1. Lung biopsy in fibrosing ILD Does it have value? Athol Wells, Royal Brompton Hospital, London UK

2. Biopsy in “IPF” RBH data 1978-1989 n=208 Biopsy rate = 55% 1978-1989 n=208 Biopsy rate = 55% 1992-1997 n=212 Biopsy rate = 15% 1992-1997 n=212 Biopsy rate = 15%

3. Data from 160 ILD cases Six expert physicians made diagnoses and recommendations on management Six expert physicians made diagnoses and recommendations on management Surgical biopsies recommended in 40% Surgical biopsies recommended in 40% Poor agreement (k=0.26) on whether to biopsy (with and without HRCT data). Poor agreement (k=0.26) on whether to biopsy (with and without HRCT data). Aziz Z et al. Radiology 2006; 238:725-33

4. This review will cover…… Is a histological diagnosis truly a “reference standard” in DILD? Is a histological diagnosis truly a “reference standard” in DILD? How physicians should think in DILD How physicians should think in DILD How biopsy fits into the diagnostic algorithm: a pragmatic view How biopsy fits into the diagnostic algorithm: a pragmatic view

5. Diagnosis – four views Suspend thought: biopsy everything Suspend thought: biopsy nothing – call everything “IIP” Suspend thought: biopsy nothing – call everything “IIP” Suspend thought: CT is truth data Suspend thought: CT is truth data Do not suspend thought Do not suspend thought

7. Part I Is biopsy truly a diagnostic gold standard?

8. Biopsy is a gold standard: not! Severe disease, co-morbidity Severe disease, co-morbidity Observer variation Observer variation “Sampling error” “Sampling error” Indeterminate appearances Indeterminate appearances

9. Biopsy in severe disease Risk/benefit ratio marginal Risk/benefit ratio marginal Risk increases as gas transfer falls below 30-35% Risk increases as gas transfer falls below 30-35% Prognostic value lessens as gas transfer falls below 30-35% Prognostic value lessens as gas transfer falls below 30-35%

10. The clinical entity of IPF Latsi PI, Am J Respir Crit Care Med, 2003; 168:531-7

12. Diagnostic variation between pathologists Stated in recent publications Stated in recent publications Historically, a curious paucity of studies in DILD Historically, a curious paucity of studies in DILD This may reflect the “iconic status” of biopsy This may reflect the “iconic status” of biopsy

13. Inter-observer agreement: 10 regional UK pathologists First choice diagnosis k = 0.38 First choice diagnosis k = 0.38 Confident diagnosis: k = 0.50 Confident diagnosis: k = 0.50 Non-confident diagnosis: k = 0.22 Non-confident diagnosis: k = 0.22 These pathologists were experienced! These pathologists were experienced! Nicholson AG. Thorax 2004; 59:500-5

14. Sampling error Heterogeneity between biopsies Heterogeneity between biopsies IPF/NSIP cases with two biopsies: 50% concordant UIP; 25% concordant NSIP; 25% discordant IPF/NSIP cases with two biopsies: 50% concordant UIP; 25% concordant NSIP; 25% discordant Discordant cases: outcome of IPF Discordant cases: outcome of IPF Flaherty KR. Am J Respir Crit Care Med, 2001; 164:1722-27

15. Just two comments……… Sampling error is less of an issue than one might think Just two comments………

16. Do not biopsy the tip of the middle lobe/lingula without good reason Appearances are often end- stage and non-specific

17. Take two (or more) biopsies when possible Take two (or more) biopsies when possible Use HRCT to select sites to sample the full morphologic spectrum Use HRCT to select sites to sample the full morphologic spectrum

19. 133 biopsies from 82 patients with DILD The problem of indeterminate appearances

20. The diagnostic process in DILD is now more like the Indian fable of the five blind men and the elephant For all these reasons, biopsy is no longer a “gold standard” The diagnostic process in DILD is now more like the Indian fable of the five blind men and the elephant

22. IIP: multidisciplinary diagnosis Suspected IIP (n=58) undergoing biopsy Suspected IIP (n=58) undergoing biopsy Leading clinicians/radiologists/pathologists Leading clinicians/radiologists/pathologists Final consensus diagnosis Final consensus diagnosis Key analysis: clinical/ HRCT diagnosis vs final diagnosis (with histology integrated). Key analysis: clinical/ HRCT diagnosis vs final diagnosis (with histology integrated). Flaherty KR et al. Am J Respir Crit Care Med 2004; 170:904-910

23. Multidisciplinary diagnosis When pre-biopsy diagnosis IPF, final diagnosis virtually always IPF When pre-biopsy diagnosis IPF, final diagnosis virtually always IPF When pre-biopsy diagnosis not IPF, diagnosis changed with biopsy in 50% When pre-biopsy diagnosis not IPF, diagnosis changed with biopsy in 50% Biopsy diagnosis changed 25% of the time Biopsy diagnosis changed 25% of the time

24. When the HRCT and clinical picture are typical of IPF….. In three good and large studies, a biopsy virtually never changed the diagnosis In three good and large studies, a biopsy virtually never changed the diagnosis The positive predictive value for a pattern of UIP is over 95%, just on HRCT alone The positive predictive value for a pattern of UIP is over 95%, just on HRCT alone DO NOT BIOPSY PATIENTS IN THIS CONTEXT

25. There is no “diagnostic gold standard” in DILD Clinical, HRCT and histological evaluation are all “silver standards” with biopsy the most argentiferous.

26. Biopsy is sometimes invaluable in DILD ……… but when? To answer this, we must understand….

27. Part II How do clinicians actually think in diffuse lung disease?

28. Guidelines for ILD ……. “Just one side, please” “Just one side, please”

29. Actually, it ought to be possible to distil the logic of what we do on just one side But there are difficulties

30. Major difficulties in ILD Multiplicity of disorders – but just a few management strategies Multiplicity of disorders – but just a few management strategies The terminology The terminology Problem of patients who do not fit exactly into a syndrome: diseases do not read medical text-books Problem of patients who do not fit exactly into a syndrome: diseases do not read medical text-books

31. Bronchiolitic disorders Constrictive bronchiolitis … follicular bronchiolitis … proliferative bronchiolitis … obliterative bronchiolitis … bronchiolitis obliterans organizing pneumonia … constrictive obliterative bronchiolitis … diffuse pan-bronchiolitis … cryptogenic organizing pneumonia … follicular obliterative bronchiolitis ….exudative bronchiolitis Constrictive bronchiolitis … follicular bronchiolitis … proliferative bronchiolitis … obliterative bronchiolitis … bronchiolitis obliterans organizing pneumonia … constrictive obliterative bronchiolitis … diffuse pan-bronchiolitis … cryptogenic organizing pneumonia … follicular obliterative bronchiolitis ….exudative bronchiolitis

32. Bronchiolitis 1 Obliterative bronchiolitis (constrictive bronchiolitis, constrictive obliterative bronchiolitis) 2 Cryptogenic organizing pneumonia (bronchiolitis obliterans organizing pneumonia, proliferative bronchiolitis) 3 Follicular bronchiolitis (follicular obliterative bronchiolitis) 4 Diffuse pan-bronchiolitis (exudative bronchiolitis)

33. Classification …… We have histological, radiological, aetiological and other classifications We have histological, radiological, aetiological and other classifications We need as clinicians a simple “what are you going to do about it?” classification. We need as clinicians a simple “what are you going to do about it?” classification. Guidelines on just one side – how should we use multi-disciplinary assessment in management? Guidelines on just one side – how should we use multi-disciplinary assessment in management?

34. Remember why we want diagnoses Differences in natural history Differences in natural history Differences in treatment Differences in treatment Differences in treated outcome Differences in treated outcome

35. There are a handful of management strategies We need an approach that is geared to their selection

36. 1. Observation alone 2. Short term steroid trial 3. Long-term “civilised” regimens 4. High dose therapy followed by 3 Plus ancillary treatments Pharmacologic strategies

37. A classification based on pragmatic management... Cause Cause Predominant morphologic abnormality Predominant morphologic abnormality Severity Severity Longitudinal behaviour Longitudinal behaviour Integrate these as follows Integrate these as follows

38. Treatment/monitoring strategies according to: Self-limited inflammation Self-limited inflammation Stable fibrotic disease Stable fibrotic disease Major inflammation with variable fibrosis Major inflammation with variable fibrosis Inexorably progressive fibrosis Inexorably progressive fibrosis Severe, rapidly progressive ILD Severe, rapidly progressive ILD

39. How predictive are serial PFT in the first year? Latsi PI et al. Am J Respir Crit Care Med 2003; 168:531-7 Change in DLco and FVC at six months and one year examined against survival. Comparison with prognostic value of histologic diagnosis

40. Natural history trumps all else

41. Self-limited inflammation Examples found in HP, sarcoidosis, some forms of IIP, drug-induced disease ……. Examples found in HP, sarcoidosis, some forms of IIP, drug-induced disease ……. Outcome good Outcome good Remove the cause Remove the cause Not all patients need treatment Not all patients need treatment Monitor to confirm regression of disease Monitor to confirm regression of disease

42. 1. Observation alone 2. Short term steroid trial 3. Long-term “civilised” regimens 4. High dose therapy followed by 3 Plus ancillary treatments Pharmacologic strategies

43. Stable/indolent fibrotic disease Examples found in HP, sarcoidosis, some forms of IIP, drug-induced disease…. Examples found in HP, sarcoidosis, some forms of IIP, drug-induced disease…. Often seen in connective tissue disease Often seen in connective tissue disease Key is not to over-react: MICO therapy…... Key is not to over-react: MICO therapy…...

44. “Indolent disease” MICO: MICO: Masterful Inactivity Masterful Inactivity with Cat-like Observation with Cat-like Observation The role of the doctor is to amuse the patient while nature takes its course The role of the doctor is to amuse the patient while nature takes its course (Voltaire) (Voltaire)

45. Limited fibrotic disease

46. 100 80 60 40 20 0 0 40 60 80 100 120 Mild Duration of follow-up (months) Extensive Survival (%) Disease extent determines mortality Goh NS, et al. Am J Respir Crit Care Med. 2008

47. 1. Observation alone 2. Short term steroid trial 3. Long-term “civilised” regimens 4. High dose therapy followed by 3 Plus ancillary treatments Pharmacologic strategies

48. Major inflammation with variable fibrosis Examples in HP, sarcoidosis, some forms of IIP, drug-induced disease…… Examples in HP, sarcoidosis, some forms of IIP, drug-induced disease…… Treat vigourously, reverse any reversible component, then consolidate Treat vigourously, reverse any reversible component, then consolidate Monitor initial response and then demonstrate stability Monitor initial response and then demonstrate stability

49. 1. Observation alone 2. Short term steroid trial 3. Long-term “civilised” regimens 4. High dose therapy followed by 3 Plus ancillary treatments Pharmacologic strategies

50. Inexorably progressive fibrosis HP, sarcoidosis, some forms of IIP HP, sarcoidosis, some forms of IIP Key to management is to find the right balance between slowing progression and poisoning the patient Key to management is to find the right balance between slowing progression and poisoning the patient Thus, crucial to identify any reversible component ………. Thus, crucial to identify any reversible component ……….

51. 1. Observation alone 2. Short term steroid trial 3. Long-term “civilised” regimens, applied with realism 4. High dose therapy followed by 3 Plus ancillary treatments Pharmacologic strategies

52. Severe, rapidly progressive ILD Some patients with IIP, drug-induced disease, simulation of diffuse lung disease by other disorders Some patients with IIP, drug-induced disease, simulation of diffuse lung disease by other disorders Policy of “treat the treatable” Policy of “treat the treatable” Pulsed therapy: IV Methyl Prednisolone versus IV Cyclophosphamide Pulsed therapy: IV Methyl Prednisolone versus IV Cyclophosphamide

53. 1. Observation alone 2. Short term steroid trial 3. Long-term “civilised” regimens 4. Ultra high dose therapy, then 3 Plus ancillary treatments Pharmacologic strategies

54. What clinicians need from a classification…. Captures clusters of disease behaviour Captures clusters of disease behaviour Articulates logical therapeutic goals Articulates logical therapeutic goals Makes approach to monitoring obvious Makes approach to monitoring obvious

55. Treatment/monitoring strategies according to: Self-limited inflammation Self-limited inflammation Stable fibrotic disease Stable fibrotic disease Major inflammation with variable fibrosis Major inflammation with variable fibrosis Inexorably progressive fibrosis Inexorably progressive fibrosis Severe, rapidly progressive ILD Severe, rapidly progressive ILD

56. Histologic and clinical classification of idiopathic interstitial pneumonias (ICCILD)

57. Self-limited inflammation RBILD RBILD

58. Stable fibrotic disease Fibrotic NSIP Fibrotic NSIP

59. Major inflammation with variable fibrosis DIP COP DIP COP

60. Inexorably progressive fibrosis IPF IPF

61. Severe, rapidly progressive ILD AIP AIP Acute exacerbation of IPF Acute exacerbation of IPF

62. Part III Where does biopsy fit into this?

63. Treatment/monitoring strategies according to: Self-limited inflammation Self-limited inflammation Stable fibrotic disease Stable fibrotic disease Major inflammation with variable fibrosis Major inflammation with variable fibrosis Inexorably progressive fibrosis Inexorably progressive fibrosis Severe, rapidly progressive ILD Severe, rapidly progressive ILD

64. We investigate in order to make these essential distinctions

65. Biopsy The classification informs biopsy decisions by sharpening risk/benefit evaluation The classification informs biopsy decisions by sharpening risk/benefit evaluation It does NOT replace biopsy: system works best when the diagnosis is secure It does NOT replace biopsy: system works best when the diagnosis is secure Biopsy decisions themselves need to be multidisciplinary Biopsy decisions themselves need to be multidisciplinary

66. The risk/benefit equation Physicians can articulate to patients exactly why a biopsy is being performed Physicians can articulate to patients exactly why a biopsy is being performed The benefit of the procedure can be balanced against the risks The benefit of the procedure can be balanced against the risks Patients can participate in decision-making Patients can participate in decision-making

67. Biopsy data informs us what patterns of disease behaviour are possible In cases in which we already know this, biopsy is redundant

68. Selected scenarios: the integration of diagnostic data Pathognomonic HRCT findings: biopsy not required … IPF Pathognomonic HRCT findings: biopsy not required … IPF Diagnosis and future disease behaviour secure when HRCT and clinical information combined: biopsy not required…… RBILD Diagnosis and future disease behaviour secure when HRCT and clinical information combined: biopsy not required…… RBILD Diagnosis and future disease behaviour uncertain after full non-invasive evaluation: biopsy required unless contraindicated Diagnosis and future disease behaviour uncertain after full non-invasive evaluation: biopsy required unless contraindicated

69. IPF/usual interstitial pneumonia Very characteristic HRCT profile Very characteristic HRCT profile Now formally incorporated in ATS/ERS non-invasive diagnostic criteria Now formally incorporated in ATS/ERS non-invasive diagnostic criteria Cardinal features: predominantly basal sub-pleural disease; honeycombing; little (or no) ground-glass attenuation Cardinal features: predominantly basal sub-pleural disease; honeycombing; little (or no) ground-glass attenuation

71. Raghu G. Chest 1999; 116:1168-74 59 biopsied patients with new-onset ILD 59 biopsied patients with new-onset ILD IPF, n=29. Many other disorders, but fibrotic NSIP not represented IPF, n=29. Many other disorders, but fibrotic NSIP not represented PPV for IPF, clinicians = 95% PPV for IPF, clinicians = 95% PPV for IPF, radiologists = 88% PPV for IPF, radiologists = 88%

72. Hunninghake GW et al. Am J Respir Crit Care Med 2001; 15:193-196 91 biopsied patients “with suspected IPF” 91 biopsied patients “with suspected IPF” IPF, n = 54. Mixture of other disorders, including NSIP (n=6) IPF, n = 54. Mixture of other disorders, including NSIP (n=6) When diagnosis confident…... When diagnosis confident…... PPV for IPF, core pulmonologists = 87% PPV for IPF, core pulmonologists = 87% PPV for IPF, core radiologists = 96% !! PPV for IPF, core radiologists = 96% !!

73. Biopsy adds NO value in typical IPF

74. Selected scenarios: the integration of diagnostic data Pathognomonic clinical or HRCT findings: biopsy not required … IPF Pathognomonic clinical or HRCT findings: biopsy not required … IPF Diagnosis and disease behaviour secure when HRCT and clinical information combined: biopsy not required… RBILD Diagnosis and disease behaviour secure when HRCT and clinical information combined: biopsy not required… RBILD Diagnosis and future disease behaviour uncertain after full non-invasive evaluation: biopsy required unless contraindicated Diagnosis and future disease behaviour uncertain after full non-invasive evaluation: biopsy required unless contraindicated

75. RBILD Exaggerated form of smoking-related respiratory bronchiolitis Exaggerated form of smoking-related respiratory bronchiolitis Generally benign/self limited although symptoms/functional impairment may be significant Generally benign/self limited although symptoms/functional impairment may be significant Is biopsy diagnostically necessary? Is biopsy diagnostically necessary?

77. RBILD vs HP Ask the patient! BAL: lymphocytosis vs pigmented macrophages

78. If CT and clinical information are conclusive when integrated … biopsy adds NO value

79. Selected scenarios: the integration of diagnostic data Pathognomonic clinical or HRCT findings: biopsy not required … IPF Pathognomonic clinical or HRCT findings: biopsy not required … IPF Diagnosis and future disease behaviour secure when HRCT and clinical information combined: biopsy not required…… RBILD Diagnosis and future disease behaviour secure when HRCT and clinical information combined: biopsy not required…… RBILD Diagnosis and disease behaviour uncertain after non-invasive evaluation: biopsy required unless contraindicated Diagnosis and disease behaviour uncertain after non-invasive evaluation: biopsy required unless contraindicated

80. Prominent ground-glass Biopsy these cases

81. HRCT in the diagnosis of IPF: the caveat Raghu: 20% atypical on HRCT Raghu: 20% atypical on HRCT Hunninghake: 20-25% atypical on HRCT Hunninghake: 20-25% atypical on HRCT If appearances are typical, an HRCT diagnosis of IPF is almost always correct If appearances are typical, an HRCT diagnosis of IPF is almost always correct The converse is NOT correct The converse is NOT correct

82. Atypical appearances do NOT exclude IPF

86. When disease is overtly progressive despite therapy and cannot be readily categorised on HRCT, always suspect atypical IPF. Biopsy these cases

87. NSIP…. or is it really UIP? UIP

88. The integration of HRCT and biopsy in UIP/NSIP Flaherty et al, Thorax, Feb 2003; 58:143-8 Biopsy, CT = NSIP Biopsy = UIP, CT = NSIP Biopsy, CT = UIP Stable/indolent fibrosis Inexorably progressive fibrosis

89. In these scenarios, biopsy informs our key goals  To prevent major inflammation (with variable fibrosis) evolving into progressive fibrosis  To convert inexorably progressive fibrotic disease into stable fibrotic disease

90. Both these goals are realistic in disorders other than IPF Only the second goal applies to IPF and it is not yet realistic in this disease

91. Biopsy data may allow full participation by patients in treatment decisions

92. Biopsy data may make the logic of management transparent, immediately understood by physicians outside the speciality

93. Summary Biopsy is no longer a “gold standard” Biopsy is no longer a “gold standard” Biopsy has a crucial role when it is not possible to broadly predict disease behaviour non-invasively Biopsy has a crucial role when it is not possible to broadly predict disease behaviour non-invasively Risk/benefit evaluation is pivotal Risk/benefit evaluation is pivotal

94. When the decision to biopsy is a close call, the views of the patient should swing the decision