Conclusion

Despite the availability of curative treatments and its relatively low incidence in developed countries, TB is considered a major global health threat, and many scientists have been focusing their research efforts on the development of novel, more effective therapeutic strategies. TB has been extensively shown to negatively impact comorbidities, and coinfections are no exception at first glance.

The literature reviewed here indicates that TB coinfection is frequently associated with exacerbation of secondary infections or increased host susceptibility. Through both epidemiological and experimental studies, TB coinfection leads to worsened clinical outcomes, including increased severity of viral or bacterial infections, prolonged disease progression, and higher mortality rates. Moreover, the complex immune balance that maintains Mtb under control can be disturbed by secondary infections, leading to reactivation and worsening of TB. Therefore, improved epidemiological surveillance of coinfections, together with integrated screening strategies for secondary pathogens in patients with TB and accurate discrimination between latent and active TB disease, could significantly improve patient outcomes. Such approaches would facilitate earlier diagnosis, better risk stratification, and more appropriate clinical management, particularly in regions where TB remains endemic and the burden of concurrent infections is high. These observations emphasize that coinfections represent a major, yet often underestimated, challenge for TB control and patient management.

Building on these insights, the therapeutic management of TB could also benefit from considering coinfections. Secondary pathogens may influence both susceptibility to TB and the progression of disease, and their presence could help explain why some individuals develop active TB following prior exposure or latent infection. Integrating this knowledge into treatment strategies, including potentially targeting both Mtb and coexisting pathogens, could help restore an immune balance favorable to TB control. Furthermore, a better understanding of the immunological alterations induced by coinfections may support the development of personalized host-directed or immunomodulatory therapies tailored to the patient’s immune status and infectious history. Such approaches could enhance protective immune responses while limiting detrimental inflammation. This perspective aligns with the concept of personalized medicine, where therapy is tailored not only to the infecting pathogen but also to the patient’s overall immunological and infectious profile.

However, this predominantly aggravating picture of coinfection outcomes is shaped by an important limitation of available clinical data. Patients captured in hospital-based studies are more likely to present with severe forms of TB or of the secondary infection. Consequently, clinical datasets largely reflect the most severe disease manifestations, whereas individuals with undiagnosed Mtb infection and mild or transient secondary infections are unlikely to seek medical care. As a result, these milder cases remain underreported, leaving a significant gap in epidemiological data and possibly leading to an underestimation of the true incidence and spectrum of TB coinfections. In addition, coinfection outcomes are strongly influenced by geographic and epidemiological factors, including regional disparities in global health, host immune status, circulating Mtb lineages, and exposure to distinct pathogens. These variables further shape patient populations captured in clinical studies and complicate direct comparisons across settings.

Experimental studies offer a more nuanced perspective, complementing the picture drawn from clinical and epidemiological data. In vitro and in vivo models suggest that Mtb infection, particularly in its chronic or latent form, could have a beneficial impact on the host’s ability to control secondary infections. This protective effect could be explained by a basal level of inflammation in the lungs and immune cell activation, creating an inhospitable environment for other pathogens. Nevertheless, demonstrating comparable protective effects in humans remains challenging due to limitations in clinical resolution, heterogeneous patient populations, and the difficulty of defining infection states and temporal relationships between pathogens. More research is needed to unravel the immune mechanisms at play in chronic Mtb infection and clarify how this condition might contribute to broader immune resilience and thus challenge the management of coinfections. Importantly, this will require the development of improved experimental models that more faithfully recapitulate the diversity of the TB disease spectrum, the chronicity of infection, and the complexity of host-pathogen interactions occurring during coinfections. Current models often fail to capture key features of human latent or subclinical TB and may therefore overlook mechanisms relevant to protection or disease exacerbation. In particular, future studies should integrate multi-omics approaches, including single-cell transcriptomics, epigenetic profiling, and immunometabolic analyses, to define how chronic Mtb infection imprints long-term immune function. Dissecting these mechanisms across tissues and disease states will be essential to understand how TB-induced immune reprogramming shapes susceptibility, protection, or pathology during coinfections.

These observations naturally connect to broader concepts of trained immunity and vaccine-induced cross-protection. Considering its protective effects on multiple infectious diseases, the use of BCG as a cross-protective vaccine against a broader spectrum of diseases could be envisaged. Interestingly, many of the pathogens against which BCG vaccination offers protection are the same as those for which chronic Mtb infection appears to provide a protective effect.197 Consequently, the mechanisms proposed to explain BCG-induced protection also serve as valuable hypotheses for understanding the protective immune profile associated with chronic Mtb infection.

Finally, these findings raise important questions in the context of global TB elimination strategies. The WHO aims to eradicate TB by 2050 and encourages researchers around the world to develop new therapeutic strategies, especially against multidrug-resistant Mtb strains.198 A major pillar of this plan is the treatment of LTBI, given its vast reservoir and its role as a silent driver of the TB pandemic through the lifelong risk of reactivation. Indeed, since the mechanisms underlying reactivation are still not fully understood or controllable, maintaining this reservoir is considered a major public health risk. This is further compounded by the fact that coinfections may act as facilitators of Mtb reactivation and progression toward subclinical or clinical disease.

As this review also highlights that chronic Mtb infection may confer partial immune protection against unrelated acute respiratory infections, it raises the question of whether large-scale elimination of LTBI could have unintended consequences on host immunity to other pathogens. Therefore, eliminating the risk of TB reactivation, which is particularly relevant in vulnerable populations such as the elderly or those with genetic conditions or chronic comorbidities, might have to be weighed against the potential benefits of LTBI-induced cross-protection against other respiratory illnesses. More detailed exploration and understanding of these coinfection models, together with properly designed assessment and mathematical modeling of the associated risks, are thus needed to help predict the impact of a TB-free world on the incidence of other respiratory infections.

In this context, the development of therapeutic vaccines that prevent the progression from LTBI to active disease might represent a promising compromise. Such strategies could simultaneously reduce the risk of reactivation and preserve any possible beneficial immunomodulatory effects of LTBI. Nonetheless, any future approach must be guided by precise surveillance and a better understanding of both reactivation mechanisms and the immunological interplay between LTBI and secondary infections.