Background

Latent tuberculosis (LTBI) affects around one-fourth of the world's population, and 10 million individuals develop TB every year [1, 2]. The two main infectious and noninfectious causes of mortality worldwide are tuberculosis and cardiovascular disease (CVD), respectively [3]. Recent research has shown that people with a history of TB have an increased risk of acute coronary syndrome [4, 5], myocardial infarction [6], ischemic strokes [7], and peripheral arterial disease [5], demonstrating that the effects of these two diseases are interrelated. Additionally, long-term CVD mortality is more likely to occur in TB patients [8, 9].

The recognition of latent tuberculosis infection (LTBI) as a condition with various host–pathogen interactions, including the possibility of intermittent mycobacterial replication and dynamic immune responses, is growing [10,11,12]. Previous research has demonstrated that individuals with LTBI exhibit higher levels of immune activation markers compared to those without LTBI [13, 14]. The increased immune activation in individuals with LTBI may elevate their susceptibility to developing atherosclerotic cardiovascular disease (CVD), as immune activation has been shown to contribute to atherosclerosis development [15]. In this review, our objective was to provide an updated understanding of the association between LTBI and cardiovascular risk factors and manifestations. Furthermore, we aimed to comprehensively elucidate the underlying pathomechanism that connects these two conditions.

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Literature searching

We conducted a literature search, using the PubMed (Medline) database. We combined both MeSH and free words terms for identifying relevant articles. We also screened reference lists of published reviews to identify additional relevant studies. Details on the search strategy are presented in Table 1.

Table 1 Literature searching on LTBI and cardiovascular manifestations
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After screening and selection of the full papers, we reached 7 articles that were eligibly included in this literature review (Table 2).

Table 2 A summary of the literature described the association between LTBI and cardiovascular events and risk factors
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Definition and diagnosis of LTBI

Classically, LTBI was defined as detectable immune sensitization to Mycobacterium tuberculosis (Mtb) in the absence of symptoms such as fever, chills, night sweats, weight loss, cough, hemoptysis, or a new opacity on a chest radiograph that indicates current disease. A positive result of either a tuberculin skin test (TST) or an interferon-gamma release assay (IGRA) indicates LTBI. This measurement, however, does not address the latent foci's length and activity, which differ from person to person depending on timing and host- and pathogen-specific characteristics [16]. LTBI is identified if a host has been exposed to Mtb, and a primary infection has been established. In particular, host age, immunological state, and interaction with the index case, including infectiousness and exposure, have a substantial impact on the outcome of LTBI [16].

The two currently accepted methods for LTBI screening in Mtb-exposed individuals are TST and IGRA. However, local inflammation may also be shown radiographically or pathologically 5–7 weeks after exposure [16]. TST or IGRA findings indicate Mtb infection. Patients first undergo screening for classic symptoms and signs of disease by a thorough history and physical examination in order to determine contacts of TB cases for LTBI. A chest radiograph and sputum swab for acid-fast bacilli are then necessary if the clinical suspicion is high enough to rule out an active disease.

In areas with high TB prevalence or in high-risk populations (such as those with HIV infection), more sensitive tests (such as sputum culture on liquid mercury or nucleic acid amplification tests like the XpertMtb/RIF®) may be required to completely rule out an active disease. This is important because the person who was previously categorized as having long-term lung injury (LTBI) but later found to have a positive sputum culture should now be classed as having an asymptomatic condition, which is sometimes referred to as a "subclinical" sickness. Patients who are immunocompromised, old, or toddlers are frequently misclassified according to existing classifications and testing protocols [16].

The natural history of TB

LTBI refers to a tuberculosis infection that remains dormant and does not progress into an active disease or show any clinical symptoms [17, 18]. The global prevalence of LTBI is currently unknown due to a lack of reliable data; however, it is estimated to affect more than 33% of the world's population [1, 19,20,21]. Contrary to previous beliefs, LTBI is characterized by ongoing mycobacterial replication and a sustained level of immune activation. Recent research has demonstrated that individuals with LTBI exhibit consistent activation of monocytes and lymphocytes, which is not observed in healthy individuals [10]. This persistent state of immunological activation may contribute to the development of atherosclerosis and ischemic heart disease [22].

TB is mainly a lung condition. When exposed to a single droplet with 1–3 tubercle bacilli in the size range of 2–5 m, the terminal bronchioles or alveoli get infected. Experimental findings indicate that to successfully cause infection, 10–50 infectious units must be breathed [23]. The pathologic indication of original infection in humans is a solitary small tubercle, which shows that an infection was started by a solitary infectious droplet [24]. This observation calls into question whether the onset of infection results in the activation of a defense mechanism that precludes the establishment of additional infectious foci. According to experimental Mtb infection models, there is a three-day wait after the initial exposure before bacilli proliferation starts. 19–20 days pass before the 19–20 days of replication are terminated by the forming adaptive immune response. Genetics may have an impact on protective immunity because it appears to develop fairly differently in each host [16].

The majority of TB cases develop within the first two years of infection, and Mtb exposure frequently results in LTBI, which has a lifetime risk of 5–10% of developing into active tuberculosis [16]. Most of the time, primary infection is accompanied by brief, ignorable minor symptoms that hesitate people to seek medical treatment. Most initial infection cases are self-limited. However, after primary TB, there can be signs of spread to common locations for delayed reactivation To maintain TB prevalence in the community at a steady state, each TB case must infect 20 contacts, resulting in a ratio of 1:20 (pulmonary TB index case: Mtb-exposed contacts) [16]. A recent analysis revealed that each TB index case transmits 3—6 contacts [16].

Evidence showed that bacterial replication occurs in LTBI. This is supported by the well-established evidence of the effectiveness of treatment that significantly reduces the progression from LTBI as an active TB disease. Firstly, isoniazid (INH), an inhibitor of cell membrane synthesis, is the most often used medication for the chemoprevention of LTBI. Cell membrane synthesis can only take place, while an organism is actively replicating [16]. Secondly, although there is minimal induction in hypoxic environments, early secreted antigenic target of 6 kDa (ESAT-6) protein and culture filtrate protein (CFP-10)—which are employed to stimulate interferon-gamma (IFN-\(\gamma\)) production for IGRA testing—are released during vigorous bacterial replication [25]. Lastly, conditions of acquired immune suppression including HIV infection and treatment with tumor necrosing factor\(\alpha\) (TNF-\(\alpha )\) inhibitors significantly raised the likelihood of TB reactivation, further showing that certain latent foci contain viable Mtb. It is still uncertain how many "latent" Mtb foci are active and how immunosuppression affects the activity. TST and IGRA may be incorrectly negative in cases of immunosuppression or active TB disease, may revert to negative following LTBI therapy, or if the initial infection happened in the distant past, thus obscuring the present definition of LTBI [16].

The normal course of illnesses may start when a susceptible host is exposed to an infectious case of pulmonary TB. The presence of acid-fast bacilli, bacillary load, and TB infectiousness has all been linked in a previous study. Compared to pulmonary TB patients with negative smears, those with positive sputum smears are more likely to develop cavitary lung lesions with caseous necrosis, which allows for extracellular reproduction and raises the bacterial burden. They also cough more forcefully and frequently, which produces more infectious aerosols, the infectious molecule that transmits Mtb [26].

The primary lung lesion is the Ghon complex, which is frequently isolated and next to larger bronchopulmonary lymph nodes. Even while lymphadenitis is frequently not seen clinically, post-mortem research revealed that caseous necrosis is more advanced in the surrounding lymph nodes than in the lung. The size, metabolic activity, and type of the infectious focus (lymph node vs. parenchymal involvement) may all affect how quickly an LTBI develops into an active TB. Patients with positive smears for cavitary pulmonary TB vary in their level of infectiousness, and some may be "super-spreaders." Superspreaders could have the highest bacterial counts as well as the worst and longest-lasting coughs. According to a prior study, TB patients' cough intensity is a reliable predictor of high transmission [27].

Pathomechanisms between LTBI and cardiovascular risk factors and events

Recent epidemiologic research has shown that even years after TB recovery, persons who have the disease have a higher risk of acquiring CVD than those who do not. These results suggest that TB may play a role in the development of CVD. A previous study reported that after adjusting for a 10-year cardiovascular risk score, HIV status, and recruitment location, LTBI was independently associated with a higher incidence of subclinical obstructive coronary artery disease (CAD). LTBI is an independent predictor of increased risk of atherosclerotic CVD. A recent meta-analysis including studies of patients with TB with a mean follow-up of five years reported a 1.5 times higher risk of major adverse cardiac events compared to those without TB [9]. Additionally, compared to the general population, long-term all-cause mortality is almost three times greater in people treated with TB, and the majority of this death are attributable to CVD [9].

In large population-based retrospective cohort studies, tuberculosis disease has been linked to an elevated risk of the acute coronary syndrome, ischemic stroke, and peripheral artery disease. In Taiwan, people with TB disease had an adjusted risk of 1.4 times higher suffering from acute myocardial infarction (AMI) and unstable angina compared to those without TB [4]. Similar to this, other studies also showed that patients with TB had adjusted risks for ischemic stroke and peripheral artery disease of 1.5 and 3.9 times greater, respectively, than controls without TB [5, 7]. It is important to highlight that the reference population used for this research did not distinguish between those with and without LTBI. On the other hand, Huaman et al. reported that LTBI was associated with an increased risk of acute myocardial infarction, independent of potential confounders [28].

A previous study recently reported that people with a history of TB disease have an almost twofold higher risk of developing AMI than those without prior TB who were matched for propensity score. Whether LTBI and active tuberculosis triggered CVD risk equally or gradually remains poorly understood [28]. Infection may induce atherogenesis and acute cardiovascular events through different pathways [29]. Hypothesis suggested that persistent immune activation is related to intermittent low-level microbial reproduction, a plausible potential factor in the relationship between LTBI and AMI [6]. Several studies have shown that Mtb replication and metabolic activities continue during LTBI, which is consistent with this hypothesis [10, 30].

Contrary to the previous conception that LTBI is a state of dormancy for mycobacteria; currently, LTBI is recognized as a continuous spectrum of host–pathogen interactions, where replicating and metabolically quiet mycobacterial populations coexist and are restricted by variable host immune responses within each granuloma [12, 22, 28]. Study findings have also suggested that persons with LTBI may have elevated levels of immune activation markers and proinflammatory cytokines in peripheral blood [28]. A potential pathogenic role for tuberculosis in CVD apparently presented similar mechanisms to those described for other pathogens that established chronic infection and latency. This is suggested by the fact that monocyte/macrophages, lymphocytes, and cytokines involved in cell-mediated immune responses against Mtb are also major drivers of atherogenesis.

Additionally, according to previous findings, markers for immune activation and proinflammatory cytokines may be present in greater amounts in the peripheral blood of people with LTBI. For instance, LTBI was linked to higher serum levels of interleukin (IL)-1, IL-6, and IL-22 as well as tumor necrosis factor, according to research conducted in Norway [6]. In India, LTBI was linked to increased concentrations of chemoattractive mediators like CD14, CXCL3, CCL2, and CCL8 as well as monocyte/macrophage activation markers [6, 31]. In contrast to controls without LTBI, Huaman et al. recently found a slight rise in plasma interferon levels in people with LTBI in the USA [28, 32].

An inflammatory profile compatible with this paradigm was observed in a Canadian study of immune activation in patients with latent and active tuberculosis. The baseline circulating levels of TNF-α, IL-1, IL-4, IL-8, and IL-22 were all considerably higher in LTBI patients compared to healthy controls with a negative tuberculin skin test (TST). In the LTBI group, IFN levels were similarly higher than in the healthy controls, while the difference was not statistically significant [6, 33].

The T-cell activation markers HLA-DR and CD38 were somewhat more expressed in CD4 + and CD8 + T cells of patients with LTBI than in healthy controls, according to Wergeland et al., although the differences were not statistically significant [13]. In a study of HIV-positive patients, LTBI/HIV coinfection was found to have considerably higher CD38 expression in CD4 + and CD8 + T cells than in HIV monoinfection [14]. Even though these findings imply that immunological activation is evident in at least some categories of LTBI patients, these studies have been constrained by small sample numbers and a lack of adjustment for potential confounders. More extensive research is required to characterize immunological activation in LTBI and its possible impact on CVD. Furthermore, as LTBI treatment alters T-cell responses to particular Mtb antigens, further study of the impact of LTBI treatment on immunological activation is necessary. Detailed pathomechanisms on how LTBI related to cardiovascular disease and risk factors are described in Fig. 1.

Fig. 1
figure 1

Pathomechanisms on the association between LTBI and the occurrence of cardiovascular events and risk factors

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Conclusions

In conclusion, we shed light on the significant role of LTBI in the persistence of the disease cycle within populations, making it a crucial reservoir for new infections and ongoing transmission of Mycobacterium tuberculosis. The association between LTBI and the manifestation of cardiovascular risk factors and events, emphasizing the chronic and persistent low inflammation, observed in LTBI cases. This article contributes to the existing literature on tuberculosis and offers valuable insights for global TB eradication efforts..

The findings presented in this article support the notion that global TB eradication strategies should not solely focus on active tuberculosis cases but also consider the identification and management of LTBI. By targeting LTBI patients, public health interventions can effectively address the reservoir of Mtb within communities and prevent the development of active disease, thus breaking the cycle of transmission. Furthermore, this review underscores the need for improved diagnostic tools and risk stratification methods to accurately identify individuals with LTBI who are at the highest risk of progression. Such advancements in diagnostics and risk assessment can optimize the allocation of resources and ensure that preventive measures are implemented where they are most needed. These insights provide a foundation for future research, policy development, and implementation of effective interventions aimed at reducing the burden of tuberculosis worldwide.