Introduction

Tuberculosis (TB) remains an important public health problem worldwide.1 Latent TB infection (LTBI) defines the condition wherein an individual is infected with Mycobacterium tuberculosis (MTB) but not presently manifesting active disease.12 For a person with documented LTBI, the projected lifetime risk of developing active TB is 10%, although preventive treatment can prevent this risk and confer a projected protective effect of 60 to 90%.134 To decrease both the incidence of active TB and the associated screening costs, LTBI screening is applied selectively to those with high risk of developing active TB.1 However, target populations for screening vary among countries and guidelines.125678

Patients with malignancy may exhibit deficits in cell-mediated immunity as either a direct effect or an indirect effect related to chemotherapy.1910 Healthy individuals can harbor LTBIs for their entire lives, but in around 5 to 15% of infected individuals, TB disease can be reactivated.1112 Immunocompromised people are at increased risk of reactivation of LTBIs, which include patients with hematological malignancies and patients undergoing immunosuppressant cancer therapies such as chemotherapy.13

Accordingly, many patients with LTBI and cancer develop active TB.11415 However, the 2018 World Health Organization (WHO) guidelines do not recommend LTBI screening for patients with cancer.16 Nonetheless, the WHO guidelines also highlight the importance of further research on the benefits and harms of LTBI screening in this patient population.117

Accurately calculating the magnitude of active TB risk faced by patients with various malignancies remains challenging.1 A recent meta-analysis by Cheon et al reported an increased risk of TB development in patients with solid cancers, particularly hematologic, head and neck, and lung cancers.1 Consequently, those patients faced a greater risk of developing active TB and would benefit from LTBI screening and treatment.118 Dobler et al further performed a meta-analysis estimating the incidence of TB relative to a reference group after adjusting for age, and found that the incidence rate ratio of TB associated with cancer was 2.61; those authors concluded that LTBI screening in patients with cancer may be needless except for patients with hematologic malignancies and children with cancer.113 Nair et al, Nanthanangkul et al, and Shu et al have also reported high prevalence of TB among cancer patients.192021Table 1 lists the different studies on prevalence of TB in cancer patients.

The precision and dependability of TB diagnoses are often doubtful, as many clinical diagnoses of TB are not confirmed using microbiological evidence such as cultures or molecular methods including polymerase chain reaction (PCR).1 Given the lack of studies exploring associations of active TB with several types of malignancies in a single population, as well as the contradictory results of previous studies, further research is needed to better define high-risk patients with malignancies.1 In this study, we aimed to find out if there is risk of active TB in patients with malignancy.

Materials and Methods

Statistical Analysis

Stata 14.0 software was used for statistical analysis. The p-value calculation was done by Pearson's chi-square test. Statistical significance was defined as p-value <0.05.

Results

Total 231,283 malignancies were diagnosed from January 1, 2019, to December 31, 2022, out of which 42 (prevalence 0.01816%) tested positive for TB. Yearwise distribution of total number of cases and TB-positive cases is shown in Fig. 1. Maximum number of samples were received in 2021. Twenty-eight samples were pulmonary, and the rest were extrapulmonary.

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Fig. 1: Yearwise distribution of total number of cases and tuberculosis (TB)-positive cases.

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The samples were tested using ZN staining, GeneXpert, PCR, and MGIT. Testwise sample distribution and result obtained by the techniques are given in Table 2. Seven samples (1.37%) tested positive in ZN staining, 10 patients (6%) had culture positive by MGIT, 20 (10.53%) and 5 (13.51%) samples were positive by GeneXpert and PCR, respectively.

Of the 906 samples, 576 were males and 330 were females. Male:female ratio was 1.75:1. Genderwise result is shown in Table 3. Incidence of TB was more common among female cancer patients than male cancer patients, but the difference was statistically insignificant (p-value = 0.592).

Age range of patients was 2 to 85 years. Mean age was 47 years. Mean age of the TB-positive cases was 43 years, while mean age of the TB-negative cases was 47 years (p-value = 0.2142). Six (14%) of the TB-positive patients were children. Most (82%) of the patients were from north India (Delhi, Haryana, Uttar Pradesh, and Uttarakhand).

Percentagewise distribution of the 42 cancer patients who tested positive for TB is given in Table 4. Maximum number of TB-positive patients were found to be suffering from carcinoma lung (28%) followed by leukemia (25%), gastrointestinal cancer (13%), and genitourinary cancer (13%), respectively. Seven of the 42 patients succumbed to the disease; the cases belonged to Hodgkin's lymphoma (75% mortality), leukemia (30% mortality), and genitourinary (20% mortality).

Discussion

In this study, it is observed that samples tested across the defined period vary by wide margins. This may be due to the reason that during COVID-19 period, few samples were received. Hence in 2019 and 2020, fewer samples were received than in 2021 and 2022.

In this study, male:female ratio was 1.75:1. However, incidence of TB was more common among female cancer patients than male cancer patients, though the difference was statistically insignificant (p-value = 0.592). Contradictory findings have been reported by Nanthanangkul et al.20

In this study, maximum number (28%) of TB-positive patients were suffering from lung cancer. Similar findings have been reported in other studies as well.1132024 Smoking may be a confounding factor for TB development in patients with lung cancer.1 Moreover, misdiagnosis is possible due to mimic finding on the chest. The first case of coexistent TB and lung cancer was reported by Bayle in 1810.252627 Lung inflammation and fibrosis from TB can induce genetic damage, which may increase the risk of lung cancer.28 Reverse causation is also possible, as occult lung cancer may cause TB infection and induce reactivation of latent TB by weakening the local immunity.24 The regulatory T cells (Tregs) play an important role in this inhibition of immune response.29 Tregs are characterized by presence of forkhead box P3 (Foxp3) molecule.29 The high expression of Foxp3 was found in lung cancer cells and in tumor-infiltrating lymphocytes (TILs).29 Cytotoxic T-lymphocyte antigen 4 (CTLA4) is constitutively expressed on Tregs and suppresses T cell activation.29 Elevated CTLA4 expression in lymphocytes in patients with lung cancer has been found.29

In this study, leukemia was associated with the second highest risk of TB development among the investigated cancers. Similar findings have been reported in other studies as well.130 Not only the disease itself but also the vigorous chemotherapy or aggressive therapeutic methods used to suppress the immune system in hematological cancer patients may lead to TB in these patients.2024 A predominance of Th2 lymphocytes, reduced percentages of T lymphocyte with costimulatory molecule expression, and impaired monocyte function play major roles in impaired immunity in leukemia.31 Neoplastic cells can produce immunosuppressive cytokines and have low expressions of costimulatory molecules.31

In this study, gastrointestinal cancers also had considerable risk of TB (14%). Similar findings have been reported by other studies.1020 Numerous studies from Taiwan and Korea have also identified gastric cancer as an important risk factor for TB.203233 Since the digestive organs are important for nutrition, digestive organ dysfunction can lead to malnutrition and opportunistic infections.20 Macrophages are a major component of TILs in gastrointestinal cancers.34 Tumor-associated macrophages play a critical role in angiogenesis, metastasis, and immunosuppression.34

In this study, genitourinary cancers also had considerable risk of development of TB (14%). Similar findings have been reported by studies conducted by Nanthanangkul et al and Wu et al.2024

In our study, mortality was highest (75%) in Hodgkin's lymphoma cases. For lymphoma, it is likely that TB infection affected bone marrow suppression.20 A primary malignancy such as Hodgkin's lymphoma may cause a suppression of the cell-mediated immunity which predisposes to associated TB infection.353637 Several studies have reported that lymphomas are at an increased risk of the development of active TB.1838 Misdiagnosis or delay in diagnosis of both TB and Hodgkin's disease may occur because of identical signs and symptoms such as fever, cough, night sweats, loss of appetite, loss of weight, hepatosplenomegaly, and mediastinal adenopathy.35 Immunosuppression is the main cause of TB in Hodgkin's disease and TB is the main cause of mortality in such cases.35 Mycobacterial infections may lead to chronic persistent inflammatory process.39 There is enough evidence that MTB can induce damage to cellular DNA involved in inflammatory carcinogenesis.39 The pathogenesis hypothesized is that mycobacterial tuberculous infection causes direct DNA damage and apoptosis inhibition, which increase mutagenesis of progeny cells, combined with angiogenesis favoring tumorigenesis.35 Specifically, various mycobacterial cell wall components are hypothesized to induce the production of nitric oxide and reactive oxygen species which are involved in mutagenesis.35 It may also be noted that both nitrative-DNA damage and oxidative-DNA damage have been implicated in inflammation-related carcinogenesis.35

A diagnosis of active TB affects the treatment administered to a cancer patient.1 For example, chemotherapy or surgery may be delayed due to a TB diagnosis or accompanying medication therapy. In a study by Nair et al, 11% of cancer patients had to be changed from curative treatment to palliative treatment or no further treatment, TB being either the direct or indirect cause in all of them.19 In another study by Ahn et al, the identification of TB infection interrupted the administration of bortezomib in patients with multiple myeloma, which significantly affected patient outcomes.140 LTBI screening at the time of diagnosis of a high TB risk cancer may prevent the development of active TB during cancer treatment and enable the suitable administration of chemotherapy.1

Immunotherapy is used to treat many different types of cancer.41 MTB reactivation may represent a direct complication of immunotherapy.41 The management of MTB among cancer patients receiving immune checkpoint blockade–based cancer immunotherapy presents challenges.41 Apart from the well-established clinical benefits of immunotherapy, the blockade of programmed death-1 (PD-1)/PD-1 ligand 1 (PD-L1) axis may simultaneously disturb the immune control of specific opportunistic infections such as TB which should be carefully managed in order to avoid compromising the result of cancer treatment and the patient's survival.41 The prompt diagnosis of a mycobacterial infection, even in a subclinical stage, is crucial to avoid later aggravation.41 Hence, screening for LTBI is suggested before initiation of an immunological checkpoint inhibitor (ICPI), especially in cancer patients with additional independent risk factors.41 However, no available data exist for the management of latent or active TB during PD-1/PD-L1 blockade.41 In general, in case of active TB, ICPIs are temporarily withheld and anti-TB treatment is timely initiated.41 It has been suggested that 2 to 4 weeks after corresponding anti-TB treatment, ICPIs should be safely restarted or initiated.41

Developments in chemotherapeutic drugs and treatment modalities for cancer patients have led to rise in life expectancies.1 It is important to identify patients at a high risk of developing active TB and provide appropriate treatment.1 Cancer patients with decreased cellular immunity face an increased risk of active TB and remain in a prolonged state of immunocompromise.1 Therefore, LTBI screening is needed to prevent opportunistic infection and should be performed at the time of cancer diagnosis, such as LTBI screening is performed at the time of human immunodeficiency virus diagnosis in developing countries.1

This study had a few limitations. First, it was performed retrospectively at a single center, and therefore, the results may not reflect the general population in India. Moreover, risk of active TB in cancer patients depends to large extent on epidemiological situation of TB in a certain geographic region. Hence, the results of this study should be carefully analyzed in countries with low TB incidence. The second shortcoming was that other factors such as the disease stage at the time of cancer diagnosis, chemotherapy, surgery, and radiotherapy were not included in the analysis.

Conclusion

In conclusion, the incidence of active TB is high in cancer patients, especially lung cancer, leukemia, gastrointestinal, and genitourinary cancers. Mortality was high in Hodgkin's lymphoma patients who developed TB. Therefore, we recommend targeted screening for TB in patients at the time of diagnosis of these high-risk cancers, followed by periodic screening. However, more studies need to be conducted from different regions to arrive at a conclusion.