1st International Conference on Emerging Zoonoses Jerusalem, Israel The articles in this section were originally presented at the 1st International Conference on Emerging Zoonoses, Jerusalem, Israel, November 24-28, 1996. The conference was cosponsored by the Centers for Disease Control and Prevention and the Israel Center for Disease Control. The Hantaviruses of Europe: from the Bedside to the Bench In Europe, hantavirus disease can hardly be called an emerging zoonosis; it is rather a rediscovered disease. Since 1934 an epidemic condition with primarily renal involvement has been described in Sweden. Nowadays, hundreds to thousands of cases per year are registered in Fennoscandia, fluctuating with the numbers of the specific Arvicoline-rodent reservoir, the red bank vole, which carries the main European serotype, Puumala (PUU). In the early 1980s, the rat-transmitted serotype, Seoul (SEO), caused laboratory outbreaks throughout Europe, and recent reports also suggest sporadic, wild rat-spread hantavirus disease. In the Balkans, at least four serotypes are present simultaneously: PUU, SEO, the “Korean” prototype Hantaan (HTN) or HTN-like types, and Dobrava, the latter causing a mortality rate of up to 20%. Moreover, recent genotyping studies have disclosed several PUU-like genotypes spread in Europe and/or Russia by other genera of the Arvicoline-rodent subfamily: Tula, Tobetsu, Khabarovsk, and Topografov. Their importance for human pathogenicity is still unclear, but serologic cross-reactions with PUU antigen might have caused their misdiagnosis as PUU-infections in the past. Hantaviruses are often heralded as new or at epidemic of “trench nephritis” during World War least as emerging pathogens, particularly in the I may in fact have been hantavirus induced. New World. However, even on the American Thousands of cases of this illness, considered an continent, application of the newest genotyping entirely new renal disease, were noted on both techniques (the bench) comparing RNA sequences sides of the front (Kriegsnephritis or néphrite de found in both human cases and rodent reservoirs guerre). Already in 1934, the typical mild renal shows a long-standing coevolution of each newly form of hantavirus disease had been described in discovered hantavirus serotype in its specific Sweden (1); it was then described in all other rodent host; this coevolution results in remarkable Scandinavian countries, where the disease was genetic stability across time and in a certain genetic appropriately called nephropathia epidemica differentiation in geographic spread. Hantaviruses from 1945 on. inducing hantavirus pulmonary syndrome emerge During World War II, more than 10,000 cases not through genetic reassortment or a recent of a rodent-borne leptospirosislike disease were mutation, but through increased exposure to noted during the 1942 German campaign in infected rodents and their excreta. While the Finnish Lapland (2). Because the snow melted, same lines of evidence also apply to the European great numbers of lemmings and field mice situation, the problem there is totally different, invaded the German bunkers. Examinations in from a historical point of view. Munich and Berlin of these rodents, air-lifted from the war theater, offered no clue. Confronted History with some distinctive clinical symptoms (e.g., In most European countries, hantavirus acute myopia and localized edema) and with disease has long been known by various (mostly repeatedly negative findings for leptospirosis in geographic) names, which suggests a long- his patients, a researcher concluded it was a new standing clinical presence (the bedside). An field-like fever disease (2). Vol. 3, No. 2, April–June 1997 205 Emerging Infectious Diseases 1st International Conference on Emerging Zoonoses Jerusalem, Israel “Old” Hantaviruses in the Old World resulted in an overall seropositivity rate of 3.3%, The Puumala (PUU) serotype, carried by the ranging from 3.5% in the European part to 0.9% red bank vole (Clethrionomys glareolus), remains the in the Far Eastern part (18). A total of 68,612 most important Western and Central European cases were registered between 1988 and 1992 serotype, with at least 1,000 serologically con- (65,906 from the European part and 2,706 from firmed nephropathia epidemica cases per year in the Far Eastern part), with morbidity rates of 1.2 Finland and hundreds per year in Sweden (3). (1982) to 8.0 (1985) per 100,000 inhabitants. The The number of documented cases in other Euro- peak year was 1985 with 11,413 registered cases pean countries was more than 1,000 in the former (19). In the European part of Russia, most cases Yugoslavia (3), 531 in France by the end of 1994 were due to milder infection with PUU-related (4), approximately 250 in Belgium by the end of viruses, with mortality rates of 1% to 2%; 1996 (J. Clement, unpub. obs.), some 200 in whereas in Far East Russia, more severe HTN- Germany by the end of 1995 (5), 138 in Greece like cases also occurred (19). by the end of 1993 (6), and 39 in the Nether- lands by the end of 1994 (7). The Wild Rat: Omnipresent, but IgG seroprevalence rates reported from some Often Overlooked of these countries, measured mostly by immuno- In Europe, the parallel spread of PUU and fluorescence assay (IFA) and/or enzyme-linked HTN (or HTN-like) viruses has been noted in immunosorbent assay (ELISA) both for PUU and such countries as Belgium and the Netherlands HTN, were 6% for Finland (8), 8% for Sweden (9), (11,20), Germany (10), and European Russia 1.7% for Germany (10), 0.9% for the Netherlands (21). A partial explanation could be that the (11), 1.6% for Belgium (12), <1% for France (4), HTN-like infection is due to serologic cross- 0.3% for Spain (13) and 4.0% for Greece (6). Most reaction with SEO. The wild rat is the only of the PUU infections were subclinical. A study hantavirus reservoir with a worldwide distri- comparing nephropathia epidemica incidence bution (22), including Europe, and SEO infections (recorded over 14 years) with IgG IFA PUU- are probably underestimated. The first docu- antibody prevalence in an area of Sweden with mented hantavirus disease in Portugal was an high rates of endemic disease found that the HTN-like infection with acute renal failure and antibody prevalence rate for men and women in icterus (23). In Portugal Clethrionomys glareolus the oldest age groups (>60 years) was 14 to 20 is not prevalent, but hantavirus-seropositive times higher, respectively, than the accumulated wild rats have been documented (24). Sixteen life-risk of being hospitalized with nephropathia cases of acute disease, mostly with acute renal epidemica (14). Thus, hospital admissions for the failure and reacting almost exclusively in IFA disease are only the tip of the iceberg. against a SEO strain (R22VP30), have been In nephropathia epidemica, acute renal failure described in North Ireland (25), another country serum creatinine values peak above 4.5 mg (>400 where C. glareolus is not prevalent, but the most mol/L) in only one-third of the cases (15). Early important hantavirus vector seems to be the wild thrombocytopenia, however, is present in 75% of rat (26). In France, three SEO-induced cases of the cases. Eye symptoms, and particularly acute acute renal failure have been reported south of myopia, are rare (25%) but distinctive first symp- the PUU-endemic region, from rural areas where toms of PUU infections. Mild transient hepatitis the rat is an agricultural pest (4). Moreover, 14 is frequent (40%), but icterus is rare (7%) (15). SEO-like cases were detected between December Noncardiogenic pulmonary edema, the hallmark 1991 and February 1992 in the Tula region (300 of Sin Nombre (or Sin Nombre-like)-induced km south of Moscow) and confirmed by plaque hantavirus disease in the New World, has been reduction neutralization tests and positive virus described in a milder, nonlethal form (acute lung isolation in three of the cases (27); these cases are injury) in some rare European PUU (and Seoul awaiting further confirmation. [SEO] virus) cases (16,17). An often overlooked fact is that hantavirus has In the former Soviet Union, hantavirus been transmitted from laboratory rats to animal disease has been recognized since 1934 and keepers first in Belgium (1979) and later in France, officially registered since 1978. Seroprevalence in the United Kingdom, and in the Netherlands studies carried out by IFA or direct blocking (28). In the earlier days, these rat-transmitted radioimmunoassay involving 115,765 persons infections were described as HTN-like by IFA or Emerging Infectious Diseases 206 Vol. 3, No. 2, April–June 1997 1st International Conference on Emerging Zoonoses Jerusalem, Israel ELISA because of cross-reactions with the proto- throughout the Balkans and that easily type screening antigen HTN 76-118, but they were accessible serologic tests are needed to permit a later confirmed as SEO-like by ELISA and blocking differential diagnosis, given the totally different ELISA (20). Because of the now established close prognosis for each infection. Moreover, prelimi- relationship between each hantavirus serotype nary evidence implicated a fourth serotype, i.e., and its rodent vector, these earlier laboratory SEO, spread by wild rats (Rattus norvegicus or infections can all be regarded as SEO-induced. Rattus rattus). Severe hantavirus disease, apparently due to SEO, was documented in 1992 in a Cana- The Balkans: A Complicated Situation dian soldier (37) and later in 1996 in a British In the Balkans, and particularly the former soldier (17), both stationed in Bosnia. These two Yugoslavia, outbreaks of hantavirus disease have patients are clinically interesting, in that the been recorded since the early 1950s, often with a former had a clear exposure to wild rats inside an death rate of 5% to 10% or even higher (29). The infested building, whereas the latter had acute elevated rates of illness and death in early renal failure and hemodynamically documented reports suggested the spread of one (or several) acute lung injury, a complication hitherto undocu- hantaviral strains, in addition to the mild PUU mented in SEO cases (38).