Hemoragijska groznica sa bubrežnim sindromom u Bosni i Hercegovini

Preko 60 godina Bosna i Hercegovina je poznata kao endemična regija za hantavirus infekcije. Najmanje tri različita Hantavirus (HTV) serotipa su endemični u BiH. Dokazano je da HTV mogu uzrokovati asimptomatsku i blagu kliničku sliku bolesti, ali i tešku bolest sa krvarenjima, prestankom rada bubrega i smrtnim ishodom. Epidemiološka istraživanja pokazuju da su rizikofaktori za nastanak HTV infekcije u BiH: život na u endemskom području, poljoprivredni radovi, rad sa otpadom, spavanje na zemlji, vojne vježbe i niži socio-ekonomski status.

Istorijski pregled

Preko 60 godina Bosna i Hercegovina je poznata kao endemična regija za hantavirus infekcije. Prvi slučaj hemoragijske groznice sa bubrežnim sindromom (HFRS) izvan Skandinavije, opisan je 1952. godine u vojnom kampu u planinskim šumama Fojnice, 25 kilometara sjevero-zapadno od glavnog grada Sarajeva. Retrospektivno, sama činjenica da je pritonealna dijaliza bila neophodna upućivala je na kliničku manifestaciju, koja je neobična za većinu blagih oblika epidemijske nefropatije, koji su do tada bili poznati. Prva dokumentovana epidemija HFRS u Evropi zabilježena je 1961. godine, opet u vojnom kampu smještenom u Fruškoj Gori (Edevik, Srbija), na samo 75 km sjeveroistočno od prethodnog epidemičnog fokusa. Za vrijeme vojnih vježbi, ukupno 46 vojnika se razbolilo, od toga 33 je imalo blagi oblik, 13 je imalo težak oblik, a bio je i 1 smrtni ishod. Važnu ulogu u ovom iznenadnom izbijanju bolesti su imali glodari koji su naselili kamp. Kontinuirano izbijanje HFRS u bivšoj Jugoslaviji (1966., 1986. i 1989.), rezultiralo je u opisu preko 1.000 slučajeva, od kojih su većina bili iz sjeverne Bosne. U toku 1981.- 1984., u akciji izlovljavanja sitnih glodavaca u okolini Fojnici, Bosna, kao najbrojnija vrsta identifikovan je žutogrli poljski miši (Apodemus flavicollis). Laboratorijskim analizama dokazano je prisustvo hantavirusnog antigena u plućima u 7,1% uhvaćenih životinja. Crvena voluharica (Myodes glareolus), glavni domaćin evropskog serotipa Pumala virusa (PPUV), pokazala se manje zastupljenom, ali inficiranom u procentu od 11%. Nešto kasnije, A. flavicolis je identificiran kao domaćin Dobrava virusa (DOBV), uzročnika teškog oblika HVBS. Već u ranim 80-tim, HFRS pacijenti iz Bosne su imali najviše titrove antitijela protiv prototipa Korejskog Hantaan, serotipa 76-118, i pokazali su najteže kliničke simptome. Za vrijeme do tada najveće epidemije u 1989.god., kada je hospitalizirano 609 oboljelih sa kliničkim znacima i simptomima karakterističnim za HFRS, od njih 226 su bili serološki potvrđeni kao Hantavirusna (HTV) infekcija, sa mortalitetom od 6,6% (15/226). BiH je još jednom potvrđena kao centar izbijanja infekcije, sa 108 serološki potvrđenih slučajeva (48%) i mortalitetom od 5,5% (6/108). Analizom kliničke slike i rezultata seroloških analiza, postalo je jasno da na području bivše Jugoslavije cirkulišu barem dva različita hantavirusa: jedan blisko srodan Hantaan virusu, nošen sa A. flavicollis, uzročnik teškog kliničkog oblika HFRS; a drugi srodan Puumala virusu, nošen sa Myodes glareolus, koji izazivaju blage oblike kliničke slike. Ista istraživanja su sprovedena i u Sloveniji. Konačno, Avsić i saradnici su izolovali hantavirus blisko srodan, ali ne i identičan sa HTN iz A. flavicollis izlovljenog u Dobravi, selu u Sjevernoj Sloveniji, gdje su se javili teški HVBS slučajevi.

U sigurno najvećoj epidemiji HFRS, koja je pogodila BiH, tokom ratnog perioda 1995.god., oboljelo je više od 1.000 ljudi. Više od 500 bolesnika, pretežno vojnika, hospitalizirano je u sjeveroistočnoj Bosni zbog akutne HFRS. Hukić i saradnici su serološkim i virološkim ispitivanjima dokazali da su uzročnici bolesti bili PUUV i DOBV. Nova, velika epidemija HFRS na Balkanskom poluostrvu buknula je ponovo 2002. god. BiH je bila značajno pogođena ovom epidemijom. Do 2012 godine, kontinuirano, svake godine bilježeni su pojedinačni slučajevi obolijevanja od HFRS. Posljednja epidemija, na području Hrvatske, Slovenije i BiH, izbila je 2012.godine. Glavna karakteristika ove epidemije u BiH nije bila brojnost oboljelih, nego težina kliničke slike i visok mortalitet.

Istraživanja u Bosni i Hercegovini

Pored brojnih istraživanja, područje BiH je ostalo neispitano u pogledu brojnosti i zastupljenosti različitih vrsta glodara – prirodnih rezervoara hantavirusa, karakteristikama HTV, poznavanju učestalosti PUU-infekcija i DOB-infekcija kod ljudi te osobitostima kliničke slike bolesti. U cilju boljeg razumijevanja biologije i ekologije Hantavirusa, te bolesti koje uzrokuje, u posljednjih 17 godina, kontinuirano smo vršili epizotiološki i epidemiološki nadzor.

U različitim ekosistemima BiH uhvatili smo 871 glodara (11 vrsta glodara).

Antitijela za Hantaviruse nađena su serumima: Apodemus flavicollis, Clethrionomus glareolus, Chionomys nivalis, Dinaromys bogdanovi i Mycrotus arvalis. DOBV je izolovan iz Apodemus flavicollis, uhvaćenog u blizini Kladnja. Bosanski DOB virus, označen je kao DOBV-Tuzla43. Analizom njegove RNA, utvrđeno je da se radi o DOB, koji se u 7% genomski sekvenci razlikuje od orginalno izolovanog soja u Sloveniji. Iz Myodes glareolus je izolovan Bosanski PUUV, ali njegova genetska analiza još nije završena.

Kao uzročnici HFRS u BiH dokazani su: PUUV (49.84%), DOBV (23.15%) i neidentifikovani Hantavirus serotip (27.00%). Ovaj nalaz govori da su najmanje tri različita HTV serotipa endemični u BiH. Dokazano je da HTV mogu uzrokovati asimptomatsku i blagu kliničku sliku bolesti, ali i tešku bolest sa krvarenjima, prestankom rada bubrega i smrtnim ishodom.

Asimptomatske infekcije u zanačajno većem procentu uzrokuje PUUV (69.8%), u odnosu na DOBV (17.5%) i neidentificirani soje HTV (12.7%). Klinička evaluacija je pokazala da u toku akutne faze bolesti DOBV uzrokuje mnogo teža oštećenja bubrega od PUUV. Nakon 10 godina nakon HFRS, funkcija bubrega se normalizuje, s tim da je glomerularna filtracija signifikantno niža poslije DOB-infekcije, nego nakon PUUV infekcije.

Epidemiološka istraživanja pokazuju da su rizikofaktori za nastanak HTV infekcije: život na endemskom području, poljoprivredni radovi, rad sa otpadom, spavanje na zemlji, vojne vježbe i niži socio-ekonomski status. Prema učestalosti obolijevanja , u BiH su definisana endemska i ne-endemska područja za Hantanvirusnu infekciju. Hantavirusna seroprevalence među stanovništvom u endemskim područjima je 7.4% , a 2.4% u ne-endemskim (P

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Bosnia and Herzegovina (B&H) has been recognized as a highly endemic region for Hantavirus infections for over 60 years. The following causative agents of HFRS were confirmed: PUUV, DOBV and unidentified Hantavirus serotypes responsible for 49.84%, 23.15% and 27.00% of hospitalized cases, respectively. These findings suggest that at least three distinct serotypes are endemic throughout Bosnia and Herzegovina.

Bosnia and Herzegovina (B&H) has been recognized as a highly endemic region for Hantavirus infections for over 60 years. In 1952, the first probable hemorrhagic fever with renal syndrome case (HFRS) was described in the region. The victim was a soldier and infection was acquired near Fojnica, Bosnia and Herzegovina. Several HFRS outbreaks in B&H have been reported up to the present time. The first documented HFRS outbreak was reported in 1967, followed by three major outbreaks in the former Yugoslavia in 1986, 1987 and 1989. The majority of cases reported in these epidemics were located in B&H. From 1989 to 1991, 55 additional cases were detected in B&H with a mortality rate of 7.3%. During the war in B&H (1995), more than 500 patients, most of them soldiers exposed to the fields in northeast Bosnia, were hospitalized with acute Hantavirus disease due either to Puumala (PUUV) or Dobrava (DOBV) as first documented by IgG and IgM ELISA and later confirmed by focus reduction neutralization test. To our knowledge, this was the first report of an epidemic caused by two different hantaviruses each carried by a different rodent species, which were apparently synchronistic and sympatric in a limited but highly endemic area. The HFRS outbreak occurred again in 2002. The last outbreak of HFRS was in 2012. The most prominent characteristic of this epidemic was high rate of mortality 11% (3/27).

To know the reservoir animal species and characteristics of Hantaviruses as well as HFRS in Bosnia and Herzegovina, we have been continuing epizotiological and epidemiological surveys.

In different ecosystems of B&H we caught 871 rodents (11 different species of rodents). Five of them (Apodemus flavicollis, Clethrionomus glareolus, Chionomys nivalis, Dinaromys bogdanovi and Mycrotus arvalis) had antibodies to Hantaviruses. DOBV was isolated from Apodemus flavicollis. The Bosnian DOBV virus, designated DOBV-Tuzla43 is more closely related to the original DOBV isolated from Apodemus flavicollis in Slovenia (3.8% nucleotide difference) than to the Greek or Albanian DOB viruses (5.9 and 8.4% nucleotide differences, respectively). Bosnian PUUV was isolated from Clethrionomus glareolus; however, our RT-PCR analyses are not completed yet.

The following causative agents of HFRS were confirmed: PUUV, DOBV and unidentified Hantavirus serotypes responsible for 49.84%, 23.15% and 27.00% of hospitalized cases, respectively. These findings suggest that at least three distinct serotypes are endemic throughout Bosnia and Herzegovina. PUUV was significantly predominant in asymptomatic hantavirus antibody-positive subjects (69.8%) compared to HFRS patients. DOBV was present in 17.5% of asymptomatic subjects and, interestingly, the preferential hantavirus serotype could not be determined in 12.7% of the asymptomatic antibody-positive subjects. Thorough clinical evaluation and follow up of affected patients has shown that during the acute phase, DOBV causes more severe renal impairment than PUUV infection. The 10 years follow up of these patients showed renal function within normal limits although after DOBV infection, glomerular filtration rate was significantly lower than after PUUV infection.

Epidemiological investigations have linked viral exposure to activities such as heavy farm work, threshing, sleeping on the ground, military exercises, and lower socioeconomic status. Hantavirus seroprevalence was 7.4% in the endemic region of B&H and 2.4% in the non-endemic region of B&H (P