Echoes of the past: how ancient TB epidemics shaped the landscape of other infections

TB is among the most ancient infectious diseases, and it has been the focus of extensive medical research for many years.55 During the 20th century, when TB remained widespread in Europe and North America, numerous studies examined its interactions with other infections, reflecting its high prevalence, chronic status and the frequent occurrence of coinfections.56,57,58,59 Two historical cases are worthy of particular note: the interaction between TB and influenza during the devastating 1889 and 1918 pandemics, and the hypothesis of cross-immunity between TB and leprosy.

Mutual shaping of TB and influenza pandemics

Since the first influenza pandemic in 1580, 32 subsequent pandemics have been documented worldwide, with five major outbreaks in the 19th and 20th centuries.60 In 1922, Abbott hypothesized that the 1918 Spanish flu pandemic had accelerated the decline of TB through selective mortality; he suggested that Mtb-infected individuals were disproportionately killed by influenza, thereby reducing subsequent TB transmission and mortality.56 This hypothesis was later supported by demographic analyses, including the overlap between age patterns of influenza mortality and TB burden in the USA.61 Excess TB mortality during the influenza pandemic was also reported in Switzerland during the 1889 Russian influenza pandemic.62 Conversely, TB may have influenced the age-specific mortality pattern of influenza: in addition to the elderly and children, young adults showed elevated risk. Descriptive data from the USA, Japan, Switzerland and the Netherlands have revealed high influenza case fatality in this particular age group, hinting at hidden risk factors. Records from Swiss sanatoria confirmed that Mtb-infected patients had a higher risk of dying from influenza than non-TB controls. Finally, as previously noted, the sharp post-pandemic decline in TB deaths further supports TB’s role in shaping influenza mortality patterns.63 Interestingly, a study of two Norwegian sanatoriums revealed that Mtb-infected patients had lower rates of influenza morbidity compared to non-Mtb-infected staff members, likely due to reduced exposure and differential contact patterns. However, they experienced higher case fatality, especially young adult women.64 Collectively, historical and epidemiological data indicate a bidirectional interaction between TB and influenza. While influenza pandemics likely increased TB mortality through selective vulnerability of Mtb-infected individuals, TB itself appears to have shaped influenza mortality patterns, particularly among young adults. Importantly, lower influenza morbidity but higher case fatality among patients with TB suggest that exposure and immune status contribute differently to infection risk and disease outcome. Together, these observations highlight how chronic bacterial infections can modulate the impact of acute viral pandemics, an insight that remains highly relevant for pandemic preparedness.

The TB/leprosy cross-immunity puzzle

Leprosy was endemic in Medieval Europe but declined significantly beginning around the 14th century,65 whereas TB persisted at epidemic levels, peaking during the so-called “White Plague” in the 17th and 18th centuries (for review66). Chaussinand was the first to hypothesize cross-immunity between TB and leprosy; based on animal experiments and epidemiological data, he theorized a disease antagonism explaining the decline of leprosy in areas where TB had become prevalent.58 Since then, several studies have investigated the interaction between TB and leprosy during the Middle Ages. Crespo et al. reviewed key parameters involved in potential cross-protection between Mtb and Mycobacterium leprae, the causative agent of leprosy, compiling historical and modern evidence in support of this idea.67 However, they also emphasized the complexity of this interaction, notably due to ecological and social factors that create heterogeneous epidemiological landscapes, making it difficult to isolate TB’s impact on leprosy’s decline.68,69 The clinical manifestations of both infections may also matter, as TB is thought to protect specifically against tuberculoid leprosy, the more prevalent form in late Medieval times, rather than the lepromatous form.70 Moreover, the historical prevalence of TB has likely been underestimated, given its latent nature and the frequent absence of bone lesions, used as the primary marker for diagnosing the infection in skeletal remains.71 Lietman et al. tested Chaussinand’s theory through transmission modeling and found that, given leprosy’s slow reproductive rate, TB could indeed have contributed to its disappearance over centuries.72 The alternative idea of selective mortality among coinfected individuals has also been considered, based on the immunological changes observed in archaeological samples containing DNA from both pathogens,73 and on the mathematical modeling of this coinfection hypothesis.74 Overall, these multidisciplinary findings suggest that the interaction between TB and leprosy cannot be explained by a single factor, but rather reflects the convergence of biological, clinical and socio-environmental determinants. While the possibility of Mtb-mediated protection marks a key conceptual turning point, this effect appears context-dependent, potentially restricted to specific clinical forms, and is further complicated by the likely underestimation of TB prevalence in historical records. This framework, summarized in Figure 1, provides a conceptual basis for exploring the immunological mechanisms underlying potential cross-protection, discussed in Section “bridging scales: from population patterns to animal models and cellular mechanisms of coinfection”.

Figure 1: Historical TB/influenza and TB/leprosy coinfection modelsDuring the 1918 influenza pandemic, TB is thought to have shaped mortality curves by disproportionately affecting adults with underlying TB, unlike infants or the elderly. In contrast, in medieval Europe, the decline of leprosy may have resulted from cross-protection conferred by TB infection or from selective mortality among coinfected individuals. Icons from BioRender. Dagan, Y. (2026) (https://BioRender.com/y4mcdyo).

The long-standing interest in coinfections with Mtb, illustrated by its historical interactions with leprosy and influenza, highlights the relevance of revisiting this question in modern contexts. Together, these examples suggest that TB may have acted as a major regulator of past epidemics by shaping host susceptibility, disease severity, and transmission potential of concurrent infections, thereby influencing the overall dynamics of secondary pathogens.

In the following sections of the review, epidemiological and experimental studies are presented separately to provide a clearer understanding of the evidence from each approach. Within both sections, coinfections are categorized according to their reported outcome: exacerbating, neutral, or protective against one or the other infection. Table S2 provides an overview of all pathogens studied in combination with TB, including their host, target organs, modes of transmission, and associated diseases.