Pulmonary Tuberculosis and Risk of Lung Cancer

Pulmonary Tuberculosis and Risk of Lung Cancer: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Infectious Diseases | Public, Environmental & Occupational Health | Respiratory System

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Lung cancer accounts for approximately 18.4% of the total cancer-related deaths, the highest of all cancer types. The prognosis of lung cancer is relatively unfavorable compared to that of other malignancies, and as a prognosis largely depends on the stage of onset, thus, the early diagnosis of lung cancer is very important.

pulmonary tuberculosis
lung cancer
meta regression
burden of tuberculosis

1. Introduction

Chronic inflammation resulting in pathological changes is a major risk factor in carcinogenesis. Inflammation is known to play a key role in carcinogenesis, such as infection with hepatitis B and C viruses in hepatocellular carcinoma, Helicobacter pylori in gastric cancer, and human papilloma virus in gynecological cancers [7]. Several meta-analyses have shown that previous inflammatory diseases in the lungs, such as pneumonia, chronic bronchitis, and pulmonary tuberculosis (TB), may increase the risk of lung cancer (relative risk ratio 1.36–1.90), independent of cigarette smoking [8,9]. According to forty-nine studies, pulmonary and extra-pulmonary TB infections increase the risk of 10 cancer types, including head and neck cancer, leukemia, lymphoma, gastrointestinal cancer, kidney cancer, bladder cancer, and lung cancer [10]. Thus, TB infection may influence the pathogenesis of lung cancer with or without cigarette smoking. To prevent the emergence of airborne transmittable TB and its progression to cancer, the control and prevention of TB is very important.

2. Pulmonary TB and Risk of Lung Cancer with All Eligible Studies

The overall association between a previous history of pulmonary TB and newly diagnosed lung cancer was statistically significant (odds ratio (OR): 2.09; 95% confidence interval (CI): 1.62–2.69, p < 0.001). There was high heterogeneity (I² = 95%), no evidence of publication bias, the egger p-value was 0.447, and no visual asymmetry in the funnel plot (Figure 2A and Figure 3A). In the subgroup analysis by TB burden, the high-burden countries showed higher OR (2.57, 95% CI: 1.68–3.93, p < 0.001) than the medium-burden (OR: 2.48, 95% CI: 1.71–3.58, p < 0.001) and low-burden countries (OR: 1.77, 95% CI: 1.22–2.56, p = 0.003). Geographically, East Asia and the Pacific region showed a prominent risk (OR: 2.49, 95% CI: 1.83–3.39, p < 0.001) compared to the Europe and Central Asia (OR: 1.60, 95% CI: 0.80–3.22, p = 0.185) or North America (OR: 1.53, 95% CI: 1.11–2.12, p = 0.010) regions. The economic income statuses of the countries also reflected the characteristics of patients with TB, and the countries with upper-middle incomes (OR: 2.57, 95% CI: 1.68–3.93, p < 0.001) demonstrated a higher risk of lung cancer than high-income status countries (OR: 1.91, 95% CI: 1.41–2.59, p < 0.001). The association between pulmonary TB and newly developed lung cancer was statistically significant regardless of the adjustment for age, sex, smoking status, and cohort type or study design. The magnitude of association was similar regardless of whether pulmonary TB was diagnosed based on medical records (OR: 2.26, 95% CI: 1.29–3.94, p = 0.004), imaging (OR: 2.13, 95% CI: 1.16–3.92, p = 0.015), or self-report/physical examination (OR: 1.96, 95% CI: 1.56–2.47, p < 0.001). The heterogeneity within subgroups remained at a high level in a majority of the subgroup analyses (Table 2).

Figure 2. Forest plots of risk estimates for the association between tuberculosis and lung cancer. (A) Meta-analysis of all eligible studies. (B) Meta-analysis of high-quality studies.

Figure 3. Funnel plot of the study estimates. (A) All eligible studies. (B) High-quality studies.

Table 2. Meta-analysis of 33 eligible cohorts to assess the association between pulmonary tuberculosis and lung cancer.

Subgroup	No. of Cohorts *	OR (95% CI)	p-Value	I² Value (%)	I² between Subgroups (%)
All cohorts	33	2.09 (1.62–2.69)	<0.001	95
TB burden of country
Low	18	1.77 (1.22–2.56)	0.003	97	12
Medium	6	2.48 (1.71–3.58)	<0.001	75
High	9	2.57 (1.68–3.93)	<0.001	81
Region of country
East Asia and Pacific	19	2.49 (1.83–3.39)	<0.001	93	58
Europe and Central Asia	7	1.60 (0.80–3.22)	0.185	98
North America	7	1.53 (1.11–2.12)	0.010	0
Economic status of country
High-income	24	1.91 (1.41–2.59)	<0.001	96	20
Upper-middle-income	9	2.57 (1.68–3.93)	<0.001	81	20
Age
Adjusted	29	2.00 (1.54–2.61)	<0.001	95	14
Not adjusted	4	3.84 (1.21–12.15)	0.022	82	14
Sex
Adjusted	22	2.23 (1.60–3.11)	<0.001	96	0
Not adjusted	11	1.90 (1.47–2.46)	<0.001	61	0
Smoking
Adjusted	22	2.03 (1.51–2.73)	<0.001	90	0
Not adjusted	11	2.19 (1.34–3.59)	0.002	98	0
Hypertension
Adjusted	2	1.92 (0.66–5.57)	0.230	99	0
Not adjusted	31	2.10 (1.62–2.73)	<0.001	92	0
Diabetes
Adjusted	2	1.72 (0.48–6.20)	0.404	99	0
Not adjusted	31	2.13 (1.63–2.77)	<0.001	94	0
Respiratory comorbidities
Adjusted	8	1.32 (0.93–1.86)	0.121	94	90
Not adjusted	25	2.51 (2.04–3.08)	<0.001	78	90
Cohort of the study
Population-based	23	1.95 (1.41–2.68)	<0.001	96	0
Hospital-based	10	2.36 (1.85–3.01)	<0.001	49	0
Study design
Prospective cohort study	4	1.96 (1.22–3.15)	0.005	84	94
Retrospective cohort study	2	3.95 (3.58–4.36)	<0.001	0
Case-control study	27	1.99 (1.56–2.53)	<0.001	89
Diagnostic method of pulmonary TB
Medical record	8	2.26 (1.29–3.94)	0.004	99	0
Imaging	3	2.13 (1.16–3.92)	0.015	80
Self-report or physical examination	22	1.96 (1.56–2.47)	<0.001	66

* Since two separate cohorts were reported in one article, a total of 33 eligible cohorts were extracted and analyzed from 32 enrolled studies. Abbreviations: CI, confidence interval; No, Number; OR, odds ratio; TB, tuberculosis.

3. Pulmonary TB and Risk of Lung Cancer with High-Quality Studies

The analysis of eight high-quality studies showed a higher OR (2.26, 95% CI: 1.29–3.94, p = 0.004) than the analysis of all the studies. There was a high heterogeneity (I² = 99%) with no publication bias, with Egger p = 0.621, and no visual asymmetry in the funnel plot (Figure 2B and Figure 3B). Of the eight articles, seven had cohorts from countries with a low TB burden, and only one had a cohort from a country with a medium TB burden. In the subgroup analysis with a TB burden, the medium-burden countries showed higher OR (4.18, 95% CI: 3.15–5.55, p < 0.001) than the low-burden countries (OR: 2.04, 95% CI: 1.12–3.73, p = 0.020). Geographically, the East Asia and the Pacific region showed a more prominent risk (OR: 2.79, 95% CI: 1.21–6.39, p = 0.016) compared to the Europe and Central Asia regions (OR: 1.79, 95% CI: 0.67–4.77, p = 0.244) (Table 3).

Table 3. Meta-analysis of high-quality studies to assess the association between TB and lung cancer.

Subgroup	No. of Studies	OR (95% CI)	p-Value	I² Value (%)	I² between Subgroups (%)
All studies	8	2.26 (1.29–3.94)	0.004	99
Country of TB burden
Low	7	2.04 (1.12–3.73)	0.020	99	78
Medium	1	4.18 (3.15–5.55)	<0.001	-
High	0	-	-	-
Region of country
East Asia and Pacific	4	2.79 (1.21–6.39)	0.016	98	0
Europe and Central Asia	4	1.79 (0.67–4.77)	0.244	99
North America	0	-	-	-

Abbreviations: CI, confidence interval; No, Number; OR, odds ratio; TB, tuberculosis.

4. Stratified and Sensitivity Analysis

The quality of the 33 included articles was evaluated using the NOS. The quality assessment of 27 case–control studies is shown in Table 4 and that of six retrospective cohort studies is demonstrated in Table 5. Meta-regression analyses were performed with continuous variables, such as the mean age at diagnosis of pulmonary TB, baseline characteristics including comorbidity, and pathological cell type of lung cancer. All the results are shown in Supplementary Table S2. Of these, patients with a low mean age at diagnosis of pulmonary TB showed a significant association between pulmonary TB and lung cancer. The primary analysis with all 32 articles estimated a regression coefficient of 0.949 (p < 0.001). The secondary analysis with eight high-quality studies with stringent TB diagnostic methods showed similar results (regression coefficient = 0.945, p < 0.001) (Figure 4).

Figure 4. Meta-regression analysis of the mean patient age and association between tuberculosis and lung cancer. (A) All eligible studies. (B) High-quality studies.

Table 4. Quality assessment of the included case–control studies using the Newcastle–Ottawa Scale.

Study	Selection				Comparability	Outcome			Quality Score
Study	Adequacy of Case Definition	Degree of Representation of Cases	Selection of Controls	Definition of Controls	Comparability of Cases and Controls on the Basis of Design or Analysis	Confirmation of Exposure	Same Method of Confirmation for Cases and Controls	Non-Response Rate	Quality Score
An et al. 2020 [20]	*	*	*	*	**	*	*	*	9
Yang et al. 2015 [22]	*	*	*	*	**		*	*	8
Yang et al. 2015 [23]	*	*	*	*	*	*	*	*	8
Hosgood et al. 2013 [25]	*	*	*	*	*		*	*	7
Lo et al. 2013 [27]	*	*	*	*	**		*	*	8
Bodmer et al. 2012 [28]	*	*	*	*	**	*	*	*	9
Koshiol et al. 2010 [31]	*	*	*	*	**		*	*	8
Park et al. 2010 [32]	*	*	*	*	**		*		7
Liang et al. 2009 [33]	*	*	*	*	**		*	*	8
Wang et al. 2009 [34]	*	*	*	*	*		*	*	7
Galeone et al. 2008 [35]	*	*	*	*	**		*	*	8
Ramanakumar et al. 2006 [36] ^a	*	*	*	*	**		*	*	8
Ramanakumar et al. 2006 [36] ^b	*	*	*	*	**		*	*	8
Zatloukal et al. 2003 [37]	*	*	*	*	**		*	*	8
Chan-Yeung et al. 2003 [38]	*	*	*	*	*		*	*	7
Kreuzer et al. 2002 [39]	*	*	*	*	*		*	*	7
Brenner et al. 2001 [40]	*	*	*	*	**		*	*	8
Kreuzer et al. 2001 [41]	*	*	*	*	*	*	*	*	8
Zhou et al. 2000 [42]	*	*	*	*	*		*	*	7
Osann et al. 2000 [43]	*	*	*	*	**		*	*	8
Mayne et al. 1999 [44]	*	*	*	*	*		*	*	7
Ko et al. 1997 [45]	*	*	*	*		*	*	*	7
Schwartz et al. 1996 [46]	*	*	*	*	**		*	*	8
Luo et al. 1996 [47]	*	*	*	*	*		*	*	7
Wu et al. 1995 [48]	*	*	*	*	**		*	*	8
Alavanja et al. 1992 [49]	*	*	*	*	**		*	*	8
Wu-Williams et al. 1990 [50]	*	*	*	*	**		*	*	8

^a,b: Two separate cohorts reported in one article. Study ^a was conducted in 1979–1986 (755 cases and 512 controls); study ^b was conducted in 1996–2001 (1205 cases and 1541 controls). A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability.

Table 5. Quality assessment of the included retrospective cohort studies using the Newcastle–Ottawa Scale.

	Selection				Comparability	Outcome			Quality Score
Study	Degree of Representation of the Exposed Cohort	Selection of the Non-Exposed Cohort	Confirmation of Exposure	Demonstration That the Current Outcome of Interest Is Absent at the Start of the Study	Comparability of Cohorts Based on Design or Analysis	Assessment of Outcome	Sufficiency of Follow-Up to Detect Outcomes	Adequacy of Follow-Up of Cohorts	Quality Score
Kim et al. 2020 [19]	*	*		*	**	*	*		7
Oh et al. 2020 [21]	*	*		*	**	*	*	*	8
Simonsen et al. 2014 [24]	*	*	*	*	*	*	*	*	8
Bae et al. 2013 [26]	*	*		*	**	*	*		7
Shiels et al. 2011 [29]	*	*	*	*	**	*	*	*	9
Yu et al. 2011 [30]	*	*	*	*	*	*	*		7

A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability.

This entry is adapted from the peer-reviewed paper 10.3390/jcm11030765

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