The earliest recorded case of lepromatous leprosy in continental Croatia

Highlights

• Two C10th–11th individuals from mainland Croatia exhibit changes compatible with lepromatous leprosy.

• Molecular analysis confirmed Mycobacterium leprae ancient DNA in the older individual.

• Leprosy in mainland Croatia probably spread from Hungary rather than Dalmatia due to geographical barriers.

Abstract

Among 89 skulls from the Bijelo Brdo site in mainland Croatia dated between the 10th and 11th centuries, two show osteological features characteristic for lepromatous leprosy. Both skulls have female traits. An adult individual exhibits inflammatory changes on the palatine process, the alveolar process of the maxilla, the inferior nasal aperture, and on the anterior nasal spine. A younger individual, between 15 and 17 years at the time of death, exhibits less pronounced changes on the inferior nasal aperture, and the anterior nasal spine. Differential diagnosis excluded fungal infections (aspergillosis, mucormycosis), bacterial infections (actinomycosis, tuberculosis), and granulomatous disorders (sarcoidosis, and treponemal diseases). Molecular genetic analysis targeting the repetitive elements RLEP (37 copies/cell) and RepLep (15 copies/cell) of the M. leprae genome confirmed the presence of the disease in the adult individual. The possible geography of the spread of this infectious disease in Croatia is discussed.

Introduction

Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae with different clinical manifestations. Depending on the immune response of the host it varies from the relatively mild (tuberculoid) form, through one or more intermediate stages to the very severe (lepromatous) stage (Ortner and Putschar, 1985; Renault and Ernst, 2015). The infection usually involves the skin, mucous membranes, soft tissues, and nerves, while skeletal involvement is present in 3–5% of patients (Resnick and Niwayama, 1995). This is generally in the lepromatous form of the disease, indicating a less effective host immune system (Roberts and Manchester, 2005). The mostly frequently affected skeletal elements are the face and the small bones of the hands and feet (Ortner and Putschar, 1985).

Cases of lepromatous leprosy have occasionally been recorded in prehistoric and antique series (Molto, 2002; Mariotti et al., 2005; Robbins et al., 2009; Köhler et al., 2017), but the vast majority of cases in Europe occurred during the Medieval period. Cases are reported from Italy (Belcastro et al., 2005; Rubini and Zaio, 2009; Rubini et al., 2012), Portugal (Antunes-Ferreira et al., 2013), Hungary (Pálfi, 1991; Marcsik et al., 2002; Pálfi et al., 2002; Donoghue et al., 2015), the Czech Republic (Strouhal et al., 2002; Likovsky et al., 2006), Scandinavia (Andersen, 1969; Arcini, 1999; Boldsen, 2005; Boldsen and Mollerup, 2006), and the United Kingdom (Manchester, 1981; Roberts, 1986, Roberts, 2002; Farley and Manchester, 1989; Taylor et al., 2000; Rawcliffe, 2006).

Four cases, dated to the period between the 8th–9th centuries CE have been recorded in Croatia (Šlaus, 2006). They originated from the medieval Radašinovci cemetery located in the hinterland of the Adriatic coast (Adamić and Šlaus, 2016) and in all four cases the presence of leprosy was confirmed by aDNA analysis (Watson et al., 2009). The osteological presence of leprosy in Croatia coincides well with the first historically documented mention of the disease in 804 CE when bishop St. Donatus brought the relics of St. Anastasia to Zadar from Constantinople. According to legend, numerous lepers from Zadar and the surrounding area were miraculously cured of the disease during the procession of these relics (Jeren, 2005). How accurately medieval chroniclers were able to diagnose leprosy is obviously debatable, but it is interesting that the first historical mention of the disease is contemporaneous with molecular-genetic and skeletal evidence for its presence in Croatia.

As in other parts of Europe, leprosy was widespread in southern Croatia (Dalmatia) between the 10th and 14th centuries (Jeren, 2005). The first leprosarium was established in Dubrovnik (Ragusa) in 1272 with the town statute of that same year expressly prohibiting sheltering lepers within city walls. Additional edicts in this statute dealt with sewage and waste disposal, and the expulsion of tanneries from the city. The tanneries were moved into areas previously inhabited by lepers so that they, in turn, were forced either into the leprosarium, or into more inhospitable areas away from the city (Bakić, 2011). Subsequently, leprosaria were founded in numerous other Eastern Adriatic communities including Trogir (1322), Split (1332), Zadar (1417), Ston (1449), and Šibenik (1467) (Bakija-Konsuo and Mulić, 2009; Bakić, 2011). The last leprosarium in Croatia was founded in 1905 in the Metković area in order to accommodate lepers from Dalmatia in times when leprosy was no longer considered to be a priority or a danger to local communities. The site may have been chosen because of its proximity to Bosnia and Herzegovina that may have harboured an endemic focus of the disease (Wokaunn et al., 2006).

In contrast to the relative abundance of historical data available for Dalmatia, historical sources mentioning leprosy and leprosaria in continental Croatia are infrequent. Only three leprosaria from this part of Croatia are mentioned in historical documents: Zagreb, Čazma and Oborovo (Ćepulić, 1942; Karbić, 1991). A property document from Prevlaka (near Oborovo) dating from 1347 mentions “A ship of lepers” on the Sava River where local lepers were isolated. Prevlaka belonged to the Order of Hospitallers whose purpose, among others, was to provide health care and in that context Dobronić suggested they provided care for the lepers in the ship on the Sava River (Belaj, 2007; Dobronić, 1984). There are no other historical sources that mention leprosy in continental Croatia. Consequently, the two Bijelo Brdo skulls discussed in this paper represent the earliest examples of lepromatous leprosy in this part of Croatia.

Bijelo Brdo is located 16 km east of Osijek, and is one of the most important archaeological sites in continental Croatia (Fig. 1). It is characterized by the presence of a material culture from the Bronze Age and two medieval cemeteries: an Avaro-Slav cemetery (Bijelo Brdo I) and the Bijelo Brdo culture cemetery (Bijelo Brdo II). The site name later became eponymous for the whole culture.

The Bijelo Brdo culture existed from the second half of the 10th century to the beginning of the 12th century. This was a multiethnic culture covering an area that includes modern Slovakia, Hungary, Slovenia, continental Croatia, north Serbia, and western Romania. In archaeological terms its main features are skeletal burials arranged in more or less parallel rows in cemeteries without churches, and various material artefacts with similar traits. In terms of subsistence strategy the culture was characterized by small villages practicing a rural and sedentary way of life based on agriculture (Demo, 2009).

Excavation of the Bijelo Brdo II horizon lasted from 1895 to 1907 and revealed the presence of 236 graves. The graves were oriented west-east, with the heads of the diseased positioned to the west (Brunšmid, 1903/4). According to the varied and rich grave goods (jewellery, pendants, buttons, knifes, and coins) the cemetery is dated from approximately 965 to 1061 CE (Tomičić, 2006). Unfortunately, as was the custom of the time, the osteological material was selectively collected. Only 89 skulls (36 male, 39 female and 14 subadults) were taken, and are currently curated at the Archaeological Museum in Zagreb, and the Croatian Natural History Museum in Zagreb. Previous studies carried out on this material report on the craniometric features of the series (Pilarić, 1968; Pilarić and Schwidetzky, 1987), and on various dental characteristics (Kranjčić et al., 2012; Vodanović et al., 2004, Vodanović et al., 2005, Vodanović et al., 2006, Vodanović et al., 2007). We were granted access to these skulls in 2013 when a detailed paleopathological analysis of the material was undertaken.