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Lung transplantation for interstitial lung diseases

Gottlieb, Jens

Current Opinion in Pulmonary Medicine: September 2014 - Volume 20 - Issue 5 - p 457–462
doi: 10.1097/MCP.0000000000000090
INTERSTITIAL LUNG DISEASE: Edited by Francesco Bonella and Steven D. Nathan

Purpose of review An overview over the role of lung transplantation in interstitial lung diseases will be given.

Recent findings Lung transplantation is an established therapy option for patients with various end-stage lung diseases. Currently, the worldwide procedural frequency is about 3600 per year. Unfortunately, the shortage of donor organs leads to approximately every sixth patient in western countries dying before a donor organ is available. The most frequent underlying clinical indications are emphysema, pulmonary fibrosis, and cystic fibrosis. In a recent registry report worldwide, 23% of all lung transplant recipients had a diagnosis of idiopathic pulmonary fibrosis. In experienced centers, candidates for transplantation are chosen according to disease-specific factors after excluding contra-indications. However, there are several challenges for lung transplantation. The number of lung transplantations performed is limited by the supply of donor organs, and the long-term survival rates are still inferior compared with other forms of solid organ transplantation.

Summary Lung transplantation offers a survival benefit in carefully selected patients with interstitial lung diseases.

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany

Correspondence to Jens Gottlieb, Department of Respiratory Medicine, Hannover Medical School, OE6870, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel: +00 49 511 532 4681; fax: +00 49 511 532 8094; e-mail: gottlieb.jens@mh-hannover.de

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INTRODUCTION

The idiopathic interstitial pneumonias are a group of clinical and pathological entities, which have different clinical features and prognosis. The most frequent form is idiopathic pulmonary fibrosis (IPF), followed by nonspecific interstitial pneumonia and other forms. IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and associated with the histo-pathologic and/or radiologic pattern of usual interstitial pneumonia (UIP) [1]. Currently, 23% of the worldwide lung transplantation (LTx) procedures are performed in patients with IPF [2▪]. The diagnosis of nonspecific interstitial pneumonia is frequently associated with connective tissue diseases (CTDs) [3]. These patients account for less than 4% of indications worldwide. Other forms of idiopathic interstitial pneumonias (including cryptogenic organizing pneumonia and desquamative interstitial pneumonia) are not typical indications for LTx.

In explanted lungs of patients transplanted for interstitial lung disease (ILD), 80% had a histological diagnosis of UIP [4]. ILD associated with CTD offers usually a more favorable prognosis, and selection criteria should be more restrictive and distinct from those of IPF patients.

Box 1

Box 1

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EPIDEMIOLOGY

According to the registry of the International Society of Heart and Lung Transplantation, currently the worldwide procedural frequency is about 3600 per year. The proportion of patients transplanted with IPF has increased constantly during recent years. With implementation of the lung allocation score (LAS) in 2005, which balances the estimated risk of death on the waiting list and predicted survival probability after transplantation, lung transplantation for IPF increased in the United States from 23% of all transplantations in 2004 to 33% in 2007, and IPF has become the most frequent disease for which lung transplantation is performed in the United States [5▪].

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CHOICE OF TRANSPLANT OPERATION

Historically, there have been three operative procedures with each procedure having its own advantages, including single lung (SLTx), bilateral or double lung (DLTx), and heart or lung transplantation (HLTx). Except rare cases of an associated severe cardiac disease as an indication for HLTx, in recent years all procedures in ILD are performed as single or sequential bilateral transplantations [2▪].

Early proponents of SLTx argued that it is technically an easier procedure to perform, has less early morbidity and mortality compared with DLTx and HLTx and allows more patients to receive lung transplants. Opponents argued that patients transplanted with a single lung are more at risk not only for developing primary graft dysfunction [6,7], but also for lower functional reserve [8] in case of acute or chronic lung allograft dysfunction, both adversely affecting early and late survival and functional outcome. Primary graft dysfunction, formerly known as reperfusion injury, may result and is often associated with prolonged ventilation and risk of infection. Nevertheless, SLTx is a satisfactory procedure in patients with ILD even with pulmonary hypertension with no differences in outcome when compared with a group without pulmonary hypertension [9].

Proponents of DLTx have argued that this procedure results in fewer ventilation or perfusion mismatches and as a result, patients are easier to look after in the immediate postoperative period. Moreover, this allows more marginal donor lungs to be utilized and hence makes best of the rare resource of donor lungs. Patients also have better pulmonary function and better long-term survival because of avoidance of native lung complications (e.g., pneumothorax, infection) and a better functional reserve. The most devastating native lung complication is lung cancer, which occurs in 4% of long-term survivors after SLTx [10].

No prospective randomized studies are available to relieve the uncertainty as to the best lung transplant procedure for patients with ILD. In practice, approximately 50% of recipients with IPF now receive DLTx [2▪].

In an extensive United States’ registry analysis, 3327 patients with IPF who had single (65%) or bilateral (35%) lung transplantation between 1987 and 2009 were studied for survival and causes of death after lung transplantation. Survival times for the two procedures did not differ after adjustment for baseline differences. DLTx seemed to result in harm within the first year (hazard ratio, 1.18) but survival benefit thereafter (hazard ratio, 0.72). Primary graft failure was a more common cause of death among patients who had bilateral rather than SLTx; in SLTx recipients’ malignancy was more frequent [11].

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GENERAL CONSIDERATIONS IN CANDIDATE SELECTION AND TIMING OF TRANSPLANTATION

The goal of lung transplantation is to improve survival and quality of life. To prolong survival by LTx, the natural expected survival without LTx should be lower than 50% in 5 years. LTx is a high-risk surgical procedure with a 3-month mortality of approximately 10–15% depending on the condition of the patient. General contra-indications for candidate selection should be respected facing the situation of donor shortage. Absolute contra-indications to lung transplantation are as follows:

  1. lack of social support,
  2. evidence of Mycobacterium tuberculosis infection and chronic infection with highly resistant pathogens,
  3. significant chest wall or spine deformity with an expected significant restrictive disorder after transplantation,
  4. tobacco and/or substance abuse without prolonged abstinence,
  5. psychiatric problems associated with impaired ability to cooperate,
  6. nonadherence to medical therapy, either present or prolonged episodes in history,
  7. untreatable significant nonrespiratory (e.g., heart, liver, kidney, brain) organ damage,
  8. recent (within 2 years) history of malignancy,
  9. class II or III obesity (BMI >35 kg/m2).

Relative contra-indications to lung transplantation are as follows:

  1. age over 65 years,
  2. class I obesity (BMI 30–35 kg/m2),
  3. severe, symptomatic ostoporosis,
  4. extensive prior chest surgery,
  5. colonization with highly resistant and virulent pathogens (e.g., Burkholderia cenocepacia or Mycobacterium abscessus),
  6. nonadherence to medical therapy, either present or prolonged episodes in history,
  7. untreatable significant nonrespiratory (e.g., heart, liver, kidney, brain) organ damage,
  8. HIV infection, given that clinically stable (CD4 cells >400/μl), compliant with therapy and undetectable viral load,
  9. hepatitis B or C without cirrhosis or portal hypertension,
  10. mechanical ventilation and/or extracorporeal support,
  11. severe atherosclerotic disease with a high risk of end-organ damage.

The International Society of Heart and Lung Transplantation recommends an upper age limit for transplantation of 65 years, although there are variations between centers and countries reflecting local views. The age criteria are influenced by data showing a progressive increase in mortality for procedures in patients over the age of 55 years [2▪]. Meanwhile in the United States, the proportion of recipients of 65 years and older has grown to 22% [5▪]. Acceptable short-term outcomes were reported in the elderly although long-term survival is of concern.

Overweight and moderate obesity are considered relative contra-indications to lung transplantation. Retrospectively, 11 411 adults were examined who underwent lung transplantation in the United States between 1998 and 2008. Compared with normal-weight recipients, the multivariable-adjusted rates of death were 14% higher for overweight recipients and 16% higher for moderately (class I) obese recipients. These relationships were no longer present when first-year deaths were excluded [12]. A BMI of equal to or greater than 35 kg/m2 is considered an absolute contra-indication to LTx in most centers.

The presence of uncontrolled systemic disease in addition in respiratory failure precludes lung transplantation. Any cancer except for nonmelanotic skin cancer should be in remission at least 2 years before listing a possible transplant candidate [13]. Smoking and illicit drug abuse is not acceptable in LTx candidates and abstinence for at least 6 months is required and should be documented by blood or urine tests (e.g., cotinine).

Good renal function is essential in view of calcineurine-inhibitor toxicity and a creatinine clearance of at least 40 ml/min/1.73 m2 is required.

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SPECIAL CONSIDERATIONS IN IDIOPATHIC PULMONARY FIBROSIS

A small single-center study has examined the survival benefit of lung transplantation in IPF. Forty-six patients accepted for lung transplantation during a 12-year period with a diagnosis of IPF were assessed using Cox proportional hazards modeling, with patients on the waiting list serving as the control group. Twenty-eight patients underwent lung transplantation, 16 patients died while waiting, and two patients remained on the active waiting list. Survival after lung transplantation was 79% at 1 year, and 39% at 5 years. The multivariable analysis showed that lung transplantation reduced the risk of death by 75% after adjustment for potential confounding variables [14]. In another single-center retrospective analysis in a transplant center, 31% of 129 patients (mean age 63 years) were transplanted and 27 died without transplant during a mean follow-up of 1.1 years. An increased risk of death was observed in candidates whose referral was delayed and in those patients with multiple comorbidities [15].

The median 5-year survival rate of unselected patients with IPF is 30–35% [16,17]. There is no cure for IPF, and treatment options are limited. Currently available pharmacological therapies have not been associated with improved survival. Lung transplantation is thus far the only treatment associated with a better survival for eligible patients.

Available longitudinal studies do not allow a clear assessment of median survival in unselected IPF patients. A retrospective longitudinal study in 238 patients suggested a median survival time of 2.9 years from the time of diagnosis and 6.8 years from the estimated onset of the illness [18]. However, analysis of recent data from clinical trials has enabled the identification of patients with a possible poor prognosis. Features associated with decreased survival are increased level of dyspnea, a diffusion capacity of lower than 40% predicted, desaturation lower than 89% during the 6-min walk test (6MWT), extensive honeycombing on high-resolution computed tomography scan, and the presence of pulmonary hypertension. Longitudinal changes, including a decrease in the forced vital capacity (FVC) of more than 10% absolute value, worsening of fibrosis on high-resolution computer tomography, and decrease in diffusion capacity, were negative prognostic indicators as well.

Recently, several scoring systems to predict prognosis have been proposed. The problems with these prognostic studies are that they are mainly retrospective and that the cohorts studied are not typical transplant candidates. Most patients are older than 65 years and have many comorbidities that independently affect survival.

International guidelines recommend that candidates with pulmonary fibrosis should be referred as early as possible, irrespective of the FVC [13]. The same group of experts suggest that these patients should be activated on the waiting list when the diffusion capacity is less than 39% predicted, or if they have a 10% or greater decrement in FVC during 6 months of follow-up, or have a decrease in their pulse oximetry below 89% [13]. The importance of desaturation in ILD patients was emphasized in a single-center retrospective study in 105 early patients, 83 of whom had IPF. Forty-six required long-term oxygen prior to the 6MWT. A oxygen saturation (SpO2) lower than 89% was associated with a 5-year survival was 20% compared with 60% in those without desaturation [19]. Suggested new and established IPF-specific indications and contra-indications for lung transplantation have been summarized. Indications for IPF are as follows.

Indications in IPF (UIP pattern on computed tomography or biopsy):

  1. SpO2 lower than 89% during 6-min walk testing,
  2. long-term oxygen therapy,
  3. FVC less than 50% predicted or absolute FVC decline more than 10%/6 months,
  4. mean PAP more than 25 mm Hg,
  5. diffusion capacity less than 35% predicted or not measurable.

Resting oxygen demand before 6MWT was examined in 104 adults (mean 62 years) with IPF enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of ILDs. The oxygen flow rate required to maintain a saturation of 96% while standing was associated with a greater mortality rate independent of FVC and 6MWT results in IPF [20▪].

A single-center study with prospective validation in 228 and 330 patients (median 68 years) identified older age, female gender, a FVC below 50%, and a diffusion capacity less than 50% as negative prognostic indicators. Three stages (stages I, II, and III) were identified on the basis of this index with 1-year mortalities of 6, 16, and 39%, respectively [21].

The development of pulmonary hypertension can complicate IPF. In a retrospective analysis of 79 patients, 32% demonstrated a mean pulmonary artery pressure (PAP) of greater than 25 mmHg. Those patients with pulmonary hypertension had a lower mean diffusing capacity, lower 6MWT and were more likely to require supplemental oxygen. One-year mortality rates were higher in those with pulmonary hypertension (28 vs. 6%) [22].

There is now increased recognition that the underlying histology of lung fibrosis associated with CTD may vary from that of IPF, particularly in those individuals with scleroderma-associated pulmonary fibrosis. A total of 324 cases of CTD–ILD (65% rheumatoid arthritis, 14% systemic sclerosis, 19% miscellaneous) and 2209 cases of IPF were followed up over an average period of 2.3 years. The median survival for cases with IPF (median 3.1 years) was significantly lower than those with CTD-ILD (median 6.6 years for rheumatoid arthritis, 8.8 years for systemic sclerosis, and 5.6 years for other ILD) [23].

It has been suggested that patients with non-IPF ILD (including sarcoidosis and scleroderma) should be evaluated for LTx if disease progression occurs in the context of advanced patients with FVCs less than 50% or those with hypoxemia (pO2 <55 mm Hg) at rest and/or ‘out of proportion’ pulmonary hypertension [24]. ‘Out of proportion’ pulmonary hypertension was recently proposed as mean PAP more than 35 mmHg, or mean PAP ≥ 25 and confidence interval < 2.0 l/min/m2) [25]. In scleroderma and sarcoidosis, significant extrapulmonary disease (especially kidney and esophageal) should also be excluded.

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ALLOCATION

Allocation criteria may differ by geographic region, including nationally and internationally. Other factors that influence allocation include urgency determined by individual characteristics or objective scoring systems and may also be on the basis of waiting times. On an international level, we frequently see the combination of several criteria. The so-called center decision with regional distribution is most common in Europe, also with a distribution according to waiting period or urgent case definition. With current allocation schemes considering waiting time with or without an urgency option, overall wait list mortality of patients with IPF is up to 49% [26].

In May 2005 and December 2011, lung allocation for transplantation in the United States and Germany, respectively, changed from a system on the basis of waiting time to a system on the basis of the LAS for patients 12 years of age and older. The LAS is a numerical value used to assign relative priority for distributing donated lungs for transplantation. The LAS takes into account various measures of a patient's health to direct donated organs toward the patients who would best benefit from a lung transplant. LAS scores range from 0 to 100, and patients with higher scores, reflecting greater predicted survival benefit, get priority. One-year wait list mortality of IPF patients has decreased from 21 to 11% since the introduction of the LAS in the United States and transplant activity for ILD has also increased since then [27]. The wait list mortality has also been reduced in Germany since the introduction of the LAS system [28].

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BRIDGING TO TRANSPLANTATION

Patients with IPF may develop respiratory failure while actively listed for transplantation. Lung transplantation of patients on mechanical ventilation is controversial because of impaired survival. In a recent retrospective analysis of all ventilated LTx candidates in a single center, factors associated with survival were evaluated [29]. In 100 intubated patients, 24% of whom had IPF, 60 required additional extracorporeal support. Sixty patients were transplanted, five were weaned from mechanical ventilation, and 38 died while on the wait list. One-year-survival rates were 57, 36, and 5% for transplanted patients, all candidates and nontransplanted candidates, respectively. Escalating therapy and an abnormal procalcitonin level were associated with poor outcomes. The successful bridging with use of an extracorporeal membrane oxygenation in awake patients with IPF has also been described [30].

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RESULTS

Unadjusted 3-month mortality rate after transplantation is 15% in IPF recipients, while the 5-year survival among those surviving at least 1 year has been reported at 61% [2▪]. Bilateral recipients can expect to attain their normal predicted FVC and forced expiratory volume in 1 second by 1 year in the absence of complications [8]. All patients can hope for restoration of a normal lifestyle with little or no functional restriction during normal activities of daily living. Six-min walking distance and maximum oxygen consumption during an incremental symptom-limited exercise test demonstrated no difference between recipients of a unilateral and bilateral procedure, [8]. Nevertheless, the functional results allow restoration of a comfortable lifestyle. Over the first year after lung transplantation, quality of life significantly increased from baseline levels for all native diseases [31▪].

There has been great interest in the study of lungs after successful lung transplantation to see if the acquired lung disease will recur in the allografts. To date, there is no evidence of IPF recurring in lung allografts. Asymptomatic recurrence of noncaseating granulomas in sarcoidosis is frequently found on transbronchial biopsies.

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CONCLUSION

Lung transplantation is an established therapeutic option for patients with various forms of end-stage lung disease. Unfortunately, the shortage of donor organs leads to approximately every sixth patient in western countries dying before a suitable donor organ becomes available. This is especially of concern in patients with IPF, the most frequent ILD referred for transplantation. In a recent worldwide analysis of transplant recipients, 23% of all recipients had the diagnosis of IPF [2▪]. In experienced centers, candidates for transplantation are chosen according to disease-specific factors after excluding contra-indications. Specific transplant recommendations have been published for ILDs including IPF. The number of lung transplants performed remains limited by the supply of donor organs and the long-term survival rates are still inferior compared with other forms of solid organ transplantation with a 5-year survival rate of approximately 55%. Lung transplantation offers a survival benefit in carefully selected patients with IPF and other forms of ILD.

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Acknowledgements

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183:788–824.
2▪. Yusen RD, Christie JD, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report – 2013; focus theme : age. J Heart Lung Transplant 2013; 32:965–978.

This official registry report summarizes data from international 43 428 adult lung transplant recipients that occurred through 30 June 2012. This report describes donor and recipient characteristics, transplant type, and recipient outcomes data with a special focus on age.

3. Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med 2007; 176:691–697.
4. Mackay LS, Anderson RL, Parry G, et al. Pulmonary fibrosis: rate of disease progression as a trigger for referral for lung transplantation. Thorax 2007; 62:1069–1073.
5▪. Valapour M, Paulson K, Smith JM, et al. OPTN/SRTR 2011 Annual Data Report: lung. Am J Transplant 2013; 13 (Suppl 1):149–177.

This registry report summarizes data from United States from 1998 to 2011 and demonstrates improved both graft and patient survival with a rapidly growing population of patients transplanted over the age of 65.

6. Boujoukos AJ, Martich GD, Vega JD, et al. Reperfusion injury in single-lung transplant recipients with pulmonary hypertension and emphysema. J Heart Lung Transplant 1997; 16:439–448.
7. Bando K, Keenan RJ, Paradis IL, et al. Impact of pulmonary hypertension on outcome after single-lung transplantation. Ann Thorac Surg 1994; 58:1336–1342.
8. Bartels MN, Armstrong HF, Gerardo RE, et al. Evaluation of pulmonary function and exercise performance by cardiopulmonary exercise testing before and after lung transplantation. Chest 2011; 140:1604–1611.
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13. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update – a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006; 25:745–755.
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In this study, a higher titrated oxygen requirement was associated with a greater mortality rate independent of FVC and 6MWT results in 104 patients with IPF [adjusted hazard ratio [per 1 L.min(-1)] 1.16, 95% confidence interval 1.06–1.27]. Findings were similar in other ILDs.

21. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012; 156:684–691.
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24. Gottlieb J. Cordier JF. European Respiratory SocietyRare indications for lung transplantation. European Respiratory Society monograph 54th ed.Sheffield:European Respiratory Society; 2011. 332–340.
25. Hoeper MM, Andreas S, Bastian A, et al. Pulmonary hypertension due to chronic lung disease: updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol 2011; 154 (Suppl 1):S45–S53.
26. Titman A, Rogers CA, Bonser RS, et al. Disease-specific survival benefit of lung transplantation in adults: a national cohort study. Am J Transplant 2009; 9:1640–1649.
27. Chen H, Shiboski SC, Golden JA, et al. Impact of the lung allocation score on lung transplantation for pulmonary arterial hypertension. Am J Respir Crit Care Med 2009; 180:468–474.
28. Gottlieb J, Greer M, Sommerwerck U, et al. Introduction of the lung allocation score in Germany. Am J Transplant 2014; 14:1318–1327.
29. Gottlieb J, Warnecke G, Hadem J, et al. Outcome of critically ill lung transplant candidates on invasive respiratory support. Intensive Care Med 2012; 38:968–975.
30. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. Am J Respir Crit Care Med 2012; 185:763–768.
31▪. Finlen Copeland CA, Vock DM, Pieper K, et al. Impact of lung transplantation on recipient quality of life: a serial, prospective, multicenter analysis through the first posttransplant year. Chest 2013; 143:744–750.
Keywords:

idiopathic pulmonary fibrosis; interstitial lung disease; lung allocation score; lung transplantation; outcome assessment; selection criteria

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