Life and death of a leprosy sufferer from the 8th-century-CE cemetery of Kiskundorozsma-Kettoshatár I (Duna-Tisza Interfluve, Hungary)-Biological and social consequences of having Hansen's disease in a late Avar Age population from Hungary.

The aim of our paper is to demonstrate a middle-aged male (KK61) from the 8th-century-CE cemetery of Kiskundorozsma-Kettoshatár I (Duna-Tisza Interfluve, Hungary), who appears to represent the lepromatous form of Hansen's disease. Leprosy has affected not only the rhinomaxillary region of his face but also his lower limbs, with severe deformation and disfigurement of the involved anatomical areas (saddle-nose and flat-foot deformity, respectively). Consequently, he would have experienced disability in performing the basic activities of daily living, such as eating, drinking, standing or walking; and thus, he would have required regular and substantial care from others to survive. Despite his very visible disease and associated debility, it seems that KK61 was accepted as a member of the community in death, since he has been buried within the cemetery boundaries, among others from his community. In addition, his grave has conformed to the mortuary practices characteristic of the Kiskundorozsma-Kettoshatár I cemetery (e.g., burial orientation, position of the body in the grave, and type and quantity of accompanying grave goods). Although distinction or segregation in life do not preclude normative treatment in death, the long-lasting survival of KK61 with Hansen's disease implies that he would not have been abandoned but cared for by others. KK61 is one of the few published historic cases with leprosy from the Avar Age of the Hungarian Duna-Tisza Interfluve. His case gives us a unique insight into the biological consequences of living with Hansen's disease and illustrates the social attitude toward leprosy sufferers in early mediaeval Hungary.

Ancient and modern pathologies and therapies: St. Gallicanus Hospital in Rome between the 18th and 20th centuries.

St. Gallicanus Hospital in Rome, Italy, created by the will of Pope Benedict XIII (1649-1730) in 1725, was the first dermatologic hospital in the world. The strong bond between science and faith, humanitarian spirit and scientific research, and the profoundness and legacy of its entire history have all contributed to its legacy. We have traced its development by examining archival documents to understand the life of the institute and the diseases that were diagnosed and treated from the 18th century to the first half of the 20th century. Some of the main diseases were leprosy, mange, scabies, ringworm, and syphilis, which were widespread in Rome during the 18th and 19th centuries and were creating a mortal threat for much of the population. St. Gallicanus Hospital was dedicated to the diagnosis, treatment, and prevention of these diseases where possible. Special attention has been directed to syphilis and the use of penicillin therapy after its introduction in 1943, especially for curbing the extensive problems created by prostitution.

Leprosy in medieval Denmark: Exploring life histories through a multi-tissue and multi-isotopic approach.

OBJECTIVES: By focusing on two Danish leprosaria (Naestved and Odense; 13th-16th c. CE) and using diet and origin as proxies, we follow a multi-isotopic approach to reconstruct life histories of patients and investigate how leprosy affected both institutionalized individuals and the medieval Danish community as a whole. MATERIALS AND METHODS: We combine archaeology, historical sources, biological anthropology, isotopic analyses (δ13 C, δ15 N, δ34 S, 87 Sr/86 Sr) and radiocarbon dating, and further analyze bones with different turnover rates (ribs and long bones). RESULTS: The δ13 C, δ15 N and δ34 S results indicate a C3 terrestrial diet with small contributions of marine protein for leprosy patients and individuals from other medieval Danish sites. A similar diet is seen through time, between males and females, and patients with and without changes on facial bones. The isotopic comparison between ribs and long bones reveals no significant dietary change. The δ34 S and 87 Sr/86 Sr results suggest that patients were local to the regions of the leprosaria. Moreover, the radiocarbon dates show a mere 50% agreement with the arm position dating method used in Denmark. CONCLUSIONS: A local origin for the leprosy patients is in line with historical evidence, unlike the small dietary contribution of marine protein. Although only 10% of the analyzed individuals have rib/long bone offsets that undoubtedly show a dietary shift, the data appear to reveal a pattern for 25 individuals (out of 50), with elevated δ13 C and/or δ15 N values in the ribs compared to the long bones, which points toward a communal type of diet and reveals organizational aspects of the institution.

Human major infections: Tuberculosis, treponematoses, leprosy-A paleopathological perspective of their evolution.

The key to evolution is reproduction. Pathogens can either kill the human host or can invade the host without causing death, thus ensuring their own survival, reproduction and spread. Tuberculosis, treponematoses and leprosy are widespread chronic infectious diseases whereby the host is not immediately killed. These diseases are examples of the co-evolution of host and pathogen. They can be well studied as the paleopathological record is extensive, spanning over 200 human generations. The paleopathology of each disease has been well documented in the form of published synthetic analyses recording each known case and case frequencies in the samples they were derived from. Here the data from these synthetic analyses were re-analysed to show changes in the prevalence of each disease over time. A total of 69,379 skeletons are included in this study. There was ultimately a decline in the prevalence of each disease over time, this decline was statistically significant (Chi-squared, p<0.001). A trend may start with the increase in the disease's prevalence before the prevalence declines, in tuberculosis the decline is monotonic. Increase in skeletal changes resulting from the respective diseases appears in the initial period of host-disease contact, followed by a decline resulting from co-adaptation that is mutually beneficial for the disease (spread and maintenance of pathogen) and host (less pathological reactions to the infection). Eventually either the host may become immune or tolerant, or the pathogen tends to be commensalic rather than parasitic.

Learning from the past in the COVID-19 era: rediscovery of quarantine, previous pandemics, origin of hospitals and national healthcare systems, and ethics in medicine.

After the dramatic coronavirus outbreak at the end of 2019 in Wuhan, Hubei province, China, on 11 March 2020, a pandemic was declared by the WHO. Most countries worldwide imposed a quarantine or lockdown to their citizens, in an attempt to prevent uncontrolled infection from spreading. Historically, quarantine is the 40-day period of forced isolation to prevent the spread of an infectious disease. In this educational paper, a historical overview from the sacred temples of ancient Greece-the cradle of medicine-to modern hospitals, along with the conceive of healthcare systems, is provided. A few foods for thought as to the conflict between ethics in medicine and shortage of personnel and financial resources in the coronavirus disease 2019 era are offered as well.

Genoa and leprosy: from the Middle Ages to the present.

During the Middle Ages, leprosy sufferers could not live in the city and were forced outside the walls. In the centuries, the Genoese area dedicated several hospitals to lepers, such as S. Lazzaro and Pammatone Hospital, a small leprosarium in the Tigullio area and San Martino Hospital from 1935. The first doctor who recognized to cure leprosy in Genoa was Goffredo, who later was also nominated rector of the community. In the early 1900's, Radaeli promoted the construction of a leprosarium behind the San Martino hospital. In 1936 Giuseppe Mariani was known for using the leprosarium to hide Italian Jews during deportation to the extermination camps. Later, Professor Aldo Baccaredda-Boy instituted the graduate school in "Leprosy and Tropical Dermatology", continued by professor Enrico Nunzi until 1990. The leprosarium was then transformed into the Department of Tropical Dermatology and finally into the Operative Unit of Social Dermatology, a national reference center.

Commingled crypts: Comparative health among Byzantine monastics in the Levant.

OBJECTIVES: Early Byzantine (A.D. 330-842) monastic rules stipulated that entrants relinquished familial connections, personal belongings and secular relationships to become part of the ascetic collective that continued in death, resulting in bioarchaeological marginalization, as was the case of the monastics excavated from the Chapel of Robebus at Mount Nebo, Jordan (ca. A.D. 491-640). It was hypothesized that compared to contemporary monastic groups, the Mount Nebo monastics experienced poorer health and gravitated to Mount Nebo, owing to its association with the Prophet Moses and proximity to the Dead Sea, Livias baths and Jordan River, all associated with curative benefits, especially for those suffering from leprosy. MATERIALS AND METHODS: The commingled remains of 73 adult males from Mount Nebo and the articulated skeletons (n = 27) from the Sanctuary of Agios Lot at Deir 'Ain 'Abata (Jordan) were assessed for paleopathology, then compared with a contemporary commingled group from the Monastery of Saint Euthymius at Khan-el-Ahmar (Judean Desert) (n = 117). RESULTS: No skeletal evidence of leprosy was observed among the groups. Most Mount Nebo individuals did not reach an older age, yet injuries, severe osteoarthritis, lower leg osteoperiostitis and antemortem tooth loss were common. The paleopathological profile was similar at Deir 'Ain 'Abata, but paleopathology was negligible at Khan-el-Ahmar. CONCLUSIONS: The similar paleopathological profiles of the Jordanian monastic groups suggest that the proximity to the Dead Sea may have attracted monastics to both sites, in addition to spirituality, but leprosy was not a factor based on the skeletal evidence.

Osteoarcheological and biomolecular evidence of leprosy from an 11-13th century CE Muslim cemetery in Europe (Orosháza, Southeast Hungary).

Orosháza site no. 10 (Southeast Hungary) contains the partially excavated archaeological remains of an 11-13th century CE Muslim merchant village and its cemetery located in close proximity to Christian villages of the same era. The skeleton of a young woman (grave no. 16) from the last phase of the cemetery use was identified with rhinomaxillary lesions associated with lepromatous leprosy. The right parietal bone also exhibited signs of cranial trauma, possibly caused by symbolic trepanation, a well-known ritual practice in the 9-11th century CE Carpathian Basin. The retrospective diagnosis of the disease was supported by ancient DNA analysis, as the samples were positive for Mycobacterium leprae aDNA, shown to be of genotype 3. Contrary to the general practice of the era, the body of the young female with severe signs of leprosy was interred among the regular graves of the Muslim cemetery in Orosháza, which may reflect the unique cultural background of the community.

Mal de Meleda: A great imitator.

Mal de Meleda is an hereditary palmoplantar keratoderma named for the Mljet Island in Croatia. The lives of those affected by this disease represent a complex situation that encompasses members of a vulnerable group. They require enlightenment and should be approached with awareness, taking into account their overall psychophysical status and the environment of each patient. Those afflicted with Mal de Meleda not only have to deal with a difficult life due to their affliction, but they also must cope with the hardships of socialization while trying to realize a normal life within their island community. This is compounded by the frequent interviews and examinations of researchers interested in the various aspects of their illness. The subject of this contribution is not about the nature of this disease, rather about the traces it has left on the (sub)consciousness of the population. It is also concerned with exploring ways of how to access patients and understanding the depth of their vulnerability. We present some thoughts tied to the interpersonal experiences of researchers and patients afflicted with Mal de Meleda.

Revisiting the tuberculosis and leprosy cross-immunity hypothesis: Expanding the dialogue between immunology and paleopathology.

OBJECTIVE: Our primary objective is to re-visit the tuberculosis and leprosy cross-immunity. hypothesis through the careful integration of immunology and paleopathology. METHODS: Using an integrated theoretical analysis that evaluates clinical literature on human innate immunological responses, paleomicrobiology, bioarchaeology, and paleopathology, we develop a multifactorial model. RESULTS: Past populations do not represent homogeneous immunological landscapes, and therefore it is likely that leprosy in Medieval Europe did not uniformly decline due to cross-immunity. CONCLUSIONS: We recommend that bioarchaeological reconstructions of past disease experience take into consideration models that include variation in immune function based on past environments and social contexts. This provides a unique opportunity to conduct comprehensive analyses on complex immunological processes. SIGNIFICANCE: Extrapolating results from experimental immunology to larger populations elucidates complexities of disease cross-immunity and highlights the importance of synthesizing archaeological, social, paleopathological and biological data as a means of understanding disease in the past. LIMITATIONS: All extrapolations from data produced from in vitro studies to past populations, using living donors, pose significant limitations where, among other factors, the full reconstruction of past environmental and social contexts can frequently be sparse or incomplete. SUGGESTIONS FOR FUTURE RESEARCH: To reduce the limitations of integrating experimental immunology with bioarchaeological reconstructions (i.e. how to use skeletal samples to reconstruct inflammatory phenotypes), we propose that osteoimmunology, or the study of the interplay between immune cells and bone cells, should be considered a vital discipline and perhaps the foundation for the expansion of paleoimmunology.

Tuberculosis and leprosy associated with historical human population movements in Europe and beyond - an overview based on mycobacterial ancient DNA.

Context: Tuberculosis and leprosy are readily recognised in human remains due to their typical palaeopathology. Both Mycobacterium tuberculosis (MTB) and Mycobacterium leprae (ML) are obligate pathogens and have been detected in ancient human populations. Objective: To demonstrate historical tuberculosis and leprosy cases in Europe and beyond using molecular methods, as human populations are associated with different mycobacterial genotypes. Methods: MTB and ML ancient DNA (aDNA) has been detected by DNA amplification using PCR, or by whole genome sequencing. Mycobacterial cell wall lipids also provide specific markers for identification. Results: In 18th century Hungary, the European indigenous MTB genotype 4 strains have been found. However, many individuals were co-infected with up to three MTB sub-genotypes. In 8th-14th century Europe significant differences in ML genotypes were found between northwest Europe compared with central, southern, or eastern Europe. In addition, several co-infections of MTB and ML were detected in historical samples. Conclusion: Both MTB and ML strain types differ between geographically separate populations. This is associated with ancient human migration after an evolutionary bottleneck and clonal expansion. The absence of indigenous leprosy in Europe today may be due to the greater mortality of tuberculosis in individuals who are co-infected with both organisms.

Impact of urbanization on tuberculosis and leprosy prevalence in medieval Denmark.

The consequences of urbanization, such as increased exposure to pathogens, have long been considered detrimental to human health. During the first half of the Danish medieval period, towns were established and throughout the period population increased. The following study analyzes the relationship between urbanization and disease frequency - specifically leprosy and tuberculosis - in four skeletal samples from medieval Denmark using a paleoepidemiological approach. Skeletons from two urban sites (Ole Wormsgade and Ribe Grey Friary) and two rural sites (Øm Kloster and Sejet), all located in the Jutland region of Denmark, were selected for this analysis (n = 204). All skeletons included date to the middle part of the Danish medieval period (AD 1200-1400). Six skeletal leprosy indicators and six skeletal tuberculosis indicators were analyzed, and disease frequencies in the samples were estimated using a probabilistic approach based on lesion sensitivity and specificity. The effect of tuberculosis on survival in urban and rural samples was evaluated using Kaplan-Meier survival analyses. The frequency of leprosy at death varied between four and 19 percent among the four cemeteries with Ole Wormsgade having the highest frequency. The estimated frequency of tuberculosis at death varied between 39 and 69 percent. Here, Sejet cemetery had the highest frequency. There were significant differences in survival for those with and without tuberculosis-related lesions between sites, but there were no significant differences between urban and rural sites. The analyses presented in this paper suggest that disease prevalence in skeletal samples cannot be sufficiently explained by urbanization alone; rather, there are likely other biological and behavioral sources of heterogeneity that are contributing factors to past disease experience.

Investigating dietary patterns and organisational structure by using stable isotope analysis: a pilot study of the Danish medieval leprosy hospital at Næstved.

During the 12th and 13th centuries, numerous leprosy hospitals were founded in Europe. Given that leprosy was not considered infectious, this may reflect social dimensions of the disease. Aiming at exploring the impact of leprosy on medieval people and the organisation of the Danish leprosarium at Næstved, we reconstructed the diet of twenty patients using stable isotopes, and compared our results with relevant historical data. The isotope results revealed a terrestrial C3 diet with a small contribution of aquatic foods. Contrary to historical evidence of daily fish consumption in the leprosy hospital, only six individuals consumed relatively large amounts of freshwater fish. Leprosaria have been considered monastic institutions, and thus a varied diet, poor in aquatic protein, questions the monastic nature of the hospital and points to a social stratification. A multi-isotope analysis of a larger sample set would add to our understanding of the diet of the leprosy patients, as well as their treatment in the leprosarium.

Leprosy at the edge of Europe-Biomolecular, isotopic and osteoarchaeological findings from medieval Ireland.

Relatively little is known of leprosy in Medieval Ireland; as an island located at the far west of Europe it has the potential to provide interesting insights in relation to the historical epidemiology of the disease. To this end the study focuses on five cases of probable leprosy identified in human skeletal remains excavated from inhumation burials. Three of the individuals derived from the cemetery of St Michael Le Pole, Golden Lane, Dublin, while single examples were also identified from Ardreigh, Co. Kildare, and St Patrick's Church, Armoy, Co. Antrim. The individuals were radiocarbon dated and examined biomolecularly for evidence of either of the causative pathogens, M. leprae or M. lepromatosis. Oxygen and strontium isotopes were measured in tooth enamel and rib samples to determine where the individuals had spent their formative years and to ascertain if they had undertaken any recent migrations. We detected M. leprae DNA in the three Golden Lane cases but not in the probable cases from either Ardreigh Co. Kildare or Armoy, Co. Antrim. M. lepromatosis was not detected in any of the burals. DNA preservation was sufficiently robust to allow genotyping of M. leprae strains in two of the Golden Lane burials, SkCXCV (12-13th century) and SkCCXXX (11-13th century). These strains were found to belong on different lineages of the M. leprae phylogenetic tree, namely branches 3 and 2 respectively. Whole genome sequencing was also attempted on these two isolates with a view to gaining further information but poor genome coverage precluded phylogenetic analysis. Data from the biomolecular study was combined with osteological, isotopic and radiocarbon dating to provide a comprehensive and multidisciplinary study of the Irish cases. Strontium and oxygen isotopic analysis indicate that two of the individuals from Golden Lane (SkCXLVIII (10-11th century) and SkCXCV) were of Scandinavian origin, while SkCCXXX may have spent his childhood in the north of Ireland or central Britain. We propose that the Vikings were responsible for introducing leprosy to Ireland. This work adds to our knowledge of the likely origins of leprosy in Medieval Ireland and will hopefully stimulate further research into the history and spread of this ancient disease across the world.

Ancient genomes reveal a high diversity of Mycobacterium leprae in medieval Europe.

Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae, the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M. leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M. leprae genomes including the so far oldest M. leprae genome from one of the earliest known cases of leprosy in the United Kingdom-a skeleton from the Great Chesterford cemetery with a calibrated age of 415-545 C.E. This dataset provides a genetic time transect of M. leprae diversity in Europe over the past 1500 years. We find M. leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M. leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M. leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M. leprae strains improves understanding the history of leprosy worldwide.