A 33-year-old male patient with fever, splenomegaly, pancytopenia and lymphocytosis
was admitted to the Department of Hematology in Rijeka. Laboratory findings, bone
marrow aspiration and biopsy excluded hemoblastosis and aplastic anemia. To exclude
primary splenic lymphoma we performed splenic aspiration where Leishmania amastigotes
were found. No cases of visceral leishmaniasis have been previously described in
the Northern Adriatic region. Considering epidemiology, a contraction of the disease in
the Velebit mountain range could be possible despite the current non-endemic status of
the region

A. Načinović-Duletić

B. Vojniković

I. Prebilić

I. Seili-Bekafigo

M. Sever-Prebilić

N. Ivaniš

S. Dokić

English

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Coll. Antropol. 26 (2002) 2: 545–550UDC 616.993.161(497.5)Original scientific paperA Case of Visceral Leishmaniasis inthe Northern Adriatic RegionM. Sever-Prebili}1, I. Prebili}1, I. Seili-Bekafigo1, S. Doki}1, N. Ivani{2,A. Na~inovi}-Duleti}1 and B. Vojnikovi}31 Department of Hematology, Internal Medicine Clinic, University Hospital Center »Rijeka«,Rijeka, Croatia2 Private Internal Medicine »Office Ivani{«, Rijeka, Croatia3 Ophthalmic Outpatients Department »Dr. B. Vojnikovi}«, Rijeka, CroatiaA B S T R A C TA 33-year-old male patient with fever, splenomegaly, pancytopenia and lymphocyto-sis was admitted to the Department of Hematology in Rijeka. Laboratory findings, bonemarrow aspiration and biopsy excluded hemoblastosis and aplastic anemia. To excludeprimary splenic lymphoma we performed splenic aspiration where Leishmania amasti-gotes were found. No cases of visceral leishmaniasis have been previously described inthe Northern Adriatic region. Considering epidemiology, a contraction of the disease inthe Velebit mountain range could be possible despite the current non-endemic status ofthe region.IntroductionThe leishmaniases are a group of dis-eases caused by the genus Leishmaniaand transmitted by female sandflies ofthe genus Phlebotomus in the Old Worldand Lutzomyia in the New World. Hu-man leishmanial infection can result inthree main forms of disease: visceral form(Kala-azar), cutaneous disease and muco-cutaneous leishmaniasis1,2. Visceral leish-maniasis is the most serious, potentiallyfatal form of the disease which has aworldwide distribution. Certain regionsare endemic areas of the disease includ-ing the countries of Europe, North Africaand the Middle East surrounding theMediterranean basin3,4. Endemic regionsin Croatia include middle and southernDalmatia, but the disease remains spo-radic. The Northern Adriatic has beenconsidered a non-endemic region. The or-ganisms causing visceral leishmaniasisin the Mediterranean region (L. infan-tum) and those in Americas (L. chagasi)are very similar and the disease is mainlycharacterized by fever, weight loss, hepa-tosplenomegaly, lymphadenopathy andpancytopenia. Routine diagnostic proce-dures include several serological methods545Received for publication May 16, 2002and microscopic examination of Giemsa--stained material obtained from the bonemarrow, lymph nodes or spleen. Mostcommonly used drugs in the treatment ofvisceral leishmaniasis are pentavalentantimony compounds.Case ReportA previously healthy, 33-year-old malepatient was admitted to the Departmentof Hematology, University Hospital Center»Rijeka«, presenting with remittent feverwhich lasted for two months, weakness,hepatosplenomegaly and pancytopenia.On admission he was febrile (38.5 °C), theliver was palpable 1 cm and the spleen 5cm below the costal margin.Laboratory tests revealed elevatedESR, pancytopenia and mild lympho-cytosis with atypical cells in the periph-eral blood (Table 1). Total serum proteinswere raised (93 g/L), albumins 39.1 g/L,gamma globulins 36.4 g/L. Serum proth-rombine time was prolonged to 19 sec-onds. Lactate dehydrogenase (LDH) waselevated (505 IU/L).The patient remained febrile for 15days with his body temperature showinga remittent pattern. Repeated blood cul-tures were negative as well as Vidal's re-action. Malaria was excluded by exami-nation of thick and thin blood films.Broad spectrum antibiotic therapy admi-nistered during the diagnosing processincluded Cefuroxime 3 750 mg/day i.v.and Netilmycin 2 150 mg/day i.v. for 5days followed by Imipenem 3 1 g/day i.v.for 7 days, but remained sine effectu.Clinically non-progressive splenic en-largement (200 mm) was visualized andmeasured by abdominal ultrasound whichalso showed an enlarged liver. Bone mar-row aspiration, ordered to exclude aleu-kemic leukemia and malignant non-Hodg-kin's lymphoma, revealed only mildplasmocytosis (7.5%) (Figure 1), whileLeishmania amastigotes could be foundneither in the bone marrow aspirate norin the bone marrow biopsy specimen.The patient's condition worsened withpersisting fever accompanied by sweatsand discomfort in the left hypochondri-um. In order to exclude primary splenic546M. Sever-Prebili} et al.: Leishmaniasis in the Northern Adriatic, Coll. Antropol. 26 (2002) 2: 545–550TABLE 1LABORATORY TEST RESULTS ON ADMISSION, AFTER THERAPY AND ONE YEAR LATERLaboratorytestsOnadmissionAfter 21 daysof therapyOne yearlaterESR (mm/h) 98 35 9E ( 1012/l) 3.7 4 4.8Hb (g/L) 98 118 141WBC ( 109/L) 2.2 4.2 6.6Lymphocytes (%) 44 40 39Platelets ( 109/L) 62 205 297dctlparPlasma cells (%) 4 0 0Atypical cells (%) 13 2 1Blast cells (%) 2 0 0Total serum proteins (g/L) 93 – 80Albumins (g/L) 39.1 – 44Gamma globulins (g/L) 36.4 – 14LDH (IU/L) 505 382 195lymphoma we decided to do splenic aspi-ration biopsy. Unexpectedly, Leishmaniaamastigotes were found in the splenic as-pirate (Figure 2), but not in the bone mar-row aspirate and biopsy specimens. Immu-nofluorescent assay (IFA) for Leishmania547M. Sever-Prebili} et al.: Leishmaniasis in the Northern Adriatic, Coll. Antropol. 26 (2002) 2: 545–550Fig. 1. Bone marrow plasmocytosis – aspiration biopsy smear( 1000, May-Grünwald-Giemsa stain).Fig. 2. Leishmania amastigotes in the splenic aspirate( 1000, May-Grünwald-Giemsa stain).showed an IgG titre of 1:2560 and theFormol gel reaction was also positive.A repeated analysis of the epidemio-logical history indicated that the patientresided in a military setting located inthe non-endemic region of the Velebitmountain range (Northern Adriatic) fortwo years and 4 months.Treatment was initiated with Pento-stam (pentavalent antimony derivate)850 mg/day for 21 days. On the third dayof Pentostam therapy the body tempera-ture fell to the normal value and the pa-tient's condition continued to improve.On the 12th day of Pentostam therapy thepatient got Staphylococcus aureus pneu-monia. Ceftriaxon therapy was adminis-tered and the body temperature normal-ized after three days. Our patient left thehospital after 50 days of hospitalization,feeling very well and being afebrile. Thespleen was palpable 1 cm below the costalmargin. We registered an improvementin the laboratory findings: ESR 35 mm/h,WBC 4 109/L, lymphocytes 40%, LDH382 U/L, atypical cells 2%, blast cells dis-appeared. IFA IgG antibody titre to Leis-hmania was 1:256 six months after thediagnosis was made. However, after oneyear the spleen was not palpable and thelaboratory tests were normal (Table 1).DiscussionA certain protraction of this patient'sdiagnostic process has been partly causedby previous diagnostics which ruled outmost of the epidemiological problems andinfectious diseases in the mountainousregion of Velebit and contemporary mili-tary setting where the patient spent twoyears and four months prior to the admis-sion to our Department of Hematology.Other non-hematological disorders werealso considered, shifting our attention tothe possible hematological causes of theleading symptoms. Therefore, our diag-nostic algorithm was targeted to excludehemoblastosis, lymphoma or aplasticanemia primarily, despite the fact that fe-ver, splenomegaly and pancytopenia werealso attributable to visceral leishmani-asis. In addition to a number of more fre-quent disorders, especially within thechronically stressed populations in thepost-war years, an atypical epidemiologi-cal history and non-endemic status of theVelebit mountain range, certainly affec-ted our diagnostic algorithm in this unex-pected case.Conventional approaches to the diag-nosis of visceral leishmaniasis includeseveral serological methods and micro-scopic examinations of the material ob-tained from the bone marrow, lymph no-des and spleen. The bone marrow may beinfiltrated with parasitized macrophageswhich usually rupture on smearing andfree parasites must be searched. In thiscase, laboratory examination, as well asbone marrow aspiration and biopsy, ex-cluded hemoblastosis but no Leishmaniaamastigotes were found. To rule out pri-mary splenic lymphoma we consideredspleen biopsy which is also a diagnosticprocedure in visceral leishmaniasis. Al-though the examination of the materialobtained from the spleen detects para-sites in 95–99% of cases1,2, splenic aspira-tion is an invasive procedure with hemor-rhage as its possible complication. Follo -wing our criteria for the spleen aspirationbiopsy (prothrombin time preferablywithin normal values or less than 5 sec-onds longer than in the normal control(10–14s), and platelet count not less than80 109/L), in order to optimize the safetyof the procedure, K vitamin and platelettransfusions were administered prior tothe splenic aspiration. We were surprisedto find Leishmania amastigotes in thespleen macrophages since there were noparasitized cells found in the bone mar-row specimens which might have alsobeen diagnostic for the disease. In thiscase, splenic aspiration biopsy was the548M. Sever-Prebili} et al.: Leishmaniasis in the Northern Adriatic, Coll. Antropol. 26 (2002) 2: 545–550key diagnostic procedure, confirmed laterby serological tests.In the past two decades there has beena resurgence of visceral leishmaniasis inthe regions where it was eradicated afterthe widespread use of chlorophenothane(DDT) in malaria prevention. Phleboto-mine populations were greatly reducedaround houses but zoonotic transmissionwas not affected. When the use of resid-ual insecticides was discontinued in ma-ny Mediterranean countries, transmis-sion to people was reestablished with anincrease in the number of leishmaniacases4. Rare autochthonous cases of vis-ceral leishmaniasis in the middle andsouthern Dalmatia have recently beendescribed in literature5,6, as well as casesof imported visceral leishmaniasis fromsouthern Croatia into the neighboringcountries. However, these sporadic caseshardly represented a significant publichealth problem7, even in the endemic re-gions. There have been no leishmaniacases reported in the northwestern, litto-ral part of the Adriatic coast where theinfection is considered extremely rareand the region non-endemic. However,outbreaks of visceral leishmaniasis haveoften followed famine, wars, civil and po-litical disturbances resulting in malnutri-tion and migration of populations. It isalso necessary to underline the existingdifferences in the clinical course of thedisease: some infected individuals de-velop subclinical infection and othersclinical disease. Reasons responsible fordifferences in the outcome of infection arenot known, but possible factors include:variations in the species of parasite andthe intensity of transmission, nutritionalstatus of the patient (malnourished in-fected children develop clinical disease,while equally exposed well-nourishedchildren develop subclinical infection), orcombinations of these or other factors.According to the epidemiological datain the medical history of our patient andthe usual length of the incubation period,there is strong ground to suspect anautochthonous infection in this region, al-though the possibility of a previously ac-quired infection with a long incubationperiod and clinical manifestation of thedisease after more than three years spentin a chronically stressful, non-endemicenvironment, cannot be completely ruledout. A combination of factors includingstress, malnutrition and a modified im-mune response might have played an im-portant role in any of these scenarios.Considering the changes in climate,higher temperatures are likely to acceler-ate maturation of the protozoal parasite,thereby increasing the risk of infection.The spread of vectors from the adjacentsouthern regions seems logical, althoughmultidisciplinary studies onsite shouldbackup these speculations in the futu-re7–11. In addition to the changes in mi-croclimate, it would be interesting to in-vestigate possible changes in the distri-bution and relations between reservoirsand vectors responsible for the transmis-sion of the disease. Future studies of themedically relevant entomofauna, not ade-quately investigated in Croatia7, couldconcentrate on the possible spread ofsandflies along the northern coast andadjacent mountains, which would con-firm the possibility of the autochthonousacquisition of the disease in the Velebitregion.Considering the increased number ofautochthonous and imported cases of vis-ceral leishmaniasis8–14, its chronic clini-cal course and a high mortality rate if notrecognized, pancytopenia, splenomegalyand fever should be timely associated andserologically tested for visceral leishma-niasis even in non-endemic regions, andduring diagnostic efforts reasonablyaimed at non-infective diseases of similarpresentation. The importance of the epi-demiological history and continuous eval-uations is crucial15, therefore, this case549M. Sever-Prebili} et al.: Leishmaniasis in the Northern Adriatic, Coll. Antropol. 26 (2002) 2: 545–550and the emerging reports raise a consid-erable amount of questions for both,epidemiologists and clinicians, to be an-swered by the future analyses that mighthelp reconsider the leishmania endemicregions in Croatia.550M. Sever-Prebili} et al.: Leishmaniasis in the Northern Adriatic, Coll. Antropol. 26 (2002) 2: 545–550R E F E R E N C E S1. HASSAN, A. M., L. A. HASSAN, Alpe AdriaMicrobiology Journal, 6 (1997) 23. — 2. LOCKSLEY,R. M., Leishmaniasis. In: ISSELBACHER K. J., E.BRAUNWALD, J. D. WILSON, J. B. MARTIN, A. S.FAUCI, D. L. KASPER (Eds.): Harrison's principlesof internal medicine. (McGraw-Hill, 1994). — 3.VASUDEVIAH, V., Leishmaniasis. In: DAMBRO, M.R., J. A. GRIFFITH (Eds.): Griffith's 5 minute clinicalconsult. (Williams & Wilkins, Baltimore, 1998). — 4.NEVA, F. A., Leishmaniasis. In: WYNGAARDEN, J.B., L. H. SMITH, J. C. BENNETT (Eds.): Cecil tex-book of medicine. (Saunders, Philadelphia, 1992). —5. POLI], V. P., N. BRADARI], D. GRGI], Lancet,349 (1997) 1666. — 6. PUNDA-POLI], V., S. SAR-DELI], N. BRADARI], Lancet, 351 (1998) 188. — 7.MULI], R., B. D. ROPAC, I. ZORI], N. BRADARI],Mil. Med., 167 (2002) 321. — 8. CHALUPA, P., J. VA-NI[TA, I. BURGET, J. STARY, M. SUKOVA, M. NO-HYNKOVA, Bratisl. Lek. Listy., 102 (2001) 84. — 9.WENZL, H., W. PETRITSCH, M. DECRINIS, F.SCHREIBER, H. WARNKROSS, H. PRISTAUTZ, G.J. KREJS, Wien. Klin. Wochenschr., 104 (2001) 757.— 10. KNE@EVI], K., V. TURKULOV, M. ]ELANO-VI], Med. Pregl., 51 (1998) 551. — 11. GRAMICCIA,M., L. GRADONI, E. POZIO, Parassitolgia, 27 (1985)187. — 12. VECSEI, A. K., U. KASTNER, M. TREBO,R. KORNMULLER, O. PICHER, E. SCHRATZBER-GER-VECSEI, H. GADNER, Wien. Klin. Wochen-schr., 113 (2001) 102. — 13. BUYUKASIK, Y., N. S.ILERI, I. C. HAZNEDAROGLU, H. DEMIROGLU, S.DUNDAR, Postgrad. Med. J., 74 (1998) 237. — 14.FENECH, F. F., Ann. Trop. Med. Parasitol., 91 (1997)747. — 15. OZBEL, Y., N. TURGAY, S. OZENSOY, A.OZBILGIN, M. Z. ALKAN, M. A. OZCEL, C. L. JAF-FE, L. SCHNUR, L. OSKAM, P. ABRANCHES, Ann.Trop. Med. Parasitol., 89 Suppl. (1995) 189.M. Sever-Prebili}Department of Hematology, Internal Medicine Clinic, University Hospital Center»Rijeka«, Kre{imirova 42, 51000 Rijeka, CroatiaPRIKAZ SLU^AJA VISCERALNE LI[MENIOZE NA PODRU^JUSJEVERNOG JADRANAS A @ E T A KNa Hematolo{kom odjelu u Rijeci hospitaliziran je 33-godi{nji mu{karac zbog po-vi{ene temperature, splenomegalije, pancitopenije i limfocitoze. Laboratorijski nalazi,punkcija i biopsija ko{tane sr`i isklju~ili su hemoblastozu i aplasti~nu anemiju. Zbogsumnje na primarni limfom slezene, u~injena je aspiracijska biopsija slezene te su umakrofagima prona|eni amastigoti li{menije. Do sada nije opisan slu~aj pojave vis-ceralne li{menioze na podru~ju sjevernog Jadrana, iako se ista javlja endemski u sred-njoj i ju`noj Dalmaciji. Prema epidemiolo{koj anamnezi, mogu}a je infestacija na po-dru~ju Velebita.

A Case of Visceral Leishmaniasis in the Northern Adriatic Region

A Case of Visceral Leishmaniasis in the Northern Adriatic Region

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