Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years.

Tuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at the worldwide scale, yet the mode and tempo of TB pressure on humans remain unknown. The recent discovery that homozygotes for the P1104A polymorphism of TYK2 are at higher risk to develop clinical forms of TB provided the first evidence of a common, monogenic predisposition to TB, offering a unique opportunity to inform on human co-evolution with a deadly pathogen. Here, we investigate the history of human exposure to TB by determining the evolutionary trajectory of the TYK2 P1104A variant in Europe, where TB is considered to be the deadliest documented infectious disease. Leveraging a large dataset of 1,013 ancient human genomes and using an approximate Bayesian computation approach, we find that the P1104A variant originated in the common ancestors of West Eurasians ∼30,000 years ago. Furthermore, we show that, following large-scale population movements of Anatolian Neolithic farmers and Eurasian steppe herders into Europe, P1104A has markedly fluctuated in frequency over the last 10,000 years of European history, with a dramatic decrease in frequency after the Bronze Age. Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia.

Sex-based tuberculosis mortality in Newfoundland, 1900-1949: Implications for populations in transition.

OBJECTIVE: During the second epidemiological transition, tuberculosis (TB) is one disease that declined substantially enough to reduce all-cause mortality. Sex-based differences in TB mortality may reveal an important dimension of population health transitions between the urbanizing and rural regions of Newfoundland. MATERIALS AND METHODS: For the island of Newfoundland, yearly age-standardized sex-based TB mortality rates were calculated using individual death records from 1900 to 1949 (n = 30 393). Multiple linear regression models predict the relative rates (RR) of sex-based mortality and the absolute difference between males and females while controlling for time and region (the urbanizing Avalon Peninsula or rural Newfoundland). Multiple linear regression models also predict the median age at death from TB while controlling for time, region, and sex to assess if TB was shifting to an older adult disease compared to those typically afflicted in ages 20-44. RESULTS: Female TB mortality was relatively and absolutely higher than males; additionally, RR and absolute differences between male and female mortality were significantly lower in rural Newfoundland than the Avalon Peninsula. Median age at death for males was significantly higher than females, and differences in median age at death increased over time. DISCUSSION: The historically high prevalence of TB throughout Newfoundland, including domestic, social, and public health responsibilities of women, likely contributed to increased exposure and transmission, leading to higher observed mortality. Sex-based TB outcomes should be considered in the discussion of the progression of the epidemiological transition as dynamic inequalities that do not necessarily fit contemporary generalizations of sex-based TB epidemiology.

Tuberculosis: the sanatorium season in the early 20th century.

The creation of hospitals providing specialist care is not a prerogative of our time. As the world wonders how to cope with new pandemics and the age-old problems of the transmission of infections and the isolation of the sick, while the COVID-19 pandemic has been raging, it might be worth glancing back at the period - just over a century ago - when sanatoriums were set up in Italy as part of the fight against consumption.

The 1918 influenza pandemic did not accelerate tuberculosis mortality decline in early-20th century Newfoundland: Investigating historical and social explanations.

OBJECTIVES: The selective mortality hypothesis of tuberculosis after the 1918 influenza pandemic, laid out by Noymer and colleagues, suggests that acute exposure or pre-existing infection with tuberculosis (TB) increased the probability of pneumonia and influenza (P&I) mortality during the 1918 influenza pandemic, leading to a hastened decline of TB mortality in post-pandemic years. This study describes cultural determinants of the post-pandemic TB mortality patterns in Newfoundland and evaluates whether there is support for this observation. MATERIALS AND METHODS: Death records and historical documents from the Provincial Archives of Newfoundland and Labrador were used to calculate age-standardized island-wide and sex-based TB mortality, as well as region-level TB mortality, for 1900-1939. The Joinpoint Regression Program (version 4.8.0.1) was used to estimate statistically significant changes in mortality rates. RESULTS: Island-wide, females had consistently higher TB mortality for the duration of the study period and a significant shift to lower TB mortality beginning in 1928. There was no similar predicted significant decline for males. On the regional level, no models predicted a significant decline after the 1918 influenza pandemic, except for the West, where significant decline was predicted in the late-1930s. DISCUSSION: Although there was no significant decline in TB mortality observed immediately post-pandemic, as has been shown for other Western nations, the female post-pandemic pattern suggests a decline much later. The general lack of significant decrease in TB mortality rate is likely due to Newfoundland's poor nutrition and lack of centralized healthcare rather than a biological interaction between P&I and TB.

Anton Ghon and His Colleagues and Their Studies of the Primary Focus and Complex of Tuberculosis Infection and Their Relevance for the Twenty-First Century.

Anton Ghon is well known in the field of childhood tuberculosis, and the tuberculosis primary focus and complex are frequently called the Ghon focus and complex; this is largely the result of the wide publication of the English translation of his monograph "Der primäre Lungenherd bei der Tuberkulose der Kinder." Ghon's studies are frequently quoted, but precise details of his monograph are neglected, his results often misquoted, and his later publications virtually unknown. This review highlights aspects of Ghon's anatomical pathology studies in children and adults not necessarily dying of tuberculosis but with signs of tuberculosis infection. Ghon found a single primary tuberculosis focus in approximately 80% of tuberculosis-infected children situated close to the pleura in two-thirds of cases. Cavitation of the focus was common, and lymphatic spread involved lymph nodes in the abdomen and neck in many children. Studies amongst adults and children frequently found the healed primary tuberculosis focus to be completely calcified without histological signs of tuberculosis activity; however, particularly in the presence of pulmonary tuberculosis, histological signs of tuberculosis activity were often found in the lymph nodes of the angulus venosus, despite apparent healing with extensive calcification. Both earlier studies and more recent investigations, with molecular biological tools, unavailable to Ghon and earlier researchers, have confirmed the presence of viable mycobacteria in apparently normal or healed thoracic nodes and also found molecular biological indications of viable mycobacteria in these nodes. As suggested by Ghon, lympho-haematogenous spread of tuberculosis may be more common than is usually appreciated.

Research on Tuberculosis in Nazi Germany and the Cruelest Medical Experiments on Jewish Children: An Observational Review.

BACKGROUND: Germany was a scientifically advanced country in the 19th and early 20th centuries, particularly in medicine, with a major interest in research and the treatment of tuberculosis. From 1933 until 1945, Nazi Germany perverted scientific research through criminal experimentations on captured prisoners of war and on "subhumans" by scientifically untrained, but politically driven, staff. This article exposes a series of failed experiments on tuberculosis in adults, experiments without scientific validity. Nonetheless, Dr. Kurt Heißmeyer repeated the experiment on Jewish children, who were murdered for the sake of personal academic ambition. It is now 75 years since liberation and the murdered children must be remembered. This observational review raises questions of medical and ethical values.

Against settler colonial iatrogenesis: Inuit resistance to treatment in Indian Hospitals in Canada.

Canada's program to examine, transfer and treat Indigenous and Inuit peoples with tuberculosis in Indian Hospitals (ca. 1936 and 1969) has generally been framed by official narratives of population health, benevolence, and care. However, letters written by Inuit patients in Indian hospitals and their kin, and which were addressed to government officials and translated by government employees, challenge this assumption. By focusing on the harmful effects of the segregation and long-term detainment of Inuit peoples away from their communities, the letters theorize TB treatment as multiply harmful and iatrogenic. The letters also showcase how Inuit peoples resisted Indian Hospital treatment and articulated the need for care and treatment to occur within a network of intimate relations, rather than in distant sanatoriums.

"1984": What Orwell could not predict. Proteomic analysis of his scripts.

George Orwell, fighter for the Republican Army during the Spanish Civil War, was shot through the throat by a sniper on 20th May 1937 and nearly killed. After receiving only a summary external treatment, on the 29th, he was cured in a Barcelona hospital where he was infected by the Koch bacillus. After fleeing from Spain on 23rd June 1937, he repaired to his cottage in Wallington, Hertfordshire, wherefrom he wrote a letter to Sergey Dynamov, Editor of Soviet journal "Foreign Literature." This typewritten letter was analyzed by application of five EVA strips (ethylene vinyl acetate studded with strong cation and anion and with C8 and C18 resins; four on the corners and one over his signature), searching for biological traces. Upon elution of the captured biologicals, trypsin digestion and Orbitrap Fusion trihybrid mass spectrometer analyses, three of the five strips yielded clear traces of six unique proteins (via proteotypic peptides) of the tuberculosis bacterium. Additionally, MALDI TOF analysis of saliva of a tuberculosis patient and the EVA strip eluates gave a spectrum of 14 peptide bands (Mr 2700 to 6700 Da range) coincident between the two samples, thus, fully confirming Orwell's pathology. These results are attributed to saliva traces on Orwell's fingertips and to the fact that the letter was written on 2nd July 1937, when Orwell's pathology was at its peak.

Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis.

Modern strains of Mycobacterium tuberculosis from the Americas are closely related to those from Europe, supporting the assumption that human tuberculosis was introduced post-contact. This notion, however, is incompatible with archaeological evidence of pre-contact tuberculosis in the New World. Comparative genomics of modern isolates suggests that M. tuberculosis attained its worldwide distribution following human dispersals out of Africa during the Pleistocene epoch, although this has yet to be confirmed with ancient calibration points. Here we present three 1,000-year-old mycobacterial genomes from Peruvian human skeletons, revealing that a member of the M. tuberculosis complex caused human disease before contact. The ancient strains are distinct from known human-adapted forms and are most closely related to those adapted to seals and sea lions. Two independent dating approaches suggest a most recent common ancestor for the M. tuberculosis complex less than 6,000 years ago, which supports a Holocene dispersal of the disease. Our results implicate sea mammals as having played a role in transmitting the disease to humans across the ocean.

Enhancing relational care through expressions of gratitude: insights from a historical case study of almoner-patient correspondence.

This paper considers insights for contemporary medical practice from an archival study of gratitude in letters exchanged between almoners at London's Brompton Hospital and patients treated at the Hospital's tuberculosis sanatorium in Frimley. In the era before the National Health Service, almoners were responsible for assessing the entitlement of patients to charitable treatment, but they also took on responsibility for aftercare and advising patients on all aspects of welfare. In addition, a major part of the work of almoners at the Brompton was to record the health and employment status of former sanatorium patients for medical research. Of over 6000 patients treated between 1905 and 1963 that were tracked for the purposes of Medical Research Council cohort studies, fewer than 6% were recorded as 'lost to follow-up'-a remarkable testimony to the success of the almoners' strategies for maintaining long-term patient engagement. A longitudinal narrative case study is presented with illustrative examples of types of gratitude extracted from a corpus of over 1500 correspondents' letters. Patients sent money, gifts and stamps in gratitude for treatment received and for the almoners' ongoing interest in their welfare. Textual analysis of letters from the almoner shows the semantic strategies that position gratitude as central to the personalisation of an institutional relationship. The Brompton letters are conceptualised as a Maussian gift-exchange ritual, in which communal ties are created, consolidated and extended through the performance of gratitude. This study implicates gratitude as central to the willingness of former patients to continue to engage with the Hospital, sometimes for decades after treatment. Suggestions are offered for how contemporary relational healthcare might be informed by this unique collection of patients' and almoners' voices.

[125 Years German Central Committee for the Fight against Tuberculosis (DZK)]. / 125 Jahre Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose e. V. (DZK).

The German Central Committee for the Fight against Tuberculosis (DZK) celebrates this year its 125th birthday. On this occasion, the DZK as one of the oldest TB organizations worldwide is looking back on the development during its history and records the results in a comprehensive book, summarized in this article. In the book, the various political changes with their impact on the DZK are mirrored, starting with the German Empire, the Weimar Republic, the so-called "Third Reich", the two German states separated after the Second World War and the current FRG. Tuberculosis (TB) was the dominant widespread disease in the 19th century, today it is the leading infectious disease worldwide. As a consequence of migration, this affects also Germany. After meanwhile - in particular in 2015/16 - risen numbers of new cases (especially of those not born in Germany, which in 2019 accounted for 72 % of all cases), the impact of drug-resistant tuberculosis (in 2019, 11.4 % of all new cases had some resistance (384 cases), including 87 cases of MDR-TB, and of these 8 cases of XDR-TB and 27 cases of pre-XDR-TB), as well as the high proportion (81,5 %) - in 2019 - of open and thus very infectious pulmonary TB among new TB cases in Germany, impressively show that TB continues to be a health problem that should not be underestimated and that is increasingly concentrated in risk groups (socially disadvantaged persons, people from high-prevalence countries, homeless people, drug addicts, alcoholics, HIV-infected persons). The DZK therefore continues to play an important role in TB control as a link between the national and international organizations responsible for combating TB.

Keeping Vaccination Simple: Building French Immunization Schedules, 1959-1999.

This article explores the history of the immunization schedule-a table that orders mandatory and recommended vaccines and their boosters through time. My study focuses on France, from the late 1950s to the 1990s. A couple of conferences at the turn of the 1960s set the parameters for immunization schedules, providing insights into their expected disciplinary functions. In the wake of these conferences, a long series of clinical trials aimed to simplify and rationalize the schedules. These trials were carried out by the International Children's Center (ICC), an institution whose aim transitioned in the mid-1960s from the standardization of the sole vaccine against tuberculosis to the simplification of the expanding immunization device for children. I draw from the ICC's experimental work on schedules to define "simplification" with regard to the notion of standardization.

Prospective Whole-Genome Sequencing in Tuberculosis Outbreak Investigation, France, 2017-2018.

During June 2017-April 2018, active tuberculosis with Beijing SIT1 isolates was diagnosed in 14 persons living in 4 distant cities in France. Whole-genome sequencing indicated that these patients belonged to a single transmission chain. Whole-genome sequencing-based laboratory investigations enabled prompt tracing of linked cases to improve tuberculosis control.

Window Period Prophylaxis for Children Exposed to Tuberculosis, Houston, Texas, USA, 2007-2017.

In this retrospective study, we assessed the safety of window period prophylaxis and proportion of tuberculin skin test (TST) conversions in children <5 years of age who were exposed to an adult with tuberculosis disease during 2007-2017. Children included in this study had unremarkable examination and chest radiograph findings and negative test results for TB infection. In total, 752 children (41% cohabitating with the index patient) received prophylaxis during the window period, usually directly observed therapy with isoniazid. Hepatotoxicity and tuberculosis disease did not develop in any child. TST conversion occurred in 37 (4.9%) children and was associated with the index patient being the child's parent (odds ratio 3.2, 95% CI 1.2-8.2). TST conversion was not associated with sputum smear results, culture positivity, or cohabitation. Thresholds for initiation of window prophylaxis in exposed young children should be low given the safety of medication and difficulties with risk stratification.

Epidemiology of Extrapulmonary Tuberculosis among Inpatients, China, 2008-2017.

We investigated the epidemiology of extrapulmonary tuberculosis (TB) among patients admitted to Beijing Chest Hospital, Beijing, China, during January 2008-December 2017. Of 19,279 hospitalized TB patients, 33.4% (6,433) had extrapulmonary TB and 66.6% (12,846) had pulmonary TB. The most frequent forms of extrapulmonary TB observed were skeletal TB (41.1%) and pleural TB (26.0%). Younger, female patients from rural areas were more likely to have extrapulmonary TB. However, patients with diabetes mellitus were less likely to have extrapulmonary TB compared with patients without diabetes. A higher proportion of multidrug-resistant (MDR) TB was observed among patients with extrapulmonary TB than among patients with pulmonary TB. We observed a large increase in MDR TB, from 17.3% to 35.7%, for pleural TB cases. The increasing rate of drug resistance among extrapulmonary TB cases highlights the need for drug susceptibility testing and the formulation of more effective regimens for extrapulmonary TB treatment.

Bacillus Calmette-Guérin Cases Reported to the National Tuberculosis Surveillance System, United States, 2004-2015.

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is used as a vaccine to protect against disseminated tuberculosis (TB) and as a treatment for bladder cancer. We describe characteristics of US TB patients reported to the National Tuberculosis Surveillance System (NTSS) whose disease was attributed to BCG. We identified 118 BCG cases and 91,065 TB cases reported to NTSS during 2004-2015. Most patients with BCG were US-born (86%), older (median age 75 years), and non-Hispanic white (81%). Only 17% of BCG cases had pulmonary involvement, in contrast with 84% of TB cases. Epidemiologic features of BCG cases differed from TB cases. Clinicians can use clinical history to discern probable BCG cases from TB cases, enabling optimal clinical management. Public health agencies can use this information to quickly identify probable BCG cases to avoid inappropriately reporting BCG cases to NTSS or expending resources on unnecessary public health interventions.

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.

Treatment on Trial: Tanzania's National Tuberculosis Program, the International Union against Tuberculosis and Lung Disease, and the Road to DOTS, 1977-1991.

Tanzania's national tuberculosis control program, created in 1977, is credited with having been the main inspiration for the World Health Organization's Directly Observed Treatment, Short-Course (DOTS) strategy for the control of tuberculosis, which was implemented from 1994. The text focuses on what previously took place in Tanzanian tuberculosis control between 1977 and the early 1990s. What was it that the International Union against Tuberculosis and Lung Disease, which was central in the effort, assisted in creating? In what sense was the program innovative? How could a country whose health system was destroyed by a deepening economic crisis in the 1980s become a lighthouse of tuberculosis control? How much consideration was given to the rise of HIV/AIDS that occurred in parallel? The paper proposes answers to these questions, and suggests that we should see the creation of the Tanzanian program as a laboratory of nascent global health.

A Vital Mediation: The Sanatorium, before and after Antibiotics.

As drug-resistant strains of tuberculosis spread across India, commentators have warned that we are returning to the sanatorium era. Such concerns might be symptomatically read in terms of loss; however, prophecies of return might also signal that there is something to be regained. Rather than lamenting the end of the antibiotic era, I shift the focus to ask about the sanatorium, not simply as a technology of the past, but as a technology of an imminent future. In examining late nineteenth- and early twentieth-century conversations about treating tuberculosis in India, I demonstrate how the the sanatorium was figured as a therapeutic technology that mediated the relationship between the body and its colonial milieu. In this light, I argue that contemporary prophecies of a future past register not simply the loss of antibiotic efficacy, but also a desire to return to a therapeutics that foregrounds issues of vitality, mediation, and environment.