History

1. History • Admitted to Wrexham Hospital • Injuries: • fractures of maxilla and mandible, floor of R orbit, nasal bones & soft tissues • fracture one rib, collapse R lung. Bilateral pneumothoraces. Onset of adult respiratory distress syndrome (ARDS) • ventilated for eight weeks. Transplant?

2. Clinical Progress • Jan 1997; referred for transplant assessment. QoL good and lung disease static • August 97; holiday in Spain! • Sept 98; sad, breathless and no QoL Isolated • Oct 98; transplant assessment

3. Pathologists and clinicians each developed their own nomenclature Differing terminologies in different countries IPF (USA and ASIA) = CFA (GB) Idiopathic BOOP (USA ) = COP (GB) + many synonyms for IPF/CFA such as: Hamman-Rich syndrome "honeycomb lung' Osler-Charcot disease Realisation - a worse prognosis with some patterns, e.g. UIP cf. DIP HRCT, correlated with pathology, separated the different groups

4. ATS – ERS classification Histological pattern Clinico-path-radiologic diagnosis DAD AIP UIP Idiopathic pulmonary fibrosis Cryptogenic fibrosing alveolitis NSIP Non-specific interstitial pneumonia Organising pneumonia Cryptogenic organising pneumonia DIP (RB) DIP (RBILD) LIP LIP

5. AIP - histopathology AIP = ARDS on histology - no identifiable aetiology in AIP Exudative phase dev. in week 1 post - insult - interstitial & intra-alveolar oedema, hyaline membranes,  type II pneumocytes, intra-alveolar haem. and interstitial mononuclear inflamm. In hrs. after insult, ?only  in neutrophils in alv. cap. and interstitial oedema Bouros D Eur Respir J 2000; 15: 412 -18

6. AIP – histopathology (2) Prolif. stage during week 2 – ↑ fibroblastic proliferation in interstitium & alveoli, ↑type II cells & nuclear atypia - ?malignant, esp. on cytology Combinations of patterns often seen Bouros D Eur Respir J 2000; 15: 412 -18

7. NSIP Definition - “an idiopathic interstitial pneumonia with a histologic patten that does not conform to the characteristic features of UIP, RB-ILD, DAD, or COP.” Main feature is a temporarily HOMOGENEOUS pattern of inflammation or fibrosis

8. Causes of NSIP CT disease (inc. undiff. CT disease) (Kinder BW AJRCCM 2007; 176: 691 – 7) 10% dev. collagen dis. (Park IN Eur Resp J 2009; 33: 68 – 76) Other diseases: PBC Hashimoto's thyroiditis Acute G/N Chronic renal failure Exposures - birds, wood stove, various occupations (e.g. grain dust in brewing, cleaning jacuzzi) Drugs (gold, penicillamine, hydralazine) DAD Smokers (assoc. emphysema) (Marten K Eur Radiol 2009; 19: 1675-85)

9. UIP (Usual Interstitial Pneumonia) Definition - “UIP is a histologic pattern seen in the clinical setting of diffuse, bilateral interstitial lung disease. Changes often distributed along the subpleural and paraseptal regions” Main feature is a PATCHY, TEMPORALLYHETEROGENEOUS fibrosis with scattered fibroblastic foci at the edge of fibrotic scars, causing lung remodeling and honeycombing

10. Differential diagnosis ofUIP histology Mixed UIP/NSIP NSIP – fibrosing pattern DIP Fibrotic phases of other interstitial diseases - LCH - EAA - DAD

11. Aetiological differentialdiagnosis of UIP pattern Collagen vascular disease Drug - induced pneumonitis Asbestosis Radiation pneumonitis Hermansky - Pudlak syndrome EAA Idiopathic UIP

12. Histological patterns are distinctive but not specific UIP - collagen diseases, asbestosis COP or idiopathic BOOP - can be seen in a variety of conditions (Tx, infection) NSIP - EAA, collagen diseases, end result of DAD, drugs etc

13. Variation in histological patterns of ILD between connective issue diseases PM/DM (13) - OP +/- NSIP (one UIP) RA (17) - Follicular bronchiolitis +/- NSIP (two UIP) Sjögrens (5) - Chronic bronchiolitis +/- NSIP SLE (2) - UIP (1), other follicular bronchiolitis & minor compnt. cellular NSIP Tansey D et al. Histopathology 2004; 44: 585-96 CTD-UIP has ↓fibroblast foci, emphysema & honeycombing, ↑ germinal centre & total inflamm. scores (Song JW Chest 2009;136: 23)

14. UIP + NSIP Cases with mixed patterns (NSIP plus UIP) 64 cases of ‘CFA’ with multiple bx. showed 25 concordant cases of UIP (present in all lobes), 8 discordant (UIP + NSIP) and 31 NSIP (3 cellular and 28 fibrotic) Patients in concordant NSIP group had significantly better survival than discordant or concordant UIP (p = 0.02 and p = 0.04, respectively) No significant diff btwn. concordant and discordant UIP grps. (p = 0.48) 75% of concordant NSIP group alive 5 years after biopsy, 17% of concordant and 37% of in the discordant UIP group alive Monaghan H et al. Chest 2004; 125: 522 – 6

15. NSIP vs. UIP UIP pattern most important predictor of prognosis Risk ratio of mortality in UIP (106 pts) >28.5, after controlling for age, symptom duration, radiology, physiology & sex NSIP pts. (28 fibrotic & 5 cellular) more likely to respond or remain stable Honeycombing on HRCT indicated UIP – sens, 90%, spec of 86% Flaherty KR et al. Eur Resp J 2002; 19: 275 – 283

16. UIP- Histological predictorsof prognosis Honeycombing Dense interstitial inflammation involving 60% or  of bx Intrapleural fat < 50% fibroblastic foci/cm2 in biopsy - median survival of 89m. cf. 49m. in those with > 50 FF/cm.2 No assocn. between FF at ∆ and DAD at autopsy Travis WD et al. Am J Surg Pathol 2000; 24: 19-33 • Titto, L et al. Thorax 2006; 61: 1091 – 5

17. Acute exacerbations of UIP Defined as acute, clinically significant deteriorations of unidentifiable cause in pts. with underlying UIP Proposed diagnostic criteria include; subjective worsening over 30 days or less, new bilateral radiographic opacities & no infection or Identifiable aetiology. Histology – DAD (75%), OP or ↑ fib. foci Potential causes include; • infection (? CMV) • disordered cell biology (loss of epithelial cell integrity, fibrocyte function, TGFβ), • abnormal coagulation (procoagulant environ. as in ARDS), and genetic factors (polymorphism in erythrocyte complement receptor 1 and mutations in surfactant protein genes) Churg A Am J Surg Pathol 2007; 31: 277 Kim DS et al ERJ 2006; 27: 143 Collard HR et al. AJRCCM 2007; 176: 636

18. CFA - EBV • IHC EBV DNA • CFA 12/27 14/27 • control 3/28 4/28 • p=0.005 p=0.007 81% of PCR assays confirmed IHC results Stewart, Egan, Hasleton et al. Am J Respir Crit Care Med 1999; 159: 1336

19. Idiopathicpleuroparenchymal fibroelastosis • Clinical presentation suggestive of chronic idiopathic interstitial pneumonia  Marked pleural & parenchymal radiographic involvement with UL predominance Pathology includes; • Marked visceral pleural fibrosis ; • Prominent, homogenous, subpleural fibroelastosis; • Sparing of parenchyma distant from the pleura; • Mild, patchy, lymphoplasmacytic infiltrates; and • Small numbers of fibroblastic foci present at the leading edge of the fibrosis. Frankel SK CHEST 2004; 126:2007–2013 Becker CD Mod Pathol 2008;21: 784 – 7

20. Bronchiolocentric interstitialpneumonia (BrIP) BrIP - marked predilection for women (80%) in middle age (40–50 years) C/O SOB, cough, wheeze, chest pain and recurrent Pneumonia. 8/12 Churg’s pts had history of inhalational exposures (wood smoke, birds, cocaine etc) CT and PFT show restrictive disease Mean FU of approx. 4 years in nine patients, 33% were DOD and 56% had persistent or progressive disease. ? BrIP a unique entity Yousem S Mod Pathol 2002; 15: 1148-53. Churg A Am J Surg Pathol 2004; 28: 62-8 Fukuaka J Am J Surg Pathol 2005; 29: 948-954

21. Bronchiolocentric interstitialpneumonia(BrIP) Centrilobular damage with peribronchiolar scarring (remodelled fibrotic lung) and very focal interstitial and air - space granulation tissue – Scar extends from centrilobular area out into peripheral lobule – Bronchiolar metaplasia – may be exuberant What should not be present 1. Granulomas – implies HP 2. Bronchiectasis – can cause a distal pattern of centrilobular injury/scar 3. Aspirated food 4. BO/OP – obliterative luminal airway damage