1: 1:256 256 + positive 1x positive 1x moderate amastigotes moderate amastigotes 3 27 27 m Herzegovina Herzegovina unknown, unknown, resident resident Fever, heavy sweating, bicytopenia, hepatosplenomegaly Fever, heavy sweating, bicytopenia, hepatosplenomegaly no no 1:1024 1:1024 + positive 1x positive 1x numerous amastigotes numerous amastigotes 4 28 28 f Montenegro Montenegro 7 mo 7 mo Fever, weight loss, splenomegaly Fever, weight loss, splenomegaly Ulcerative colitis Ulcerative colitis 1:1 1:128 28 + positive 2x positive 2x 4 28 28 f Montenegro Montenegro sea sea-cost cost 7 mo 7 mo Ulcerative colitis Ulcerative colitis positive 2x positive 2x rare amastigotes rare amastigotes 5 68 68 f Herzegovina Herzegovina unknown, unknown, resident resident Fever, pancytopenia, hepatosplenomegaly Fever, pancytopenia, hepatosplenomegaly Diabetes mellitus, Diabetes mellitus, Anemia Anemia 1: 1:2048 2048 + negative 1x negative 1x ex iuvantibus ex iuvantibus 6 63 63 f Montenegro Montenegro sea sea-cost cost 12 mo 12 mo Fever, fatigue, cough, weight loss, muscular Fever, fatigue, cough, weight loss, muscular pain,hepatosplenomegaly pain,hepatosplenomegaly no no 1:1 1:16384 6384 + positive 1x positive 1x numerous amastigotes numerous amastigotes 7 44 44 m Montenegro Montenegro unknown, unknown, Trombocytopenia, skin rashes, hepatosplenomegaly Trombocytopenia, skin rashes, hepatosplenomegaly no no 1:1 1:16384 6384 + positive 1x positive 1x sea sea-cost cost resident resident numerous amastigotes numerous amastigotes 8 33 33 f Montenegro Montenegro sea sea-cost cost unknown, unknown, frequently frequently Fever, pancytopenia, moderate hepatosplenomegaly Fever, pancytopenia, moderate hepatosplenomegaly Chronic Chronic meningo eningo- encephalitis encephalitis 1: 1:2048 2048 + positive 1x positive 1x Numerous Numerous amastigotes amastigotes traveling traveling 9 22 22 m Herzegovina Herzegovina unknown, unknown, resident resident Fever, nocturnal sweating, cough, fatigue, weight loss, Fever, nocturnal sweating, cough, fatigue, weight loss, pancytopenia, hepatosplenomegaly pancytopenia, hepatosplenomegaly no no 1: 1:32 32± negative negative + positive 2x positive 2x rare amastigotes rare amastigotes 10 10 69 69 m Montenegro Montenegro sea sea-cost cost unknown, unknown, frequently frequently traveling traveling Fever, headaches, Fever, headaches, bicytopenia, bicytopenia, cough, nocturnal cough, nocturnal sweating, fatigue, sweating, fatigue, muscular pain, artralgia, muscular pain, artralgia, hepatosplenomegaly hepatosplenomegaly Chronic renal hronic renal failure, failure, DM DM 1: 1:6536 6536 + positive 2x positive 2x rare amastigotes rare amastigotes traveling traveling hepatosplenomegaly hepatosplenomegaly 11 11 34 34 m Montenegro Montenegro sea sea-cost cost unknown, unknown, resident resident Fever, sweating, weight loss, pancytopenia, Fever, sweating, weight loss, pancytopenia, hepatosplenomegaly hepatosplenomegaly no no 1:4096 1:4096 + positive 2x positive 2x rare amastigotes rare amastigotes 12 12 44 44 m Montenegro Montenegro sea sea-cost cost unknown, unknown, frequently frequently traveling traveling Trombocytopenia, skin rashes, hepatomegaly Trombocytopenia, skin rashes, hepatomegaly no no 1: 1:256 256 + positive 1x positive 1x numerous amastigotes numerous amastigotes traveling traveling 13 13 11 11 m Herzegovina Herzegovina unknown, unknown, resident resident Fever, sweating, weight loss, pancytopenia, Fever, sweating, weight loss, pancytopenia, hepatosplenomegaly hepatosplenomegaly no no 1: 1:64 64 + positive 1x positive 1x moderate amastigotes moderate amastigotes 14 14 19 19 f Herzegovina Herzegovina 8 mo 8 mo Fever, Fever, pancytopenia pancytopenia, hepatosplenomegaly, hepatosplenomegaly, lymphadenopathy lymphadenopathy no no 1: 1:1024 1024 + positive 2x positive 2x rare rare amastigotes amastigotes Conclusion Conclusions The diagnosis of VL would have been missed in these patients if diagnosis had been solely on one diagnostic method. Inadequate sensitivity of the initial BM smears and rare false-negative reactions of the strip-test and IHA requires introduction of molecular diagnosis.

Upload: others

Post on 05-Jan-2022

1 views

Category:

Documents


0 download

TRANSCRIPT

A Comparative Evaluation of Three Methods for Diagnosis of VisceralA Comparative Evaluation of Three Methods for Diagnosis of VisceralLeishmaniasisLeishmaniasis in Serbiain Serbia

ZoricaZorica DakićDakić11, M. Pelemiš, M. Pelemiš2,32,3, G. Stevanović, G. Stevanović2,32,3, L. Lavadinović, L. Lavadinović2,32,3,, J. PolugaJ. Poluga2,32,3, B. Milošević, B. Milošević2,32,3,, N. IndjićN. Indjić44,,O. DulovićO. Dulović2,32,3, I. Ofori, I. Ofori--BelićBelić11,, M. PavlovićM. Pavlović2, 32, 3

11Parasitological LaboratoryParasitological Laboratory, Service of Microbiology, Service of Microbiology, Clinical Center of Serbia, Belgrade, Serbia, Clinical Center of Serbia, Belgrade, Serbia22Faculty of Medicine,Faculty of Medicine, University of Belgrade,University of Belgrade, Serbia;Serbia; 33Clinic of Infectious and Tropical Diseases,Clinic of Infectious and Tropical Diseases,CCS, Belgrade, SerbiaCCS, Belgrade, Serbia44Center of Preventive Medical Care, Belgrade, SerbiaCenter of Preventive Medical Care, Belgrade, Serbia

A Comparative Evaluation of Three Methods for Diagnosis of VisceralA Comparative Evaluation of Three Methods for Diagnosis of VisceralLeishmaniasisLeishmaniasis in Serbiain Serbia

ZoricaZorica DakićDakić11, M. Pelemiš, M. Pelemiš2,32,3, G. Stevanović, G. Stevanović2,32,3, L. Lavadinović, L. Lavadinović2,32,3,, J. PolugaJ. Poluga2,32,3, B. Milošević, B. Milošević2,32,3,, N. IndjićN. Indjić44,,O. DulovićO. Dulović2,32,3, I. Ofori, I. Ofori--BelićBelić11,, M. PavlovićM. Pavlović2, 32, 3

11Parasitological LaboratoryParasitological Laboratory, Service of Microbiology, Service of Microbiology, Clinical Center of Serbia, Belgrade, Serbia, Clinical Center of Serbia, Belgrade, Serbia22Faculty of Medicine,Faculty of Medicine, University of Belgrade,University of Belgrade, Serbia;Serbia; 33Clinic of Infectious and Tropical Diseases,Clinic of Infectious and Tropical Diseases,CCS, Belgrade, SerbiaCCS, Belgrade, Serbia44Center of Preventive Medical Care, Belgrade, SerbiaCenter of Preventive Medical Care, Belgrade, Serbia

A Comparative Evaluation of Three Methods for Diagnosis of VisceralA Comparative Evaluation of Three Methods for Diagnosis of VisceralLeishmaniasisLeishmaniasis in Serbiain Serbia

ZoricaZorica DakićDakić11, M. Pelemiš, M. Pelemiš2,32,3, G. Stevanović, G. Stevanović2,32,3, L. Lavadinović, L. Lavadinović2,32,3,, J. PolugaJ. Poluga2,32,3, B. Milošević, B. Milošević2,32,3,, N. IndjićN. Indjić44,,O. DulovićO. Dulović2,32,3, I. Ofori, I. Ofori--BelićBelić11,, M. PavlovićM. Pavlović2, 32, 3

11Parasitological LaboratoryParasitological Laboratory, Service of Microbiology, Service of Microbiology, Clinical Center of Serbia, Belgrade, Serbia, Clinical Center of Serbia, Belgrade, Serbia22Faculty of Medicine,Faculty of Medicine, University of Belgrade,University of Belgrade, Serbia;Serbia; 33Clinic of Infectious and Tropical Diseases,Clinic of Infectious and Tropical Diseases,CCS, Belgrade, SerbiaCCS, Belgrade, Serbia44Center of Preventive Medical Care, Belgrade, SerbiaCenter of Preventive Medical Care, Belgrade, Serbia

Clinical Center of SerbiaClinical Center of Serbia

A Comparative Evaluation of Three Methods for Diagnosis of VisceralA Comparative Evaluation of Three Methods for Diagnosis of VisceralLeishmaniasisLeishmaniasis in Serbiain Serbia

ZoricaZorica DakićDakić11, M. Pelemiš, M. Pelemiš2,32,3, G. Stevanović, G. Stevanović2,32,3, L. Lavadinović, L. Lavadinović2,32,3,, J. PolugaJ. Poluga2,32,3, B. Milošević, B. Milošević2,32,3,, N. IndjićN. Indjić44,,O. DulovićO. Dulović2,32,3, I. Ofori, I. Ofori--BelićBelić11,, M. PavlovićM. Pavlović2, 32, 3

11Parasitological LaboratoryParasitological Laboratory, Service of Microbiology, Service of Microbiology, Clinical Center of Serbia, Belgrade, Serbia, Clinical Center of Serbia, Belgrade, Serbia22Faculty of Medicine,Faculty of Medicine, University of Belgrade,University of Belgrade, Serbia;Serbia; 33Clinic of Infectious and Tropical Diseases,Clinic of Infectious and Tropical Diseases,CCS, Belgrade, SerbiaCCS, Belgrade, Serbia44Center of Preventive Medical Care, Belgrade, SerbiaCenter of Preventive Medical Care, Belgrade, Serbia

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

IntroductionIntroduction In former Yugoslavia, visceral leishmaniasis was endemic in Macedonia, southern Serbia, Montenegro coast, south Herzegovina and Dalmatia. From 1945-1955, three epidemic waves of VL were recorded in Serbia. In subsequent three years, 17 cases were reported, the result of eradication of malaria vectors. Rareautochthonous cases were noticed in 1968 and 1969 in Nis. According to epidemiological data, 39 VL cases were reported in Serbia and Montenegro from 1991 to 2000, withonly one being imported. Today, the predominant VL risk in Serbian citizens is the stay at the Montenegrian sea-coast, where as many as 10 cases have been diagnosedeach year in Bar. A retrospective diagnostic study of VL was carried out from December 2004 to August 2011 and included all patients with suspected VL referred to theParasitological Laboratory, Cinical Center of Serbia, Belgrade. This study compared efficiency of three methods for the diagnosis of VL.

PatientsPatients andand methodsmethods All patients with suspected VL (n=44) were examined by Giemsa-stained bone marrow smears, by the rapid dipstick rK39 test (DiaSys Europe,England) and indirect hemagglutination assay (Siemens, former Behring Diagnostics, Germany). Positive IHA result was defined as titer >1:64. Patients with suspected VL,were defined as patients with a history of fever of ≥14 days with either clinical splenomegaly or wasting syndrome. Clinical suspicion was supported if the patient was from thean endemic area or had travelled to one this area in the recent past. Diagnosis of VL was confirmed on the demonstration of Leishmania amastigotes in Giemsa-stained BMsmears. If the initial BM smear was negative but the clinical index of suspicion high, parasitological investigation was repeated, or the diagnosis based on the clinicalpresentation and positive serology. The control group included 62 patients with other diagnoses (imported malaria and other infectious and non-infectious diseases), who weretested by IHA and strip-test, without BM aspiration.

ResultsResults VL was diagnosed in 14 patients (8 male and 6 female; age, 11 to 69 years, mean 40). Eleven of them (79%) were treated at the Clinic of Infectious and TropicalDiseases, Belgrade. The infection was contracted in Montenegro (n=8), Herzegovina (n=4), southern Serbia and Portugal (n=1, each). The initial examination of BM smearswas successful in 85.7% patients. At the first examination, two patients had negative BM smears. In only one, parasitological investigation was repeated and VL wasconfirmed. In another patient, diagnosis was based on clinical picture, positive serology and therapeutic effect. Both the strip-test and IHA performed with a sensitivity of92.9%, specificity 96.7% and a positive predictive value of 92.9%. The density of Leishmania amastigotes and antibody titer by IHA were not always in correlation with eachother or with the clinical condition. One patient had positive both the strip-test and IHA (1:256), while parasitological investigation was negative; further examination confirmedliver and spleen multi-focal micro-abscesses. All patients in control group tested negative with both the strip-test and IHA.

PatientPatientNoNo

AgeAge SexSex Origin ofOrigin ofinfectionsinfections

IncubationIncubationperiodperiod

Clinical presentationClinical presentation PreexistentPreexistentdisesesdiseses

IHAIHAtitertiter

StripStrip--testtestresultresult

Dg by BMDg by BMsmearssmears

PatientPatientNoNo

AgeAge SexSex Origin ofOrigin ofinfectionsinfections

IncubationIncubationperiodperiod

Clinical presentationClinical presentation PreexistentPreexistentdisesesdiseses

IHAIHAtitertiter

StripStrip--testtestresultresult

Dg by BMDg by BMsmearssmears

11 2424 mm south Serbiasouth Serbia 18 mo18 mo Fever with sweating, weight loss, pancytopenia,Fever with sweating, weight loss, pancytopenia,hepatosplenomegalyhepatosplenomegaly

nono 1:10241:1024 ++ positive 1xpositive 1xnumerous amastigotesnumerous amastigotes

11 2424 mm south Serbiasouth Serbia 18 mo18 mo Fever with sweating, weight loss, pancytopenia,Fever with sweating, weight loss, pancytopenia,hepatosplenomegalyhepatosplenomegaly

nono 1:10241:1024 ++ positive 1xpositive 1xnumerous amastigotesnumerous amastigotes

22 6868 ff MontenegroMontenegroseasea--costcost

3 mo3 mo Fever, pancytopenia, hepatosplenomegalyFever, pancytopenia, hepatosplenomegaly SarcoidosisSarcoidosis 1:1:256256 ++ positive 1xpositive 1xmoderate amastigotesmoderate amastigotes

MontenegroMontenegroseasea--costcost

positive 1xpositive 1xmoderate amastigotesmoderate amastigotes

33 2727 mm HerzegovinaHerzegovina unknown,unknown,residentresident

Fever, heavy sweating, bicytopenia, hepatosplenomegalyFever, heavy sweating, bicytopenia, hepatosplenomegaly nono 1:10241:1024 ++ positive 1xpositive 1xnumerous amastigotesnumerous amastigotes

44 2828 ff MontenegroMontenegroseasea--costcost

7 mo7 mo Fever, weight loss, splenomegalyFever, weight loss, splenomegaly Ulcerative colitisUlcerative colitis 1:11:12828 ++ positive 2xpositive 2xrare amastigotesrare amastigotes

44 2828 ff MontenegroMontenegroseasea--costcost

7 mo7 mo Fever, weight loss, splenomegalyFever, weight loss, splenomegaly Ulcerative colitisUlcerative colitis 1:11:12828 ++ positive 2xpositive 2xrare amastigotesrare amastigotes

55 6868 ff HerzegovinaHerzegovina unknown,unknown,residentresident

Fever, pancytopenia, hepatosplenomegalyFever, pancytopenia, hepatosplenomegaly Diabetes mellitus,Diabetes mellitus,AnemiaAnemia

1:1:20482048 ++ negative 1xnegative 1xex iuvantibusex iuvantibusnegative 1xnegative 1xex iuvantibusex iuvantibus

66 6363 ff MontenegroMontenegroseasea--costcost

12 mo12 mo Fever, fatigue, cough, weight loss, muscularFever, fatigue, cough, weight loss, muscularpain,hepatosplenomegalypain,hepatosplenomegaly

nono 1:11:163846384 ++ positive 1xpositive 1xnumerous amastigotesnumerous amastigotes

77 4444 mm MontenegroMontenegroseasea--costcost

unknown,unknown,residentresident

Trombocytopenia, skin rashes, hepatosplenomegalyTrombocytopenia, skin rashes, hepatosplenomegaly nono 1:11:163846384 ++ positive 1xpositive 1xnumerous amastigotesnumerous amastigotes

77 4444 mm MontenegroMontenegroseasea--costcost

unknown,unknown,residentresident

Trombocytopenia, skin rashes, hepatosplenomegalyTrombocytopenia, skin rashes, hepatosplenomegaly nono 1:11:163846384 ++ positive 1xpositive 1xnumerous amastigotesnumerous amastigotes

88 3333 ff MontenegroMontenegroseasea--costcost

unknown,unknown,frequentlyfrequentlytravelingtraveling

Fever, pancytopenia, moderate hepatosplenomegalyFever, pancytopenia, moderate hepatosplenomegaly ChronicChronic mmeningoeningo--encephalitisencephalitis

1:1:20482048 ++ positive 1xpositive 1xNumerousNumerous amastigotesamastigotes

MontenegroMontenegroseasea--costcost

unknown,unknown,frequentlyfrequentlytravelingtraveling

ChronicChronic mmeningoeningo--encephalitisencephalitis

positive 1xpositive 1xNumerousNumerous amastigotesamastigotes

99 2222 mm HerzegovinaHerzegovina unknown,unknown,residentresident

Fever, nocturnal sweating, cough, fatigue, weight loss,Fever, nocturnal sweating, cough, fatigue, weight loss,pancytopenia, hepatosplenomegalypancytopenia, hepatosplenomegaly

nono 1:1:3232±±negativenegative

++ positive 2xpositive 2xrare amastigotesrare amastigotes

1010 6969 mm MontenegroMontenegroseasea--costcost

unknown,unknown,frequentlyfrequentlytravelingtraveling

Fever, headaches,Fever, headaches, bicytopenia,bicytopenia, cough, nocturnalcough, nocturnalsweating, fatigue,sweating, fatigue, muscular pain, artralgia,muscular pain, artralgia,hepatosplenomegalyhepatosplenomegaly

CChronic renalhronic renal failure,failure,DMDM

1:1:65366536 ++ positive 2xpositive 2xrare amastigotesrare amastigotes

unknown,unknown,frequentlyfrequentlytravelingtraveling

Fever, headaches,Fever, headaches, bicytopenia,bicytopenia, cough, nocturnalcough, nocturnalsweating, fatigue,sweating, fatigue, muscular pain, artralgia,muscular pain, artralgia,hepatosplenomegalyhepatosplenomegaly

1111 3434 mm MontenegroMontenegroseasea--costcost

unknown,unknown,residentresident

Fever, sweating, weight loss, pancytopenia,Fever, sweating, weight loss, pancytopenia,hepatosplenomegalyhepatosplenomegaly

nono 1:40961:4096 ++ positive 2xpositive 2xrare amastigotesrare amastigotes

1212 4444 mm MontenegroMontenegroseasea--costcost

unknown,unknown,frequentlyfrequentlytravelingtraveling

Trombocytopenia, skin rashes, hepatomegalyTrombocytopenia, skin rashes, hepatomegaly nono 1:1:256256 ++ positive 1xpositive 1xnumerous amastigotesnumerous amastigotes

unknown,unknown,frequentlyfrequentlytravelingtraveling

1313 1111 mm HerzegovinaHerzegovina unknown,unknown,residentresident

Fever, sweating, weight loss, pancytopenia,Fever, sweating, weight loss, pancytopenia,hepatosplenomegalyhepatosplenomegaly

nono 1:1:6464 ++ positive 1xpositive 1xmoderate amastigotesmoderate amastigotes

1414 1919 ff HerzegovinaHerzegovina 8 mo8 mo Fever,Fever, pancytopeniapancytopenia,, hepatosplenomegaly,hepatosplenomegaly,lymphadenopathylymphadenopathy

nono 1:1:10241024 ++ positive 2xpositive 2xrarerare amastigotesamastigotes

ConclusionConclusionss The diagnosis of VL would have been missed in these patients if diagnosis had been solely on one diagnostic method. Inadequate sensitivity of the initial BMsmears and rare false-negative reactions of the strip-test and IHA requires introduction of molecular diagnosis.