Tuberculosis and lung damage: from epidemiology to pathophysiology

Shruthi Ravimohan; Hardy Kornfeld; Drew Weissman; Gregory P. Bisson

doi:10.1183/16000617.0077-2017

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FIGURE 1
Mechanisms and radiographic features associated with airflow obstruction and restrictive ventilatory defects in patients with a history of tuberculosis. FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity.
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FIGURE 2
Immune mediators of tissue remodelling and lung function impairment in tuberculosis. Transcription factors, cytokines and chemokines that drive expression of tissue-degrading enzymes or directly mediate cavitation and/or fibrosis are shown in green. Matrix metalloproteinases (MMP) that promote granuloma and cavitation are depicted in purple. HIF: hypoxia inducible factor; NF: nuclear factor; IL: interleukin; TNF: tumour necrosis factor; TGF: transforming growth factor; IFN: interferon; mtROS: mitochondrial reactive oxygen species. ^#: IL-1β regulates fibrogenesis in idiopathic pulmonary fibrosis and may play a role in tuberculosis. Pathological processes contributing to the progression of lesions may influence the development of airflow obstruction and restrictive ventilatory patterns of pulmonary impairment.
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FIGURE 3
Conceptual model of factors that potentially contribute to lung impairment after tuberculosis (TB). MTB: Mycobacterium tuberculosis.

TABLE 1

Definitions for processes contributing to lung remodelling during pulmonary tuberculosis (TB) and pulmonary impairment after TB

Term	Definition
Pulmonary cavitation	Process by which normal pulmonary tissue is obliterated, becoming gas-filled spaces or cavities in the lung. This process initially involves caseous necrosis of lipid pneumonia lesions, producing caseous pneumonia. During caseation, alveolar cells and septa are destroyed along with neighbouring vessels and bronchi. Cavities form when these regions of caseous pneumonia liquefy, fragment and are released upon coughing.
Pulmonary fibrosis	Results from long-term lung tissue injury that is characterised by excessive extracellular matrix deposition in the lung. Replacement of normal lung parenchyma with collagenous tissue results in architectural changes in the lung, such as thickening and stiffening of the lung walls.
Bronchiectasis	Manifests as irreversible bronchial dilatation and thickening of the bronchial wall. Elastic and muscular components of the bronchial wall are destroyed in bronchiectasis. Bronchial dilatation associated with bronchiectasis in TB may be due to multiple factors, including traction from surrounding tissue fibrosis, caseous necrosis that makes its way into the bronchi, and elevated luminal pressure due to coughing. Bronchiectasis can also predispose to recurrent exacerbations of purulent sputum production and possibly bacterial pneumonia in subsequent years.
Pulmonary impairment after TB	A broad term we use in this review to refer to lung dysfunction that includes airflow obstruction, restrictive ventilatory defects and impaired gas exchange. Pulmonary impairment after TB is probably downstream of a wide variety of lung remodelling events, some of which are described above. Given the lung's considerable reserve, these structural changes may manifest as symptoms and pulmonary disability over a period of time.

TABLE 2

Summary of epidemiological studies investigating pulmonary impairment after tuberculosis (TB)

First author [ref.]	Type of study	Setting	Sample size n	Exposure	Outcome	Association/finding	Major limitation
Akkara [18]	Cross-sectional	India	257	Treated TB (2 weeks post-treatment completion)	Airflow obstruction measured by FEV₁ and FVC	Airflow obstruction in 86.8% of patients	Lung impairment before TB treatment initiation was not measured to relate to lung impairment after treatment completion and determine causality. Long-term lung disability was not assessed.^#
Willcox [13]	Cross-sectional	South Africa	71	History of TB (up to age 16 years)	Airflow obstruction defined as RV >120% pred and/or FEV₁/FVC ratio <70% pred with TLC >80% of pred	Obstruction in 68% of patients Obstruction with some restriction in 20% Non-obstructive decrease in lung volume in 17%	Lung impairment before TB treatment initiation was not measured to relate to lung impairment after treatment completion and determine causality. Lung function was evaluated only in patients who could be traced after several years of attending a TB clinic. Selection of patients in this way may have contributed to survivor bias and underestimated lung dysfunction.
Manji [19]	Cross-sectional	Tanzania	501	Treated TB (20 weeks of anti-TB therapy)	Airflow defects measured by FEV₁ and FVC	Lung impairment in 74% of patients Obstruction in 42% Restriction in 13% Mixed pattern in 19%	Lung impairment before TB treatment initiation was not measured to relate to lung impairment after treatment completion and determine causality. Long-term lung disability was not assessed.^#
Hnizdo [2]	Retrospective	South Africa	27 660	History of 1, 2 or ≥3 episodes of TB	Airflow obstruction defined as FEV₁ <80%	Prevalence of airflow obstruction after 1 episode of TB (18.4%), 2 episodes of TB (27.1%) and ≥3 episodes of TB (35.2%) Lung impairment is greatest in the first 6 months following TB diagnosis and stabilises 6 months post-TB treatment completion	Only male mine workers were assessed.
Ross [4]	Matched retrospective	South Africa	185 TB cases versus 185 age-matched controls without history of TB	History of TB	Lung function loss over time measured by FEV₁ and FVC	History of TB was associated with an adjusted mean loss of 40.3 mL·year⁻¹ in FEV₁ (95% CI 25.4–55.1) and 42.7 mL·year⁻¹ in FVC (95% CI 27–58.5) compared to controls	Only male mine workers were assessed. Patients were included in the study only if they were still working in the mines at follow-up, nearly 4.5 years after baseline measures. Several subjects had left the mines by follow-up. Selecting only those still working at the mines may have contributed to survivor bias and underestimated lung function.
Rhee [20]	Retrospective	Republic of Korea	595	Destroyed lung resulting from a past history of TB	Lung function loss measured by FEV₁ and FVC	Lung impairment after TB in 76.8% of patients	Cohort consisted of hospitalised TB patients with destroyed lungs, thereby limiting the generalisability of findings to less advanced patients. PFTs were not standardised.
Plit [3]	Prospective cohort	South Africa	74	TB treatment	Lung function at the end of TB treatment	54% of patients had an improvement in lung function 28% of patients had obstructed airflow 24% of patients had restricted airflow Only study to date that has investigated an association between inflammation and lung function: elevated C-reactive protein correlated with decreased FEV₁ % after TB treatment completion, independent of smoking	Cohort consisted of hospitalised patients with severe TB, thereby limiting the generalisability of findings to less advanced patients. Long-term lung disability was not assessed.^#
Maguire [7]	Prospective cohort	Indonesia	69	TB treatment	Lung function over the course of TB treatment	Lung function improved over the course of TB treatment; however, 25% of the patients had residual moderate-to-severe TB (FEV₁ <60%) at treatment completion	Study was restricted to 69 of 115 patients who attended all follow-up visits. Those included were more likely to have been cured and had better lung function at diagnosis compared to those not included. This may have underestimated the extent of lung dysfunction among patients with a history of TB. Long-term lung disability was not assessed.^#
Ralph [8]	Prospective cohort	Indonesia	200	TB treatment	Lung function over the course of treatment and at treatment completion	47% of TB patients had moderate-to-severe pulmonary impairment at baseline 27% of TB patients had residual moderate-to-severe pulmonary impairment at the end of treatment	Long-term lung disability was not assessed.^#
Pasipanodya [5]	Case–control	USA	107 active TB cases versus 210 latent TB controls	Treated TB (20 weeks of anti-TB therapy)	Airway obstruction defined as FEV₁/FVC <70% pred and FVC >80% pred	TB patients on anti-TB therapy have significantly higher odds of pulmonary impairment versus controls with latent TB, OR 5.4 (95% CI 2.98–9.68)	Lung impairment before TB treatment initiation was not measured to relate to lung impairment at treatment completion and determine causality. Long-term lung disability was not assessed.^#
Amaral [10]	Cross-sectional, population-based study of adults	18 high and low-/middle-income countries	14 050	History of TB	Airflow defects: obstruction defined as post-bronchodilator FEV₁/FVC less than LLN; restriction defined as post-bronchodilator FVC less than LLN	Obstruction: adjusted OR 2.51 (95% CI 1.8–3.42) Restriction: adjusted OR 2.31 (95% CI 1.42–3.19)	Self-report of TB was used to determine association with airflow obstruction. This approach may have resulted in recall bias.
Menezes [12]	Cross-sectional, population-based	5 Latin American cities	5571 patients; 132 with a diagnosis of TB	History of TB	COPD	Prevalence of COPD in 30.7% versus 13.9% comparing those with and without history of TB, respectively Smoking adjusted OR 2.33 (95% CI 1.5–3.62)	History of TB was not confirmed by medical records. Lung function was not measured
Lee [21]	Retrospective	Taiwan	3176 pulmonary TB cases versus 15 880 matched controls	History of TB	COPD	History of TB is an independent risk factor of COPD (HR 2.05, 95% CI 1.77–2.39)	Patients were considered to have a history of TB and COPD based on medical treatment records. Lung function was not measured.
Byrne [11]	Systematic review and meta-analysis	Multiples countries		History of TB	COPD	History of TB was significantly associated with COPD in adults over 40 years (pooled OR 3.05, 95% CI 2.42–3.85)	All studies included in the meta-analysis were cross-sectional. Thus, precluding determination of a temporal and causal effect of TB on COPD.

FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; RV: residual volume; TLC: total lung capacity; PFT: pulmonary function test; LLN: lower limit of normal; COPD: chronic obstructive pulmonary disease. ^#: the study by Hnizdo et al. [2] demonstrated that lung impairment peaks 6 months after diagnosis, but improves 6 months post-treatment completion before stabilising to become chronic. These studies determined lung function at treatment completion, thus their findings may not represent residual lung impairment.

TABLE 3

Immunogenetic studies of lung dysfunction potentially relevant to pulmonary impairment after tuberculosis (TB)

Biomarker/gene	Polymorphism	Implication on lung pathology/function	Reference
TB
MMP-1	MMP-1 -1607G (1G) (rs1799750)	Extensive fibrosis after 1 year of TB treatment Cavitary disease Endobronchial TB and tracheobronchial stenosis	[145–147]
MCP-1+MMP-1	MCP-1 -2518G (G/G) (rs1024611) MMP-1 -1607GG (2G/2G) Guanine insertion at this locus	Permanent lesions after TB treatment Fibrosis Bronchiectasis	[148]
TOLLIP	TOLLIP rs5743899 rs3750920	Decreased TOLLIP mRNA expression Increased inflammatory cytokine expression Increased risk for TB	[149]
COPD
MMP-1+MMP-12	MMP-1 2G+MMP-12 nsSNP (rs652438)	Increased rate of lung function decline	[150]
MMP-9	MMP-9 -1562C/T	Increased risk of COPD in a Korean population	[151]
MMP-12	MMP-12 rs652438 and rs2276109	Severe (GOLD stage III) and very severe COPD (GOLD IV), lower FEV₁ %	[152]
TIMP-2	TIMP-2 +853G/A -418G/C	Increased risk for COPD Decreased transcription and stability of mRNA	[153]
TNF-α	TNF-α -308G/A (rs1800629)	Increased risk of COPD Increased yearly reduction in FEV₁ Chronic bronchitis Elevated TNF-α, IL-8, and myeloperoxidase in sputum	[154,155]
IL-8	IL-8 rs4073 rs2227306 rs2227307	Significant decrease in FEV₁ and FVC during follow-up of COPD patients	[156]
IPF
TGF-β+TNF-α	TGFβ (rs1800469) +TNF-α (rs361525)	Additive effect on lung impairment measured as FEV₁	[157]
IL-6	IL-6 -174G/C	Decrease in FEV₁	[158]
IL-1RA	IL-1RN +2018C/T (rs419598) Variable number tandem repeat (VNTR)*2 rs2637988	Risk for fibrosing alveolitis and IPF Increased susceptibility for IPF Decreased IL-1RA mRNA levels that may predispose to IPF	[159, 160]
TNF-α	TNF-α -308G/A (rs1800629)	Fibrosing alveolitis risk	[159]
IL-6	IL-6 intron 4A/G	Lower carbon monoxide diffusion	[161]
TGF-β	TGF-β Codon 10T/C(rs1982073) Codon 25G/C(rs1800471)	Decreased gas exchange in IPF patients	[162, 163]
MUC5B	MUC5B rs35705950 rs868903	Associated with pulmonary fibrosis in genome-wide association studies Increased MUC5B expression	[164–166]
TOLLIP	TOLLIP rs5743890 rs111521887 rs5743894	Associated with reduced TOLLIP expression in lung tissue from IPF patients rs5743890 linked to mortality in IPF patients

MMP: matrix metalloproteinase; MCP: monocyte chemoattractant protein; COPD: chronic obstructive pulmonary disease; TIMP: tissue inhibitor of metalloproteinase; TNF: tumour necrosis factor; IL: interleukin; IPF: idiopathic pulmonary fibrosis; TGF: transforming growth factor; GOLD: Global Initiative for Chronic Obstructive Lung Disease; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity.

TABLE 4

Summary of key research priorities to address pulmonary impairment after tuberculosis (TB)

Epidemiological studies

Population-based studies that determine the prevalence of: 1) lung function defects by type (airflow obstruction, restrictive ventilatory
defects, gas exchange abnormalities, V′/Q mismatch and mixed defects); and 2) lung damage by type (cavitation, fibrosis and bronchiectasis)
Investigate risk factors (host, environmental, pathogen) associated with PIAT
Measure impact of PIAT on quality of life
Determine the prevalence of PIAT and characterise lung deficits in specific patient populations, such as those co-infected with HIV, who have
diabetes mellitus or are infected with multidrug-resistant TB

Basic/translational science

Delineate the immunopathogenesis of pulmonary cavitation, fibrosis and bronchiectasis in pulmonary TB
Determine the immunogenetic correlates of hyper-inflammation and tissue damage in pulmonary TB utilising genome-wide association
studies similar to those in IPF and COPD
Identify key biomarkers or immune pathways as targets for immunomodulation to reduce lung pathology in pulmonary TB

Clinical/translational science

Diagnosis and diagnostic tests: investigate the utility of chest radiographs, CT, PET-CT, pulse oximetry, 6-min walk test and PFTs prior and
post-TB treatment in diagnosing those at increased risk for PIAT
Prevention and treatment:
Develop effective vaccines to prevent TB and lung tissue damage post infection
Develop novel drugs and biologics for TB that not only shorten treatment duration, but also reduce lung tissue injury
Investigate the use of adjunctive host-directed therapy to treat TB and associated lung pathology
Evaluate the efficacy of the use of common COPD and anti-fibrotic medications in preventing and/or treatment of post-TB lung injury
These initiatives would be informed by studies that address the basic/translational science priorities described above

V′/Q: ventilation/perfusion; PIAT: pulmonary impairment after TB; IPF: idiopathic pulmonary fibrosis; COPD: chronic obstructive pulmonary disease; CT: computed tomography; PET: positron emission tomography; PFT: pulmonary function test.