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Tuberculosis and lung damage: from epidemiology to pathophysiology

Shruthi Ravimohan, Hardy Kornfeld, Drew Weissman, Gregory P. Bisson
European Respiratory Review 2018 27: 170077; DOI: 10.1183/16000617.0077-2017
Shruthi Ravimohan
1Dept of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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  • For correspondence: shruthir@pennmedicine.upenn.edu
Hardy Kornfeld
2Dept of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
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Drew Weissman
1Dept of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Gregory P. Bisson
1Dept of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
3Dept of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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  • FIGURE 1
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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.

  • FIGURE 2
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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.

  • FIGURE 3
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    FIGURE 3

    Conceptual model of factors that potentially contribute to lung impairment after tuberculosis (TB). MTB: Mycobacterium tuberculosis.

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  • TABLE 1

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

    TermDefinition
    Pulmonary cavitationProcess 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 fibrosisResults 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.
    BronchiectasisManifests 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 TBA 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 studySettingSample size nExposureOutcomeAssociation/findingMajor limitation
    Akkara [18]Cross-sectionalIndia257Treated TB
    (2 weeks post-treatment completion)
    Airflow obstruction measured by FEV1 and FVCAirflow obstruction in 86.8% of patientsLung 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-sectionalSouth Africa71History 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 predObstruction 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-sectionalTanzania501Treated TB (20 weeks of anti-TB therapy)Airflow defects measured by FEV1 and FVCLung 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]RetrospectiveSouth Africa27 660History of 1, 2 or ≥3 episodes of TBAirflow 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 retrospectiveSouth Africa185 TB cases versus 185 age-matched controls without history of TBHistory of TBLung function loss over time measured by FEV1 and FVCHistory 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]RetrospectiveRepublic of Korea595Destroyed lung resulting from a past history of TBLung function loss measured by FEV1 and FVCLung impairment after TB in 76.8% of patientsCohort 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 cohortSouth Africa74TB treatmentLung function at the end of TB treatment54% 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 cohortIndonesia69TB treatmentLung function over the course of TB treatmentLung function improved over the course of TB treatment; however, 25% of the patients had residual moderate-to-severe TB (FEV1 <60%) at treatment completionStudy 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 cohortIndonesia200TB treatmentLung function over the course of treatment and at treatment completion47% 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–controlUSA107 active TB cases versus 210 latent TB controlsTreated TB (20 weeks of anti-TB therapy)Airway obstruction defined as FEV1/FVC <70% pred and FVC >80% predTB 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 adults18 high and low-/middle-income countries14 050History of TBAirflow defects: obstruction defined as post-bronchodilator FEV1/FVC less than LLN; restriction defined as post-bronchodilator FVC less than LLNObstruction: 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-based5 Latin American cities5571 patients; 132 with a diagnosis of TBHistory of TBCOPDPrevalence 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]RetrospectiveTaiwan3176 pulmonary TB cases versus 15 880 matched controlsHistory of TBCOPDHistory 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-analysisMultiples countriesHistory of TBCOPDHistory 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/genePolymorphismImplication on lung pathology/functionReference
      TB
       MMP-1MMP-1 -1607G (1G) (rs1799750)Extensive fibrosis after 1 year of TB treatment
      Cavitary disease
      Endobronchial TB and tracheobronchial stenosis
      [145–147]
       MCP-1+MMP-1MCP-1 -2518G (G/G)
      (rs1024611)
      MMP-1 -1607GG (2G/2G) Guanine
       insertion at this locus
      Permanent lesions after TB treatment
      Fibrosis
      Bronchiectasis
      [148]
       TOLLIPTOLLIP
      rs5743899 rs3750920
      Decreased TOLLIP mRNA expression
      Increased inflammatory cytokine expression
      Increased risk for TB
      [149]
      COPD
       MMP-1+MMP-12MMP-1 2G+MMP-12 nsSNP
      (rs652438)
      Increased rate of lung function decline[150]
       MMP-9MMP-9 -1562C/TIncreased risk of COPD in a Korean population[151]
       MMP-12MMP-12
      rs652438 and rs2276109
      Severe (GOLD stage III) and very severe COPD (GOLD IV), lower FEV1 %[152]
       TIMP-2TIMP-2
      +853G/A
      -418G/C
      Increased risk for COPD
      Decreased transcription and stability of mRNA
      [153]
       TNF-αTNF-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-8IL-8
      rs4073
      rs2227306
      rs2227307
      Significant decrease in FEV1 and FVC during follow-up of COPD patients[156]
      IPF
       TGF-β+TNF-αTGFβ (rs1800469)
      +TNF-α (rs361525)
      Additive effect on lung impairment measured as FEV1[157]
       IL-6IL-6 -174G/CDecrease in FEV1[158]
       IL-1RAIL-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-αTNF-α -308G/A
      (rs1800629)
      Fibrosing alveolitis risk[159]
       IL-6IL-6 intron 4A/GLower carbon monoxide diffusion[161]
       TGF-βTGF-β
      Codon 10T/C(rs1982073)
      Codon 25G/C(rs1800471)
      Decreased gas exchange in IPF patients[162, 163]

       MUC5BMUC5B rs35705950
      rs868903
      Associated with pulmonary fibrosis in genome-wide association
       studies
      Increased MUC5B expression
      [164–166]

       TOLLIPTOLLIP
      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.

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          G.P. Bisson ERR-0077-2017_Bisson

          S. Ravimohan ERR-0077-2017_Ravimohan

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        Tuberculosis and lung damage: from epidemiology to pathophysiology
        Shruthi Ravimohan, Hardy Kornfeld, Drew Weissman, Gregory P. Bisson
        European Respiratory Review Mar 2018, 27 (147) 170077; DOI: 10.1183/16000617.0077-2017

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        Tuberculosis and lung damage: from epidemiology to pathophysiology
        Shruthi Ravimohan, Hardy Kornfeld, Drew Weissman, Gregory P. Bisson
        European Respiratory Review Mar 2018, 27 (147) 170077; DOI: 10.1183/16000617.0077-2017
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        • Article
          • Abstract
          • Abstract
          • Introduction
          • Search strategy
          • PIAT
          • Mediators of lung damage and dysfunction in TB
          • Genetic predisposition for lung injury in TB
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        • Respiratory infections and tuberculosis
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