Idiopathic Pulmonary Fibrosisppt - casemedicinecom.ppt by censhunay

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									Idiopathic Pulmonary Fibrosis

       Brian D. Southern

    Senior Talk August 2008
                  OBJECTIVES

Know the definitions of ILD, IIP, and IPF

Understand the pathogenesis of IPF

Appreciate the clinical features
Realize how the diagnosis of IPF is made
Know current therapies

Become aware of areas of current research
and novel therapeutic approaches
Be able to summarize current thinking about
IPF
          Interstitial Lung Disease (ILD) or
     Diffuse Parenchymal Lung Disease (DPLD)

 Any process that results in
inflammatory-fibrotic infiltration of the
alveolar septa resulting in effects on the
capillary endothelium and alveolar
epithelium.



 Generic term used to describe many
conditions that cause breathlessness
and/or cough and are associated with
radiographic bilateral lung abnormalities.
                                             Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.




“Death occurred about three months and a half after the onset of the acute
disease and the lung was two thirds of the normal size, grayish in color, and hard
as cartilage. Microscopically these areas showed advanced fibrotic changes and
great thickening of the alveolar walls.”
 - Sir William Osler, 1892
                           INTERSTIAL LUNG DISEASES
Connective Tissue Diseases              Treatment-Related / Drug-Induced
Scleroderma                             Antibiotics – nitrofurantoin, sulfasalazine
Polymyositis-Dermatomyositis            Antiarrhythmics – amiodarone, propanolol
Systemic Lupus Erythematosus            Anti-inflammatories – gold, penacillamine
Rheumatoid Arthritis                    Anti-convulsants – dilantin
Mixed Connective Tissue Disease         Chemotherapeutic agents – bleomycin, cyclophosphamide,
Ankylosing Spondyitis                   methotrexate, azathioprine
                                        Therapeutic radiation
                                        Oxygen toxicity
Primary (Unclassified)
                                        Narcotics
Sarcoidosis
Langerhans cell histiocytosis
                                        Occupational and Environmental Diseases
Amyloidosis
Pulmonary vasculitis
                                        Inorganic                               Organic
Lipoid pneumonia
Lymphangitic carcinomatosis
                                        Silicosis                               Bird breeder’s lung
Bronchoalveolar carcinoma
                                        Asbestosis                              Farmer’s lung
Pulmonary lymphoma
                                        Hard-metal pneumoconiosis               Bacteria – e.g. NTB mycobacteria
Gaucher’s Disease
                                        Coal worker’s pneumoconiosis            Fungi – e.g. Aspergillus
Niemann-Pick Disease
                                        Berylliosis                             Animal protein – e.g. Avian
Hermansky-Pudlak syndrome
                                        Aluminum oxide fibrosis                 Chemical sensitizers -
Neurofibromatosis
                                        Talc pneumoconiosis                        e.g. isocyanates
Lymphangioleiomyomatosis
                                        Siderosis (arc welder)
Tuberous Sclerosis
                                        Stannosis (tin)
ARDS
AIDS
Bone Marrow Transplantation             Idiopathic Fibrotic Disorders
Postinfectious                          Acute interstitial pneumonitis (Hamman-Rich syndrome)
Eosinophilic pneumonia                  Idiopathic Pulmonary Fibrosis
Alveolar Proteinosis                    Familial Idiopathic Pulmonary Fibrosis
Diffuse Alveolar Hemorrhage Syndromes   Desquamative intersitial pneumonitis
Alveolar microlithiasis                 Respiratory bronchiolitis
Metastatic calcification                Cryptogenic organizing pneumonia
                                        Nonspecific interstitial pneumonitis
                                        Lymphocytic interstitial pneumonia (Sjögrens Syndrome, AIDS, Hashimoto’s)
                                        Autoimmune pulmonary fibrosis (inflammatory bowel disease, PBC, ITP, AIHA)
ATS/ERS International Multidisciplinary Consensus Classification of the
Idiopathic Interstitial Pneumonias, Am J Respir Crit Care Med. 2002
                           QUICK HISTORY OF IIP
 In 1969, Liebow and Carrington described 5 types of chronic interstitial
        pneumonias based on histology:

1. Usual interstitial pneumonia (UIP)
2. Bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage
   (BIP)
3. Desquamative interstitial pneumonia (DIP)
4. Lymphocytic interstitial pneumonia (LIP)
5. Giant cell interstitial pneumonia (GIP)

 In 2002, the ATS/ERS published their consensus classification of IIP based on
Clinical-Radiologic-Pathologic categories:

          Clinical-Radiologic-Pathologic Diagnosis     Histologic Pattern

          Idiopathic Pulmonary Fibrosis (Cryptogenic   Usual interstitial pneumonia
          fibrosing alveolitis)
          Nonspecifiic interstitial pneumonia          Nonspecific interstitial pneumonia
          (provisional)
          Cryptogenic organizing pneumonia             Organizing pneumonia

          Acute interstitial pneumonia                 Diffuse alveolar damage

          Respiratory bronchiolitis ILD                Respiratory bronchiolitis

          Desquamative interstitial pneumonia          Desquamative interstitial pneumonia

          Lymphoid interstitial pneumonia              Lymphoid interstitial pneumonia
ATS/ERS International Multidisciplinary Consensus Classification of the
Idiopathic Interstitial Pneumonias, Am J Respir Crit Care Med.
 USUAL INTERSTITIAL PNEUMONIA PATTERN


The UIP pattern can be seen in the following conditions:
   o IPF
   o Familial IPF
   o Collagen vascular diseases
   o Drug toxicity
   o Chronic hypersensitivity pneumonitis
   o Asbestosis
   o Hermansky-Pudlak syndrome



The term UIP is usually reserved for patients in whom the
lesion is idiopathic



UIP ≈ IPF
     USUAL INTERSTITIAL PNEUMONIA PATTERN


Key histologic features:

1. Dense fibrosis with remodeling of lung architecture , frequent honeycomb
   fibrosis
2. Fibroblastic foci usually at the edge of scarring
3. Patchy lung involvement
4. Usually subpleural distribution




Important negative findings:

1.   No active lesions typical of other ILD’s
2.   Lackof marked interstitial chronic inflammation
3.   No (or rare) granulomas
4.   No evidence of inorganic dust deposits (e.g. asbestos bodies)
5.   Lack of marked eosinophilia
USUAL INTERSTITIAL PNEUMONIA PATTERN




Mason: Murray & Nadel's Textbook of Respiratory
Medicine, 4th ed.




                                                  Idiopathic Pulmonary Fibrosis, Gross and
                                                  Huninghake, NEJM, 2001.
                               HONEYCOMB PATTERN




Pictures taken from http://mediswww.meds.cwru.edu/ecsample/yeartwo/pulmonary/interstitial.html
       IDIOPATHIC PULMONARY FIBROSIS

ATS definition: “IPF is a distinctive type of chronic
fibrosing interstitial pneumonia of unknown cause
limited to the lungs and associated with a surgical lung
biopsy showing a histologic pattern of UIP.”




 • A distinct type of chronic fibrosing interstitial pneumonia
 • Unknown cause
 • Limited to the lungs
 • Associated with a histologic pattern of usual interstitial
   pneumonia (UIP)
                      EPIDEMIOLOGY
 Estimated to affect approx 5 million people worldwide

 The most common (and deadly) interstitial lung disease

 Most cases are sporadic, but rare cases of familial IPF have
been described




                                    Raghu et. al., Am J of Resp Crit Care Med 2006
EPIDEMIOLOGY




         Raghu et. al., Am J of Resp Crit Care Med 2006
                CLINICAL PRESENTATION

Middle age 50-70s

New onset of progressive exertional dyspnea and non-
productive cough

Most have symptoms for 12-18 months prior to definitive
evaluation

Constitutional symptoms are uncommon

Weight loss, fever, fatigue, myalgias, or arthralgias
occasionally present
Detailed occupational and exposure history
                      PHYSICAL EXAM

Bibasilar late inspiratory fine crackles (Velcro rales)

Tachypnea

Clubbing – 40-75% - late in disease course

Cardiac exam usually normal until middle-late stages
     - augmented P2, right-sided heave, S3 gallop

Cyanosis

Rash, arthritis, myositis should suggest an alternate
diagnosis
                                                           CXR

                                                                        16% of patients with
                                                                        ILD have normal
                                                                        chest x-rays




    Idiopathic Pulmonary Fibrosis, Gross and Hunninghake, NEJM, 2001.




Courtesy of W. Richard Webb, MD.
CXR
                CXR




Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.
                            PFTs
PFT’s   = Restrictive pattern

Reduced TLC, VC, and/or RV (decreased compliance)

Normal or increased FEV1/FVC

Decreased DLCO




                         Source: images.md
                           ABG
ABG   =   Hypoxemia, respiratory alkalosis

Decreased PaO2 with rest or exercise

Increased A-a gradient


Other lab tests that might be useful?

Elevated ESR
Hypergammaglobulinemia
Low-titer positive ANA (21% patients with IPF)
RF
Circulating immune complexes
Cryoimmunoglobulins
                                                          HIGH RES CT
Can be used to detect disease, especially in pts with no
or minimal changes on CXR
Can determine extent and severity of disease activity
Can now be used to differentiate IPF from other ILD




                                                                      Peripheral, subpleural fibrosis

                                                                      Alternating areas of normal tissue

                                                                      Honeycombing

                                                                      Traction bronchiectasis

                                                                      Later stages - more diffuse
                                                                      reticular pattern prominent in
                                                                      lower lung zones associated with
                                                                      thickened interlobular septa




  Idiopathic Pulmonary Fibrosis, Gross and Hunninghake, NEJM, 2001.
                                  BAL in IPF
 Role and value of serial BAL in IPF previously unknown

 Increased inflammatory cells in IPF, but no predominant type

 Kinder et al, Chest, Jan 2008
  156 subjects with biopsy proven UIP/IPF enrolled between 1982-1996

  BAL within 3 weeks of lung biopsy

  Linear relationship between increasing neutrophil percentage and the risk of
  mortality

  Each doubling in the neutrophil percentage was associated with a nearly 30%
  increased risk of death or transplantation in adjusted analysis ([HR] 1.28;
  95% CI, 1.01 to 1.62; p = 0.04). There was no association with lymphocyte or
  eosinophil percentage.

  Suggests that BAL fluid neutrophil percentage at the time of diagnosis of IPF is an
  independent predictor of time to death.
                             LUNG BIOPSY
 Gold Standard for diagnosis of IPF (and IIP’s)
 Large piece of lung parenchyma is required, optimally from several sites
 Transbronchial biopsy is only useful for ruling out other disorders
 Can be performed by thoracotomy, thorascopy, or VATS




                     OTHER STUDIES IN IPF

 Gallium Scanning (67Ga)       used for staging “alveolitis” in ILD, e.g sarcoidosis
                                Not useful – difficult to interpret, very low specificity


 VQ scan                       reveals patchy, non-segmental areas of decreased V
                                decreased perfusion in lower lung zones
                                increased perfusion of upper lung zones (due to PH)
  ATS/ERS CRITERIA FOR DIAGNOSIS OF IPF IN
      ABSENCE OF SURGICAL LUNG BIOPSY
Major Criteria:
Exclusion of other known causes of ILD

Abnormal PFTs that include evidence of restriction and impaired gas exchange

Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT

Transbronchial lung biopsy or BAL showing no features to support alternative dx

Minor Criteria:
Age > 50

Insidious onset of otherwise unexplained dyspnea on exertion

Duration of illness greater than 3 months

Bibasilar inspiratory crackles (dry or “Velcro”-type in quality)


ALL of the major criteria plus at least THREE minor criteria.
          NATURAL HISTORY / PROGNOSIS
Worst prognosis of all the ILD’s
Disease course is variable
5-year survival rate is 30-50%
Median survival after diagnosis is less than 3 years
40% IPF patients die of respiratory failure
Others die of complicating illnesses, mainly CAD and
infections
End-stage disease is characterized by severe PH with cor
pulmonale that does not improve with oxygen
Incidence of bronchogenic carcinoma is increased in
patients with IPF
Factors associated with shortened survival:
     Increased neutrophil count
     older age
     poor pulmonary function at presentation
     recent deterioration in results of PFT’s
     advanced fibrosis
                 ACUTE EXACERBATIONS OF IPF
 Traditional view: slow, steady decline in lung fuction  respiratory failure
 Several recent clinical trials have shown that multiple subclinical and
       acute exacerbations lead to decline in pulmonary function


 Martinez et al, Ann Intern Medicine, 2005
168 patients in the placebo group of a trial evaluating interferon-γ1b (mild-mod IPF)

Measures of physiology and dyspnea assessed at 12-week intervals; hospitalizations;
and the pace of deterioration and cause of death over a median period of 76 weeks.

Minimal physiologic deterioration or worsening severity of dyspnea over time

Frequent hospitalizations for respiratory disorders (23%, 21% died)

IPF was the primary cause of death in 89% who died
Acute clinical deterioration preceded death in 47%


 Kim et al, Eur Resp J, 2006
Analysis of 147 IPF patients demonstrated 2-year frequency of acute exacerbations was
9.6%
                ACUTE EXACERBATIONS OF IPF
Consensus group in 2007 defined acute exacerbation:
               Diagnosis of IPF
               Unexplained development of worsening of dyspnea within 30 days
               HRCT with new ground-glass abnormalities
               No evidence of pulmonary infection by ET aspirate or BAL
               Exclusion of alternative causes, e.g. HF, PE


Treatment:  Broad-spectrum antibiotics
            High-dose steroids (prednisone 1 mg/kg)
                  GENETIC SUSCEPTIBILITY?
Up to 3% of cases of IPF appear to cluster in families (Familial IPF)


Armanios et al, NEJM 2007.

 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for
  mutations in hTERT and hTR (telomerase RT and telomerase RNA)
 Demonstrated that mutation was inherited in autosomal dominant fashion
  with variable penetrance
 Those with IPF had mutant telomerase and short telomeres
 Telomeres shorten with each cell division and ultimately lead to apoptosis
 Proposed that fibrosis occurs due to death of alveolar cells
              ASSOCIATED RISK FACTORS

 Up to 75% of index patients with IPF are current or former
smokers



 Latent viral infections have also been reported to have an
association




 Given the similarity between asbestosis and IPF, is there a
causative environmental agent?


 Chronic aspiration?
                            GERD AND IPF

Raghu et al, Eur Resp J, Oct 2006.

 65 consecutive patients with IPF were subjected to 24-h pH monitoring
  and esophageal manometry
 133 patients with intractable asthma and GERD used for comparison
 Prevalence of GERD in IPF patients was 87% but only 47% had symptoms
 GERD was higher in IPF patients (76% versus 57%; p = 0.020)
 Despite tx with standard dose PPI, 12/19 still had abnormal pH

 Conclusion: GERD is highly prevalent and often clinically occult in patients
  with IPF, and often does not respond entirely to standard dose PPI
                      PATHOGENESIS

                    Originally thought inflammation  fibrosis
                        Animal models

                        Early IPF is dominated by inflammatory cells

                        Asymptomatic relatives of patients with familial IPF
                        have evidence of alveolitis in the absence of disease



                    Alveolar macrophage thought to play a major role

                        Secretes proinflammatory and profibrotic cytokines

                        Promote collagen deposition




PROBLEMS:   1) Little inflammation is seen histologically
            2) Measurements of inflammation do not correlate
            3) Anti-inflammatory therapies DO NOT WORK!
                            PATHOGENESIS
 Starting around 1998, studies began to demonstrate that inflammation is
NOT a prominent finding in most cases of IPF/UIP.




 These sites are typical in alveolar epithelial injury


 Abnormal wound healing involving epithelial cells and fibroblasts


 Activated epithelial cells release potent fibrogenic molecules and cytokines,
such as TNFα and TGFβ1
PATHOGENESIS
PATHOGENESIS
                     TREATMENT



ATS recommendation (2000):

       Prednisone + Azathioprine or Cyclophosphamide




Consensus recommendation (2008):

       Prednisone + Azathioprine + N-acetylcysteine
                                    STEROIDS


Cochrane Systematic Review in 2003
Fifteen studies were selected as potentially eligible for meta-analysis. After further
analysis of full text papers, no RCTs or CCTs were identified as suitable and therefore no
data was available for inclusion in any meta-analysis. All studies were excluded due to
inadequate methodologies.


 Currently there is no evidence to support the routine use of
corticosteroids alone in the management of IPF.
                                     AZATHIOPRINE
 Raghu et al, Am Rev Respir Dis 1991.

     • 27 newly diagnosed patients with IPF
     • Prednisone + Azathioprine vs. Prednisone + Placebo, follow-up 9 years
     • After 1 year, P+A had better lung function, but was not significant
     • 43% (6/14) died vs. 77% (10/13)
                                                                        P = 0.16
                                                          1.0           P = 0.02 (age adjusted)

                                         Probability of
                                                          0.8
 Side effects:                                                                  Azathioprine +
      leukopenia,                        Survival         0.6                    Prednisone (n = 14)
       GI-related
                                                          0.4
                                                                                Prednisone (n = 13)
                                                          0.2

                                                            0
                                                                0 1 2 3 4 5 6 7 8 9
                                                                        Years

Raghu G, et al. Am Rev Respir Dis. 1991;144:291-296.
                         CYCLOPHOSPHAMIDE
   Collard et al, Chest, 2004
     • Retrospective study looking at 164 patients with IPF from 1984-2002
     • 82 patients on prednisone and oral cyclophosphamide vs. 82 patients on
          prednisone alone
     • No difference in survival from time of initial visit




 Multiple other small studies have been unimpressive
 Toxicity is major (pancytopenia, hemorrhagic cystitis, GI-related)
                       N-acetylcysteine (NAC)
 Demedts et al, NEJM, 2005.
   • 182 patients with UIP
   • Prednisone + Azathioprine + High-dose NAC (600mg TID) vs. P/A
   • Significant difference in the deterioration of VC and DLCO at 12 months
        Relative difference of 9% and 24% respectively
   • Oxidant-antioxidant imbalance?




                                                                        Mortality, P =
                                                                             NS

                                                                         7/80 (9%)
                                                      NAC+Pred+Aza

                                                      Pred+Aza+          8/75 (11%)
                                                      Placebo
                           LUNG TRANSPLANT
 IPF is the most common ILD among referrals for transplant and the 2 nd
most frequent disease for which lung transplantation is performed

 Criteria:      Evidence of UIP plus any of the following:

                    DLCO < 39% predicted
                    Decrement in FVC > 10% during 6 months
                    Decrease in pulse ox below 88% during 6-minute walk test
                    Honeycombing on HRCT


 5-year survival for lung transplant in IPF is 40-50%


 SLT has been the standard treatment


 Living donor lobar lung transplant (LDLLT) - Date et al, Chest 2005

        9 patients with IIP dependent on systemic steroids (up to 50mg/day)
        Transplant of two lower lobes from two healthy relatives
        After 10-48 months of follow-up 8/9 still alive (one died of acute rejection)
                             PERFENIDONE

Mechanism of Action:        inhibits TGF-β-stimulated collagen synthesis
                            decreases the extracellular matrix
                            blocks fibroblast proliferation in-vivo

Currently in Phase III trials in the U.S. (CAPACITY)


Phase III trial in Japan ended last month:

     Included 267 patients in 73 different centers
     Pirfenidone 1800 mg/day vs. 1200 mg/day vs. placebo
     VC, SpO2 on exertion, number of acute exacerbations were primary endpoints

     At week 52:   Difference in VC between groups was 70mL and 80mL
                    No significant difference in lowest SaO2 on exertion
                    No significant difference in the number of acute exacerbations
                    Significant difference in progression-free survival


Adverse effects: rash, GI effects, fatigue
                OTHER TREATMENT OPTIONS
Interferon gamma-1b:        important in “wound healing”
                            PCRT suggested a possible mortality benefit
                            Large multinational trial (INSPIRE) was stopped when the
                           primary endpoint of mortality benefit was not achieved


           Drug                     Mechanism          Status
           Bosentan                 Endothelin         Phase III
           (BUILD-1)                receptor
                                    agonist
           Etanercept               TNF-α blocker      Phase II
           Imatinib                 C-Abl and PDGF Phase II
                                    TK-inhibitor
           FG-3019                  Anti-CTGF          Phase II
                                    monoclonal Ab      planned


Limited data:      Methotrexate
                   Cyclosporine
                   Colchicine
                   Penicillamine
                                SUMMARY


 IPF is the most common ILD with the worst prognosis

 The most important distinction is differentiate IPF from the other IIP’s

 Biopsy is the gold standard for diagnosis, histology = UIP pattern with
  fibroblast foci (hallmark of IPF)
 Most common presentation is 50-60 y.o. male with progressive dyspnea
  and non-productive cough
 Most common physical exam findings are “Velcro” rales +/- clubbing

 Most important diagnostic studies are CXR, PFT’s, ABG, and HRCT

 Higher BAL neutrophil percentage at time of diagnosis = worse prognosis?

 If certain clinical criteria are met, can diagnose IPF without biopsy

 Acute exacerbations are now recognized to be an important target for
  therapy
                                SUMMARY


 Possible genetic component involving mutant telomeres, resulting in
  apoptosis of alveolar cells
 Newly accepted hypothesis that fibrosis is a result of aberrant “wound
  healing” resulting from repeated injury of unknown cause
 There is a high correlation with GERD in IPF
 There is still no effective therapy for IPF
 Current recommendation is steroids + azathioprine + NAC
 SLT improves 5-year survival, LDLLT shows promise in advanced disease
 Perfenidone will likely be the next option in therapy for IPF
 There are a number of novel therapies on the horizon
                                                              References
Mason: Murray & Nadel’s Textbook of Respiratory Medicine, 4th ed. Chapter 53 – Approach to Diagnosis and Management of the Idiopathic
             Interstitial Pneumonias. King and Schwarz, 2005.

American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic
             Interstitial Pneumonias. Am J Respir Crit Care Med. Vol 165, pp 277-304, 2002.

Verma and Slutsky , Idiopathic Pulmonary Fibrosis – New Insights. NEJM. Vol 356, No 13: pp 1370-1372, 2007.

Gross and Hunninghake, Idiopathic Pulmonary Fibrosis. NEJM. Vol 345, No 7: pp 517-525, 2001.

Kinder BW et al. , Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest. Vol 133(1): pp 226-32, Jan 2008.

Martinez FJ et al. (IPF Study Group). The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis. Ann Intern Med. Vol 142: pp 963-967,
                2005.

Kim DS et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Resp J. Vol 27: pp143-150, 2006.

Selman et al. Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy.
                Annals of Internal Medicine. Vol 134: 2, pp. 136-151, 2001.

Raghu, G et al . Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective, double-blind
                randomized, placebo-controlled clinical trial. Am. Rev. Respir. Dis. 144: 291-296, 1991.

Collard et al, Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest.
                 125(6):2169-74, 2004.

Maurits Demedts et al, High-dose acetylcysteine in Idiopathic Pulmonary Fibrosis. NEJM, Vol 353: 2229-2242, 2005.

Armanios MY et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. NEJM 356: 1317-26, 2007.

Noth and Martinez. Recent Advances in Idiopathic Pulmonary Fibrosis. Chest 132: 637-50, 2007.

Noble PW. Idiopathic Pulmonary Fibrosis: Natural History and Prognosis. Clin Chest Med 27, S11-16, 2006.

American Thoracic Society, Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment. Am. J. Respir. Crit. Care Med., Volume 161, Number 2, 646-
                664, 2000.
Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database of Systematic Reviews 2003, Iss 3.

Raghu G et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. Vol 28(4): 884-5,
                2006.
Orens 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. The Journal of Heart and Lung
                Transplantation. Volume 25, Issue 7, Pages A1-A20, 745-868 (July 2006)
Date et al. A New Treatment Strategy for Advanced Idiopathic Interstitial Pneumonia*: Living-Donor Lobar Lung Transplantation
               Chest, Sep 2005; 128: 1364 – 1370.

								
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