Review
Lung transplantation for idiopathic pulmonary fibrosis

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Summary

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis. Lung transplantation is the only intervention shown to increase life expectancy for patients with IPF, but it is associated with disease-specific challenges. In this Review, we discuss the importance of a proactive approach to the management of IPF comorbidities, including gastro-oesophageal reflux, pulmonary hypertension, coronary artery disease, and malignancy. With a donor pool too small to meet demand and unacceptably high mortality on transplant waiting lists, we discuss different systems used internationally to facilitate organ allocation. We explore the rapidly evolving landscape of transplantation for patients with IPF with regards to antifibrotic therapy, technological advances in extracorporeal life support, advances in understanding of the genetics of the disease, and the importance of a holistic multidisciplinary approach to care. Finally, we consider potential advances over the next decade that are envisaged to improve transplantation outcomes in patients with advanced IPF.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring lung disease of unknown cause. It has a poor prognosis with a median survival of 3·8 years (95% CI 3·5–3·8) from time of diagnosis in adults aged 65 years or older.1 IPF is characterised by a usual interstitial pneumonia pattern on high-resolution CT scanning, as defined by basal predominant reticulation, traction bronchiectasis and honeycombing. Histologically, these features are represented by heterogenous paraseptal fibrosis, architectural distortion, and fibroblastic foci.2

The antifibrotic drugs pirfenidone3 and nintedanib4 slow the rate of lung function decline, but despite treatment, the usual course of the condition is for patients to progress inexorably to end-stage respiratory failure, secondary pulmonary hypertension, and death. Comorbidities including cardiac disease and gastro-oesophageal reflux contribute to the disease burden, and acute exacerbations accelerate decline towards death. When medical options have been exhausted, the only treatment with the potential to improve quality of life and survival is lung transplantation.

In this Review, we consider the indications and specific challenges associated with lung transplantation in IPF. We discuss modifiable patient factors and perioperative management strategies that can be used to optimise outcomes. We address the discordance between transplantation referral criteria for IPF and the realities of organ availability, and describe novel technological approaches to support patients until organs become available. Finally, accurately predicting IPF disease course remains a challenge; therefore, we consider methods of ensuring that the most suitable patients with IPF are referred for lung transplantation at the most appropriate time.

Section snippets

When to consider referral for transplantation

The poor prognosis and the potential for accelerated decline in IPF mean that early referral is recommended.5 Robust survival data for IPF in the era of antifibrotic therapy are awaited, given the low mortality in clinical trials. Although pooled analyses of clinical trials have demonstrated a beneficial effect of pirfenidone6 and nintedanib7 on mortality, clinical trials exclude patients with comorbidities and advanced disease—ie, the patient group with the highest mortality. Real-world

Pulmonary hypertension

Perhaps the most important comorbidity is pulmonary hypertension, evident in up to 85% of patients with IPF on the US transplant waiting list,20 and underestimated by transthoracic echocardiography,21 leaving right heart catheterisation as the only accurate diagnostic method (figure 1). No proven benefits have been reported for interventions to treat pulmonary hypertension in the preoperative period, but accurate assessment of mean pulmonary artery pressure and right ventricular function is

Current indications and timing

Patients listed for lung transplantation are generally accepted as being those for whom no other treatment option is available, who have a greater than 50% chance of death within 2 years without transplantation, and a projected postoperative survival of at least 5 years. The ISHLT provides recommendations for transplant listing of appropriate patients with interstitial lung disease (panel 2).5

Palliative care for patients with IPF awaiting lung transplantation

Early palliative care referral is recommended as an adjunct to disease-focused care in IPF.51 The UK

Organ allocation

The first successful isolated lung transplantation, performed in 1983, was for pulmonary fibrosis.69 Since then, limited donor organ availability, uptake of less than 30% of organs offered for transplant, and a broadening of the indications for lung transplantation have resulted in demand exceeding supply and contributed to mortality on the waiting list. Historically, patients with IPF have had higher waiting list mortality than patients with other common indications for transplantation, with

Single versus bilateral lung transplant

The surgical procedures used for lung transplantation are SLT, BSSLT (figure 3), bilateral lobar transplantation, and heart-lung transplantation. Little evidence exists regarding the merits of SLT versus BSSLT in IPF, but in most cases, BSSLT is done, and the percentage of bilateral transplants is increasing.77 According to reports from the ISHLT database, 39% of patients with IPF receive an SLT and 61% receive a BSSLT.77

Across all lung transplantation indications, the advantages of BSSLT are

Future directions

IPF remains an unpredictable disease of unknown cause. In coming years, a more sophisticated understanding of the interaction between host genetics and environmental influences should allow a more nuanced definition of IPF disease endotypes. Not all patients with IPF appear to progress at the same rate and treatment responses vary between individuals. Integrating novel molecular biomarkers with radiological modelling95 and deep learning algorithms96 could allow physicians to better identify

Search strategy and selection criteria

We obtained the articles for this Review by searching PubMed for articles published from Jan 1, 1986, to Jan 25, 2019, using the individual search terms “IPF”, “idiopathic pulmonary fibrosis”, “lung transplantation”, “antifibrotic”, “pirfenidone”, “nintedanib”, “transplant listing”, “PPFE”, “telomeropathy”, “lung allocation score”, “ECMO”, “extra-corporeal life support”, “single lung transplant”, “bilateral lung transplant”, and “ex vivo lung perfusion”; we also searched the term “IPF” in

References (97)

  • D Hayes et al.

    Effect of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis after lung transplantation: an analysis of the United Network of Organ Sharing registry

    J Heart Lung Transplant

    (2015)
  • AW Castleberry et al.

    Coronary revascularization in lung transplant recipients with concomitant coronary artery disease

    Am J Transplant

    (2013)
  • M Koprivanac et al.

    How important is coronary artery disease when considering lung transplant candidates?

    J Heart Lung Transplant

    (2016)
  • M Kreuter et al.

    Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis

    Lancet Respir Med

    (2016)
  • G Raghu et al.

    Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial

    Lancet Respir Med

    (2018)
  • MG Hartwig et al.

    Fundoplication after lung transplantation prevents the allograft dysfunction associated with reflux

    Ann Thorac Surg

    (2011)
  • E Cantu et al.

    J Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease

    Ann Thorac Surg

    (2004)
  • T Lee et al.

    Lung cancer in patients with idiopathic pulmonary fibrosis: clinical characteristics and impact on survival

    Respir Med

    (2014)
  • LE Hendriks et al.

    Lung cancer in idiopathic pulmonary fibrosis patients diagnosed during or after lung transplantation

    Respir Med Case Rep

    (2012)
  • J Jacob et al.

    Functional associations of pleuroparenchymal fibroelastosis and emphysema with hypersensitivity pneumonitis

    Respir Med

    (2018)
  • CA Newton et al.

    Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival

    J Heart Lung Transplant

    (2017)
  • D Visca et al.

    Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial

    Lancet Respir Med

    (2018)
  • G Leuschner et al.

    Outcome of lung transplantation in idiopathic pulmonary fibrosis with previous anti-fibrotic therapy

    J Heart Lung Transplant

    (2018)
  • R Vos et al.

    Pirfenidone in restrictive allograft syndrome after lung transplantation: a case series

    Am J Transplant

    (2018)
  • M Kreuter et al.

    Palliative care in interstitial lung disease: living well

    Lancet Respir Med

    (2017)
  • M Alakhras et al.

    Body mass index and mortality in patients with idiopathic pulmonary fibrosis

    Chest

    (2007)
  • CS King et al.

    Idiopathic pulmonary fibrosis: effects and optimal management of comorbidities

    Lancet Respir Med

    (2017)
  • KO Lindell et al.

    Palliative care and location of death in decedents with idiopathic pulmonary fibrosis

    Chest

    (2015)
  • CJ Ryerson et al.

    Pulmonary rehabilitation improves long-term outcomes in interstitial lung disease: a prospective cohort study

    Respir Med

    (2014)
  • RD Yusen et al.

    Lung transplantation in the United States, 1999–2008

    Am J Transplant

    (2010)
  • ES Weiss et al.

    Lung allocation score predicts survival in lung transplantation patients with pulmonary fibrosis

    Ann Thorac Surg

    (2009)
  • G Thabut et al.

    Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis

    J Thorac Cardiovasc Surg

    (2003)
  • M Cypel et al.

    Extracorporeal life support as a bridge to lung transplantation

    Clin Chest Med

    (2011)
  • M Biscotti et al.

    Awake extracorporeal membrane oxygenation as bridge to lung transplantation: a 9-year experience

    Ann Thorac Surg

    (2017)
  • MG Hartwig et al.

    Improved results treating lung allograft failure with venovenous extracorporeal membrane oxygenation

    Ann Thorac Surg

    (2005)
  • MA Villavicencio et al.

    Single- versus double-lung transplantation in pulmonary fibrosis: impact of age and pulmonary hypertension

    Ann Thorac Surg

    (2018)
  • BC Gulack et al.

    what is the optimal transplant for older patients with idiopathic pulmonary fibrosis?

    Ann Thorac Surg

    (2015)
  • ES Weiss et al.

    Survival after single versus bilateral lung transplantation for high-risk patients with pulmonary fibrosis

    Ann Thorac Surg

    (2009)
  • MG Hartwig et al.

    Staging of bilateral lung transplantation for high-risk patients with interstitial lung disease: one lung at a time

    Am J Transplant

    (2016)
  • JB Orens et al.

    A review of lung transplant donor acceptability criteria

    J Heart Lung Transplant

    (2003)
  • ME Bowdish et al.

    A decade of living lobar lung transplantation: perioperative complications after 253 donor lobectomies

    Am J Transplant

    (2004)
  • SLF Walsh et al.

    Deep learning for classifying fibrotic lung disease on high-resolution computed tomography: a case-cohort study

    Lancet Respir Med

    (2018)
  • G Raghu et al.

    Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline

    Am J Respir Crit Care Med

    (2018)
  • TE King et al.

    A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis

    N Engl J Med

    (2014)
  • L Richeldi et al.

    Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis

    N Engl J Med

    (2014)
  • M Fisher et al.

    Predicting life Expectancy for pirfenidone in idiopathic pulmonary fibrosis

    J Manag Care Spec Pharm

    (2017)
  • HE Jo et al.

    Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry

    Eur Respir J

    (2017)
  • KR Flaherty et al.

    Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia

    Am J Respir Crit Care Med

    (2003)
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