ILD) Or „Diffuse Parenchymal Lung Diseases“ (DPLD); Idiopathic Interstitial Pneumonias (IIP

Interstitial lung diseases (ILD) or „diffuse parenchymal lung diseases“ (DPLD); Idiopathic interstitial pneumonias (IIP)

Alan Altraja

Department of Pulmonary Medicine, University of Tartu Interstitial lung diseases (ILD) or „diffuse parenchymal lung diseases“ (DPLD) (ATS/ERS consensus, 2002)

Diffuse parenchymal lung diseases (Interstitial lung diseases): this group contain: • Idiopathic interstitial pneumonias (IIP) • Interstitial lung diseases with known cause (pulmonary manifestations of the systemic connective tissue diseases and vasculitis, hypersensitivity pneumonitis (HP) (or allergic alveolitis), interstitial lung diseases caused by exposures to drugs, physical factors etc.) • Granulomatous diseases (sarcoidosis etc.) • Other (histiocytoses, alveolar proteinosis, lymphangioleiomyomatosis etc.) • Non-specific (end-stage) pulmonary fibrosis

Normal Restriction

A. Altraja ©2017 Pathophysiology of the gas diffusion in interstitial lung diseases • Prolongation of the diffusion trajectory • Shrinkage of the diffusion surfaces (alveolar filling, replacement of the lung tissue by fibrosis, honeycombing, sometimes in combination with emphysema)

Capillaries Alveoli Alveoli Capillaries

Normal Restriction

Diffuse parenchymal lung diseases (DPLD; ILD)

DPLD of known cause: Idiopathic interstitial Granulomatous DPLD (e.g. Other forms of DPLD (e.g. LAM, associated with collagen pneumonias sarcoidosis, HP etc. HX, PAP, eosinophilic vascular disease etc. pneumonias etc.)

DPLD of known cause - Idiopathic Other idiopathic exposure-related: drugs, pulmonary interstitial occupational, environmental fibrosis (IPF) pneumonias etc. Unclassifiable Desquamative Respiratory interstitial bronchiolitis pneumonia interstitial (DIP) lung disease Major Acute Cryptogenic interstitial organizing pneumonia pneumonia (AIP) (COP) Rare

Non-specific Lymphocytic Pleuro- Other rare units interstitial interstitial parenchymal pneumonia pneumonia fibroelastosis (NSIP) (LIP) (PPF)

Diffuse parenchymal lung diseases (DPLD; ILD)

DPLD of known cause - Idiopathic Other idiopathic exposure-related: drugs, pulmonary interstitial occupational, environmental fibrosis (IPF) pneumonias etc. Linked to smoking Desquamative Respiratory interstitial bronchiolitis pneumonia interstitial (DIP) lung disease

Acute Cryptogenic interstitial organizing pneumonia pneumonia (AIP) (COP)

Non-specific Lymphocytic Pleuro- Other rare units Smoking-related IPs interstitial interstitial parenchymal pneumonia pneumonia fibroelastosis (NSIP) (LIP) (PPF)

A. Altraja ©2017 (ATS/ERS consensus, AJRCCM 2002, 2013) DPLD/ILD associated with smoking Separate entity – smoking-related IPs: • DIP • RB-ILD Additionally, interstitial lung diseases from the non-IIP group: • Pulmonary Langerhans cell histiocytosis (PLCH) • Acute eosinophilic pneumonia (AEP) (2/3 smokers) A clear link to smoking also in: • IPF, AE-IPF, CPFE, NSIP, AIP • Some variants of asbestosis (Norbet et al. 2015) • Pulmonary manifestations of systemic connective tissue diseases (CTD) (or collagen vascular diseases, CVD): RA (Antoniou et al. 2013) • Smoking-related interstitial fibrosis (SRIF) (Katzenstein, 2013)

Vassallo, Limper, Ryu, 2011, Antoniou et al. 2013; Norbet et al. 2015; Margaritopoulos et A. Altraja ©2017 al. 2016; Hagmeyer & Randerath, 2015; Katzenstein, 2013 Association with all DPLD/ILD with smoking 1. Chronic ILD that are associated with smoking • RB-ILD • DIP • Adult pulmonary Langerhans cell histiocytosis (PLCH) 2. Acute ILD that are associated with smoking • Acute eosinophilic pneumonia (AEP) • Syndromes of pulmonary hemorrhage 3. ILD that are more frequent in smokers • IPF • ILD due to rheumatoid arthritis 4. ILD that may occur less frequently in smokers • Hypersensitivity pneumonitis • Sarcoidosis

A. Altraja ©2017 Vassallo, Limper, Ryu, 2011; Margaritopoulos et al. ERR 2015 Classification of interstitial lung diseases by clinical- temporal course Acute: up to 3 months • AIP: course 1-2 weeks (1-2 months) • COP Episodic course • COP: <3 months • As differential diagnoses also: pulmonary vasculitis, pulmonary hemorrhages, eosinophilic pneumonias, hypersensitivity pneumonitis Subacute-to-chronic: • NSIP: course months to years Chronic course • IPF: course >12 months • LIP: course >12 months BTS, Thorax, 2008 A. Altraja ©2017 The current classification of idiopathic interstitial pneumonias (IIP)

Clinical diagnosis Histopathological finding Usual IIP Fibrosing IIP Idiopathic pulmonary fibrosis (IPF) Usual interstitial pneumonia (UIP)

Idiopathic non-specific interstitial Non-specific interstitial pneumonia (NSIP) pneumonia (iNSIP) Smoking-related Desquamative interstitial pneumonia (DIP) Desquamative interstitial pneumonia (DIP) IIP

Respiratory bronchiolitis-associated Respiratoorne bronchiolitis-associated interstitial lung disease (RB-ILD) interstitial lung disease (RB-ILD)

Acute and Acute interstitial pneumonia (AIP) Diffuse alveolar damage (DAD) subacute IIP Cryptogenic organizing pneumonia (COP) Organizing pneumonia (OP)

Rare IIP Idiopathic lymphoid interstitial pneumonia Lymphoid interstitial pneumonia (LIP) (LIP) Idiopathic pleuroparenchymal Reddy TL et al. ERJ 2012 fibroelastosis (PPFE) Unclassifiable IIP

Reversible and self- Some cases of Remove possible cause Short-term (3-6-month) limited RB-ILD observation to confirm disease regression Reversible disease Cellular NSIP, Initially achieve Short-term observation with risk of some cases of response to confirm treatment progression fibrotic NSIP, DIP, and then rationalize response. Long-term and COP longer term therapy observation to ensure that gains are preserved Stable with residual Some cases of Maintain status Long-term observation to disease fibrotic NSIP assess disease course Progressive, Some cases of Stabilize Long-term observation to irreversible disease fibrotic NSIP assess disease course with potential for stabilization Progressive, IPF, some cases of Slow progression or Long-term observation to irreversible fibrotic NSIP progression with assess disease course disease despite exacerbations and need for transplant therapy or effective palliation

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013 What to do if there is a suspicion of an ILD? • The primary task – the physician should suspect one • Diagnostics: the process is dynamical • Essential: multidisciplinary approach: • Based on communication between the clinician, radiologist, sometimes also pathologist and other specialists • The clinical data are primary: • Onset of the disease, course until now, clinical manifestation • Exposures • Smoking status • Concomitant diseases (especially those having interstitial pneumonias as their manifestations) • Lung function: postbronchodilator spirometry, diffusing capacity of the lung, 6-minute walk test (6MWT etc.) • Laboratory findings (serology) (Lynch, J Thoracic Imaging 2009) • Radiology: Chest X-ray for screening, HRCT for diagnostics

• Is the lung disease a manifestation of a systemic (connective tissue) disease • Has the disease (developed as a result of) a known etiology

• If not, then it is most probably an idiopathic lung disease •Then, the next question is: whether this could be idiopathic pulmonary fibrosis (IPF) •IPF has poor response to treatment and bad prognosis •Recently, treatments have become available for IPF

• Progressive dyspnea, dry cough and end-inspiratory crackles on auscultation („velcro rales“) are characteristic of the majority of IIP

• Fever and shorter history of the current disease is typical of AIP and COP • Fever and rapid clinical progression also in acute exacerbations of IPF • In NSIP, RB-ILD, DIP, and LIP, but especially in IPF, the symptoms progress relatively slowly and fever is not characteristic • A significant smoking history refers to DIP, RB-ILD, and NSIP, but plays, to lesser extent, a role even in other IIP

Wells et al., BTS Guidelines: Thorax 2008 A. Altraja ©2017 Raghu et al., ATS/ERS/JRS/ALAT Guidelines: AJRCCM 2011 Approach to the patient with possible ILD: detailed history • All complaints and symptoms • E.g. in IPF: dyspnea > cough > fatigue > depression > anxiety (Garibaldi et al. 2015) • Exposures • Respiratory risk factors (full data on smoking) • Occupational history • Living, residency, travel, hobbies • Family history in ILD (IPF, CTD, sarcoidosis etc.) • Infections (HIV etc.) • Medication history: Pneumotox® (The Drug-Induced Respiratory Disease Website, the Appstore etc.) (http://www.pneumotox.com/drug/index/P/) • Previous illnesses • Signs and symptoms of systemic diseases (Raynaud’ phenomenon, skin, dysphagia, reflux, joints, myalgia, proximal muscle weakness, sicca symptoms, systemic symptoms etc.) • Respiratory symptoms (cough, wheeze, hemoptysis, (pleuritic) chest pain etc.) Wells et al., BTS Guidelines: Thorax 2008; A. Altraja ©2017 Raghu et al., ATS/ERS/JRS/ALAT Guidelines: AJRCCM 2011; Garibaldi et al. Respirology 2015 Status of the patient with possible ILD • Proper thinking is the pre-requisite of the early diagnosis • Demographics of the patient • Auscultation: • Bibasilar end-expiratory velcro-rales • 1969, Richard A. DeRemee, Mayo Clinic (DeRemee, Minnesota Med 1969) • Has become a “trademark”, albeit not specific for IPF • Screening: • Age: • Age ≥70 in a patient with ILD vigorously supports IPF • Age <50 years makes IPF very improbable • Smoking (incl. smoking history) • First order relatives of the patient with IPF • Low-dose HRCT • The diagnosis of IPF/ILD might be a by-product of screening for other pulmonary diseases (cancer, TB etc.) A. Altraja ©2017 Cottin V & Cordier JF, Eur Respir J 2012; Cordier JF & Cottin V, Eur Respir J 2013 Chest X-ray of a patient suggestive of ILD: valid for screening

• A 68-year-old man • 3 months from the onset of symptoms • Later diagnosed as having IPF

A. Altraja ©2017 Studies on the patient with possible ILD • Blood tests, serum biochemistry (electrolytes, renal and liver function tests, coagulometric tests), urinalysis • Chest X-rays (valid for screening or initial diagnosis only) • Lung function tests (forced spirometry with bronchodilator test), measurements of diffusing capacity of the lung; standardized exercise tests (6MWT, ISWT) • Serologic testing to detect possible connective tissue disease (CTD) • Rheumatoid factor (RF), anti-CCP • ANA + other anti-nuclear antibodies • Scl-70 (anti-topoisomerase) • Jo-1 (anti-histidyl-tRNA) (50-100%-l in DM/PM patients) • ACA (anti-centromere antibodies) • anti-Ro/SSA • anti-La/SSB • anti-Ku • Anti-RNP (against A, C, and 68 kDa); anti-Sm (against B/B', D1, D2, D3, E, F, and G) • If ANA-positive cases, lupus anticoagulant, anti-cardiolipin antibodies) • In practice, ANA, ANCA-panel, and ENA (Extractable Nuclear Antigen Antibodies) panel is often determined Wells et al., BTS Guidelines: Thorax 2008; A. Altraja ©2017 Raghu et al., ATS/ERS/JRS/ALAT Guidelines: AJRCCM 2011 The panel of IgG autoantibodies against extractable nuclear antigens (ENA)

• The panel against 6 widely tested ENA • Sm (Smith): against Smith antigen: specific of systemic lupus erythematosus (SLE) (99%) • Anti-RNP (ribonucleoprotein) antibodies: in SLE and mixed connective tissue disease • Anti-SSA/Ro (Sjögren’s syndrome antigen A) antibodies: 85% of patients with Sjögren’s syndrome • Anti-SSB/La (Sjögren’s syndrome antigen B) antibodies: 85% of patients with Sjögren’s syndrome • Scl70 (anti-scleroderma 70 kDa antigen or DNA topoisomerase I) or ”anti- topo I”: in 56% of patients with systemic sclerosis • Jo1: anti-histidyl-tRNA synthase antibodies: in polymyositis and dermatomyositis, but not in other myopathies; specific • In the presence of pulmonary fibrosis • Reference values: <20 ENA units: negative; ≥30 ENA units: positive • This panel is done, when ANA IgG results have appeared positive • Anti-CCP • ANCA panel

A. Altraja ©2017 Lung function measurements in ILD • Restrictive pattern along with decreased diffusing capacity are generally typical •All patients need to undergo post-bronchodilator spirometry and transfer test with carbon monoxide (to measure/calculate DLco, Kco, TLC etc.) • In COP and RB-ILD, an obstructive component may be present • COPD may accompany in smokers as a concomitant disease! • In IPF and fibrotic NSIP, the diffusing capacity of the lung (DLco) is one of the most precise diagnostic-prognostic markers • In IPF, a >10% fall in FVC >15% in DLco within 6-12 may refer to rapidly progressing disease phenotype and high risk of death (the same does rapid desaturation during 6MWT)

Wells et al., BTS Guidelines: Thorax 2008 A. Altraja ©2017 Raghu et al., ATS/ERS/JRS/ALAT Guidelines: AJRCCM 2011 The diagnostic algorithm for IPF/ILD The suspicion is the point ! Suspicion: Multi-disciplinary discussion (MDD) Identifiable causes of ILD Yes No HRCT Possible UIP; UIP inconsistent with UIP (Surgical) lung biopsy UIP, probable or possible UIP; non- classifiable fibrosis Multi-disciplinary discussion (MDD)

• Changes on chest X-ray are non-specific and of lower sensitivity and only just refer to the presence of abnormalities • Only frank honeycombing may refer to IPF/UIP • The main task of the chest X-ray: to suspect an ILD • All patients with such a suspicion need to undergo high- resolution computed tomography (HRCT) of the chest (see the respective requirements further)

A. Altraja ©2017 HRCT: the protocol for the diagnosis of ILD •Inspirium scan, without contrast medium •The contrast medium may enforce the finding of false ground glass opacity •Axial and coronal reconstructions •Image interval ≤ 20 mm („volume CT“, „incremental CT“) •Slice thickness ≤ 2 mm •High resolution algorithm •Expirium scans, if suspicion of HP (mosaic attenuation) •Additional prone scans, if suspicion of purely hypostatic attenuations

Prosch H, CIPF, Prague 11.03.2016 The necessity of HRCT in the diagnosis of ILD and IIP

All patients a suspicion of an ILD need to undergo high- resolution computed tomography (HRCT)

• The main task of HRCT is to describe the patterns characteristic of particular ILD, especially that of IPF/UIP • The major proofs of lung fibrosis include: • Honeycombing • Traction bronchiectasis or bronchiolectasis

A. Altraja ©2017 What is the „ground glass opacity“? (DIP, NSIP, RB-ILD, acute exacerbation of IPF, AIP): The “ground glass opacity” (GGO) is: • Semi-transparent opacity that does neither hide completely nor distort the underlying lung architecture

What is the substrate of GGO? • May represent slight cellular inflammation and alveolar septal thickening • May also reflect presence of immature, ”young” fibrosis (Remy-Jardin et al., 1993)

A. Altraja ©2017 Bronchoscopy with its ancillary methods (BAL, TBB, c-TBB) in the diagnostic work-up of IIP/ILD • The application depends on that what particular IIP/ILD is suspected • Need to be performed before commencing the treatment Bronchoalveolar lavage (BAL): • Lymphocytosis may refer to a good responsiveness to glucocorticosteroids and better prognosis, but also to an alternative diagnosis (sarcoidosis, hypersensitivity pneumonitis etc.) • In cases with definitive UIP pattern radiographically (on HRCT imaging), BAL may not be necessary (though predominating neutrophilia is quite specific of IPF) • Many centers consider bronchoscopy and BAL mandatory in ILD Transbronchial biopsy (TBB): • Material too scarce to warrant disease-specific morphology; is not indicated in the diagnostic work-up of rare lung diseases (if not otherwise indicated (e.g. sarcoidosis, COP etc.) • TBB may be applied in certain very diffuse or bronchocentric diseases like sarcoidosis etc. • Has been replaced by transbronchial cryobiopsy (c-TBB)

Wells et al., BTS Guidelines: Thorax 2008 A. Altraja ©2017 Raghu et al., ATS/ERS/JRS/ALAT Guidelines: AJRCCM 2011 Transbronchial cryobiopsy (c-TBB) in IFP/ILD • Major area of use: confirmation of the diagnosis, when ”possible UIP” is the case • Studies on other ILD of less quality (NSIP and DIP, acceptable with BAL) • „Standardized protocols“ are being available • In the majority of studies: • Intubation, i.v. anesthesia (propofol), under X-ray surveillance • After extraction, prompt closure of the segmental bronchus with a Fogarty balloon catheter to avoid major bleeding; control of hemostasis after 4 min. • Biopsy ≥1,5 apart from visceral pleura is safe (pneumothorax) • Freezing time ≥5…6 seconds provides better quality specimens • Pneumothorax ≤28% • Less studies on results with obtaining biopsies from different ipsilateral lobes – practically valuable knowledge, as the „pattern“ could vary between different segments and lobes

•1 week after c-TBB (4 specimens) from the basal segments of the RLL •„Holes“ in segments 8 and 9

A. Altraja ©2017 Morphological diagnosis of the IIP/ILD • Bronchoscopy with methods of cytology and biopsy (see) • Trans-bronchial needle aspiration (TBNA) or endobronchial ultrasound- guided trans-bronchial needle aspiration (EBUS-TBNA): not useful, however, is suitable for lymph node staging of lung cancer, the diagnosis of sarcoidosis, inflammation etc. • Surgical lung biopsy (SLB) under video-assisted thoracoscopic surgery (VATS): used to obtain the histopathological diagnosis in the absence of contraindications; especially in those lacking the classical radiographic (HRCT) UIP pattern* • VATS-biopsy is associated with risks: perioperative mortality 4%); contraindicated if FVC<50% and/or DLco <30% • The c-TBB has emerging popularity • *The list of diseases, in which the diagnosis does not require SLB, is increasing:

• IPF: if the clinical and radiographic criteria are met (Raghu et al., 2011) • RB-ILD • COP: TBB or c-TBB may be sufficient (Wells et al., BTS Guidelines: Thorax 2008)

• An increasing list of ILD/IIP requires no lung biopsy for the diagnosis (IPF, DIP, RB-ILD, COP, HP etc.) • The histopathology is required there, where it is necessary • However, knowledge on the patterns is essential for differential diagnosis in complex situations encountered • Less invasive methods for biopsying: transbronchial cryobiopsy (c-TBB)

A. Altraja ©2017 The morphological diagnosis of idiopathic interstitial pneumonias (IIP) The morphological diagnosis of IIP: it is necessary that the histopathology is interpreted in correlation with the clinical and radiographic findings (often during multidisciplinary team (MDT) discussions in competence centers) • Low magnification views are interpreted The main questions: 1. Is the process diffuse or focal? 2. What is the principal localization of the lesion(s)? •Subpleural (paraseptal) •Alveo-septal •Bronchiolocentric •Lymphangitic (perilymphatic) •Random 3. Is/are the finding(s) temporally homo- or heterogeneous 4. What is the general evolutionary phase of the lesion(s): (acute, subacute, or mature fibrosis with tissue remodeling A. Altraja ©2017 Is/are the histopathological finding(s) temporally homo- or heterogeneous in IIP/ILD? • Temporally heterogeneous: in the same specimen/section, there are changes that belong to different evolutionary phase in different locations/compartments (e.g. acute, subacute, chronic changes) • Temporally homogeneous: the changes are uniform across the whole specimen/section in terms of their evolutionary phase • Acute changes: necrosis of the alveolar epithelium, hyaline membranes, interstitial edema, fibrin deposition • Subacute changes: filling of the interstitial tissue or airspaces (alveoli, bronchiole) with fibromyxoid granulation tissue • Chronic changes: scar formation, fibrosis and remodeling (honeycombing, traction bronchiectasis or bronchiolectasis, collagen deposition) The significance: makes reference to the response to treatment

Exclusion of sarcoidosis, lung cancer, Transbronchial biopsy (TBB, c-TBB) rare ILD

LUNG BIOPSY Pathological interpretation: diffuse or focal disease

Diffuse DIP, NSIP, LIP Focal: IPF/UIP, COP, RB-ILD

Temporally homogeneous Temporally Temporally homogeneous heterogeneous Scarce mononuclear Intensive mononuclear infiltrate infiltrate Fibromyxoid tissue Centrilobular in airspaces macrophages Few macrophages Many macrophages

NSIP DIP LIP COP RB-ILD IPF/UIP

• The treatment should not be commenced before all necessary efforts have been done to establish the final diagnosis

A. Altraja ©2017 Acute exacerbations as the common feature of interstitial lung diseases • Acute exacerbations of IPF are common and well known, however, other IIP can also exacerbate (Park et al. Chest 2007) • Known also in CTD-IP (Suda et al. Respir Med 2009) IPF • A classical course variant (phenotype) with acute exacerbations is known • The probability is 5-20% per year (see further) NSIP • The probability of acute exacerbations is 4.2% per year in CTD-IP • Rheumatoid arthritis • Systemic sclerosis

A. Altraja ©2017 Park et al., Chest 2007; Travis et al. ATS/ERS Consent, AJRCCM 2013 Management of connective tissue disease (CTD)-associated IP Non-CTD cause identified (e.g. No CTD-specific autoantibodies hypersensitivity, drug- or features; no CTD-associated associated pathological features; no pneumonitis, infection) alternative cause identified

An IIP is present Interstitial Prsesence of specific pneumonia autoantibodies, CTD-specific Positive specific autoantibodies, clinical features ± CTD-associated absence of CTD features ± CTD- histopathology associated histopathology

Definite CTD-ILD Possible CTD-ILD

Surveillance for Clinically No No Clinically significant evidence significant disease? disease? of progression Yes

Yes Non-UIP UIP

Immunosuppressive therapy Fischer A, DuBois R. Lancet Consider treatment as for IPF 2012; 380: 689-698 vs. immunosuppression Interstitial pneumonia with autoimmune features (IPAF) • The problem: some patients with an IIP or other idiopathic ILD have clinical, serologic, or morphologic features that suggest the presence of a systemic autoimmune process, but do not meet diagnostic criteria for a defined CTD

The classification criteria: 1. Presence of an interstitial pneumonia (by HRCT or surgical lung biopsy) and 2. Exclusion of alternative etiologies and 3. Does not meet the criteria of a defined CTD and 4. At least one feature from at least two of these domains: A. Clinical domain B. Serologic domain C. Morphologic domain

A. Altraja ©2017 Fischer A et al., ERS/ATS Statement ERJ 2015; 46; 976 The clinical domain in IPAF 1. Distal digital fissuring (i.e. “mechanic hands”) 2. Distal digital tip ulceration 3. Inflammatory arthritis or polyarticular morning joint stiffness ⩾60 min 4. Palmar telangiectasia 5. Raynaud’s phenomenon 6. Unexplained digital edema 7. Unexplained fixed rash on the digital extensor surfaces (Gottron’s sign)

Fischer A et al., ERS/ATS Statement ERJ 2015; 46; 976 The serologic domain in IPAF 1. ANA ⩾1:320 titer, diffuse, speckled, homogeneous patterns or a. ANA nucleolar pattern (any titer) or b. ANA centromere pattern (any titer) 2. Rheumatoid factor ⩾2× upper limit of normal 3. Anti-CCP 4. Anti-dsDNA 5. Anti-Ro (SS-A) 6. Anti-La (SS-B) 7. Anti-ribonucleoprotein 8. Anti-Sm(ith) 9. Anti-topoisomerase (Scl-70) 10. Anti-tRNA synthetase (e.g. Jo-1, PL-7, PL-12; others are: EJ, OJ, KS, Zo, tRS) 11. Anti-PM-Scl 12. Anti-MDA-5

A. Altraja ©2017 Fischer A et al., ERS/ATS Statement ERJ 2015; 46; 976 The morphologic domain in IPAF 1. Suggestive radiology patterns by HRCT: a. NSIP b. OP c. NSIP with OP overlap d. LIP 2. Histopathology patterns or features by surgical lung biopsy: a. NSIP b. OP c. NSIP with OP overlap d. LIP e. Interstitial lymphoid aggregates with germinal centers f. Diffuse lymphoplasmacytic infiltration (with or without lymphoid follicles) 3. Multi-compartment involvement (in addition to IP): a. Unexplained pleural effusion or thickening b. Unexplained pericardial effusion or thickening c. Unexplained intrinsic airways disease (by PFT, imaging, or pathology) d. Unexplained pulmonary vasculopathy

A. Altraja ©2017 Fischer A et al., ERS/ATS Statement ERJ 2015; 46; 976 Approach to the diagnosis in ILD: conclusions • Multidisciplinary approach • Classification  more mechanism-based • IPF remains the major DPLD: • A progressive, irreversible, and ultimately fatal, but also unpredictable disease • Not idiopathic anymore • The diagnosis is changing • MDD is useful, but also imperfect • For clinical approach: • Think critically • Watch the literature • Be rigorous in assessment, but flexible in categorization • Pay attention to patient’s condition, biology, and environment – precision medicine • Encourage treatment, but be clear that some patients fail to respond • Using therapies without an efficacy feedback is unacceptable

• Idiopathic pulmonary fibrosis (IPF) • (Idiopathic) non-specific interstitial pneumonia (i)(NSIP)

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013 Idiopathic pulmonary fibrosis (IPF) • Peak incidence occurs in the 6th life decade (50-70-yearsed) • Slightly more common in men than in women • Definition: a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathological and/or radiologic pattern of usual interstitial pneumonia (UIP)

• UIP or “Usual Interstitial Pneumonia (in Estonian “tavaline interstitsiaalne pneumoonia”) refers to a particular, pre- defined histopathological finding present in the peripheral lung (see further)

A. Altraja ©2017 The ATS/ERS/JRS/ALAT Criteria: Raghu et al., AJRCCM 2011 IPF epidemiology: incidence and prevalence • IPF is the commonest disease in the group of IIP: 55% of all IIP (Meltzer et al. 2008; Kim et al. 2006)

• In Finland, (According to the ERS/ATS criteria) 16-18/100,000 (Hodgson et al., 2002), the same in Great Britain (Wells et al. 2008) • In the EU, 1.25…23.4/100,000; 40,000 new cases annually (Orphanet Report Series, 2011)

• Incidence and prevalence increase rapidly with age In >75-year-old people: • Incidence 160/100,000 inhabitants per year • Prevalence 250/100,000 inhabitants

•Databases that rely on data from health care systems tend to overestimate the prevalence of IPF (varying diagnostic criteria, inappropriate coding etc.) •Investigations based on national registries and questionnaires tend to underestimate the number of patients with IPF •Prevalence 0.5-27.9/100,000 •Incidence 0.22-8.8/100,000 per year •The mortality has had a trend towards increase before the advent of the contemporary antifibrotic treatment: •0.92/100,000 (1968–1972)  5.1/100,000 (2006–2008) •Higher among men and elderly patients

A. Altraja ©2017 Kaunisto et al. BMC Pulmonary Medicine 2013 IPF epidemiology (continued) • No clear race distribution (King et al., 2000; Raghu et al. 2011) • A familiar variant is known (5%) (Böing et al. 2013); mutations in the genes of SP-A2, SP-C, telomerase complex • Median age of falling ill: 70 years (USA, Great Britain) (Wells et al. 2008); in general, during 5-7 decades • Main age at the diagnosis: 66 years (Raghu et al., 2011), • 2/3 of the patients are >60 years old • Slight male predominance (1.5…1.7:1) (Johnston et al., 1997) • The majority of the patients are former smokers • 5-year mortality: 50-80% • Median survival: 3 years (Great Britain, data before the era of antifibrotic management, Wells et al. 2008) • The proportion of IPF among the causes of death rapidly increases in advanced age Mortality due to IPF is clearly underestimated • Böing et al. SVDLD 2013; A. Altraja ©2017 Annesi-Maesano et al. SVDLD 2013 Risk factors for IPF • Smoking (risk 1.6…2.3) • Environmental factors: • Work in dusty environments [stone, metal (steel, brass, lead), wood and agricultural dusts (animal- and plant-derived)] • Microorganisms • Viral infections (Epstein-Barr, CMV, HCV, adenovirus E1A, human herpes virus 7 and 8) • Gastroesophageal reflux • Genetic factors • Familiar occurrence: 5%; autosomal dominant inheritance, with variable penetrance •Is connected with telomerases (telomerase reverse transcriptase hTERT) •In sporadic cases: IL1, -4, -6, -8, -10, 12, TNF-α, lymphotoxin α • Geographic clustering

A. Altraja ©2017 Raghu et al., AJRCCM 2011; King, ILD, 5th ed. 2011 Pathogenesis of IPF • Injury to alveolar epithelium and activation of the latter • Secretion of plasminogen activator inhibitor (PAI) -1 and -2: formation of fibrin matrix • PDGF, TGF-β, TNF-α, endothelins: migration and proliferation of fibroblasts • Gelatinase A: disruption of the alveolar basement membrane • Telomeric apoptosis of the alveolar epithelium • Formation of the (myo)fibroblast foci • TIMP-2 • FGF-2, VEGF: angiogenesis • Angiotensin II: (telomeric) apoptosis of the alveolar epithelium, filling of the tissue defect with connective tissue • Imbalance between MMPs and TIMPs: fibrosis and dysfunctional re- epithelization • Epithelial-mesenchymal transition (EMT)

Clinical findings are, with some differences, similar also in other chronic IIPs • Breathlessness (not otherwise explainable chronic dyspnea on exertion) is the main symptom • Insidiously appearing, but continuously progressive (during 0.5-3 last years) dyspnea • Patients over >50-60 years of age, more frequently in men • Dry cough, often resistant to antitussive medicines • Finger clubbing in 25-50% • Bibasilal end-inspiratory fine crackles on auscultation termed as “velcro rales”  refer to involvement of the alveolar level!); later, the velcro rales spread onto the whole lung fields • A practical means for screening for IPF and early detection of the disease: www.soundsofIPF.com • No fever in IPF (out of exacerbation or concomitant infections) • If there is fever  a reference to other IIPs (AIP, COP, NSIP) or other ILD (sarcoidosis, hypersensitivity pneumonitis etc.) • Fever is characteristic of acute exacerbations of IPF (see further) Raghu et al., AJRCCM 2011 A. Altraja ©2017 King, ILD, 5th ed. 2011 Survival in IPF: lower than in most malignancies •Data from the pre-antifibrotic drug era 5-year survival (%) 5-year survival

Malignancies of various locations Bjoraker JA et al. Am J Respir Crit Care Med 1998; Du Bois RM Eur Respir Rev 2012 Early diagnosis of IPF: proper thinking • Demographics of the patient • Auscultation: • Bibasilar end-expiratory velcro-rales • 1969, Richard A. DeRemee, Mayo Clinic (DeRemee, Minnesota Med 1969) • Has become a “trademark”, albeit not specific for IPF • Screening: • Age: • Age ≥70 in a patient with ILD vigorously supports IPF • Age <50 years makes IPF very improbable • Smoking (incl. smoking history) • First order relatives of the patient with IPF • Low-dose HRCT • The diagnosis of IPF/ILD might be a by-product of screening for other pulmonary diseases (cancer, TB etc.)

A. Altraja ©2017 Cottin V & Cordier JF, Eur Respir J 2012; Cordier JF & Cottin V, Eur Respir J 2013 Lung function abnormalities in IPF The changes are, with some insignificant differences, similar also in other chronic IIPs • Restrictive pattern of the decrease in ventilation function (the main outcome measure on spirometry is FVC; that can be normal in early disease) • Diffusing capacity of the lung: a fall in both DLco and Kco (usually at the moment of diagnosis) • In patients with lone IPF, the DLco % predicted is usually by only 20- 25% less than the lung volumes (in % predicted)

• Arterial blood gases and pulse oximetry: decreased PaO2 (or SaO2 or SpO2) already at rest, with a rapid fall during exercise • In smokers, who have concomitant chronic obstructive pulmonary disease, the lung volumes have relatively better preserved (VC % and FVC % are much higher than the DLco % or Kco % (King et al., 2000)); in these patients, both obstructive and restrictive patterns are present

•The diagnosis of IPF requires the following:

1. Exclusion of other known causes of ILD (e.g. domestic and occupational environmental exposures, connective tissue diseases, and drug toxicity) 2. The presence of a UIP pattern on HRCT in patients not subjected to surgical lung biopsy 3. Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy

Raghu et al., AJRCCM 2011;

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013 HRCT criteria for the UIP pattern I Main criteria („UIP pattern“, all 4 criteria required): • Subpleural, basal predominance • Reticular abnormality • Honeycombing with or without traction bronchiectasis • Absence of features listed as inconsistent with • UIP pattern (see third column) „Possible UIP pattern“ (all 3 features required): • Subpleural, basal predominance • Reticular abnormality • Absence of features listed as inconsistent with UIP pattern (see third column) • Subject to changes in the nearest future: If there are traction bronchiectasis visible in otherwise „possible UIP pattern“  this refers to the „definite UIP pattern“, because traction bronchiectasis is a very strong sign of fibrosis (Raghu et al. 2016)

„Inconsistent with UIP Pattern“ (the presence of any of these 7 features strongly speaks against UIP): • Upper or mid-lung predominance • Peribronchovascular predominance • Extensive ground glass abnormality (extent > reticular abnormality) • Profuse micronodules (bilateral, predominantly upper lobes) • Discrete cysts (multiple, bilateral, away from areas of honeycombing) • Diffuse mosaic attenuation/air-trapping (bilateral, in ≥3 lobes) • Consolidation in bronchopulmonary segment(s)/lobe(s)

Identifiable causes of ILD Yes No HRCT Possible UIP; UIP inconsistent with UIP (Surgical) lung biopsy UIP, probable or possible UIP; non- classifiable fibrosis Multi-disciplinary discussion (MDD)

IPF Judgement: IPF or other (particular) Other ILD ILD A. Altraja ©2017 Raghu et al., AJRCCM 2011 HRCT: the protocol for the diagnosis of ILD •Inspirium scan, without contrast medium •The contrast medium may enforce the finding of false ground glass opacity •Axial and coronal reconstructions •Image interval ≤ 20 mm („volume CT“, „incremental CT“) •Slice thickness ≤ 2 mm •High resolution algorithm •Expirium scans, if suspicion of HP (mosaic attenuation) •Additional prone scans, if cases of suspicion of purely hypostatic attenuations

Prosch H, CIPF, Prague 11.03.2016 Radiographic findings of IPF on chest X-ray

• A 68-year-old male patient • About 3 months after onset of symptoms • Bilateral, but not completely symmetrically distributed opacities concentrated to the lower lung fields • Clearly visible honeycombing

A. Altraja ©2017 Treatment-refractory IPF: radiographic findings on chest X-ray • The same 68-year-old male patient • About 3 months after start of the treatment • Bilateral, but not completely symmetrically distributed opacities concentrated to the lower lung fields • Clear radiographic progression, involvement of new areas of the lung parenchyma by the disease • Increased rigidity of the lung parenchyma, shrinkage of the lung volumes

A. Altraja ©2017 Usual interstitial pneumonia (UIP) in a patient with IPF: radiographic findings on chest X-ray • A 75-year-old male patient • Bilateral peripheral, not completely symmetrical reticular opacities, concentrated to the lower lung fields • Honeycombing

A. Altraja ©2017 CT (thick-layer) findings in IPF • A 68-year-old male patient • The same patient, about 3 months later • About 3 months after onset of • Clear radiographic progression, symptoms involvement of new areas of the lung • Honeycombing, traction parenchyma by the disease bronchiectasis and bronchiolectases, • On thick-layer CT scan, the little ground glass opacities characteristic changes are not clearly visible

A. Altraja ©2017 HRCT (thin-layer) findings in IPF • A 68-year-old male patient The same patient, about 3 months About 3 months after onset of • • later symptoms Clear radiographic progression, Clear honeycombing, traction • • involvement of new areas of the lung bronchiectases and bronchiolectases, parenchyma by the disease just little ground glass opacities

•Axial reconstruction of HRCT scan of a 66-year-old male patient with progressive dyspnea during the last 15 years •Subpleural opacities consisting mainly of honeycombing with lower lobe predominance; traction bronchiectases are visible, but consolidations and ground glass opacities are absent

A. Altraja ©2017 HRCT findings of UIP in IPF • A 74-year-old male patient with treatment-resistant IPF. Progression of lung fibrosis and honeycombing with about 5 months (right panel). There is practically no ground glass opacification present .

• Interstitial fibrosis visible in the lower and posterior parts of the lungs • Little ground glass opacities may be present, however, they cannot dominate

A. Altraja ©2017 The radiographic compatibility to UIP determines the prognosis • Patients with IPF, who have radiographically (on HRCT scan) definite „UIP pattern“ (left panel), have shorter survival than those with ”possible UIP” (no honeycombing, right panel)

Sumikawa et al., AJRCCM 2008 Localization of the parenchymal changes in IPF: why there? •Bibasilar, subpleural, reticular opacities •Fibroblastic foci are predominantly in the periphery of the lung (subpleural localization ) •At the level of FRC, the alveoli are semi-open •In inspirium, the peripheral alveoli expand heterogeneously and are subjected most to the mechanical stress •Along with progression of the fibrosis, the next (more central and cranial) alveoli appear to be as „peripheral“ and need to respond to the mechanical stress overload

•This ventilation-based phenomenon is responsible for the ”propeller blade sign”: in IPF, the early changes are in the lower posterior, then in the lateral middle, and finally, in the anterior upper parts of the lungs A. Altraja ©2017 Selman & Pardo, AJRCCM 2014 Differential diagnosis of the radiographic findings in IPF HRCT of the lungs: • Not distinguishable form the UIP that has developed as a manifestation of systemic connective tissue diseases (systemic sclerosis, polymyositis/dermatomyositis (”UIP- CTD”) or asbestosis •In asbestosis, pleural thickenings or plaques are usually present • A similar picture develops in the end-stage sarcoidosis (Padley et al. 1996): large cysts and peribronchovascular nodules may be present • Hypersensitivity pneumonitis (HP) (Lynch et al., 1995): poorly defined micronodules • Pleuroparenchymal fibroelastosis: pleurogenic thickening is primary; no lower lobe predominance

•Axial (left panel) and coronal (right panel) reconstructions of HRCT scan of a 76-year-old patient with bird fancier’s lung; the patient had had progressive dyspnea during the past 6 years •Reticular opacities with upper lobe predominance; confluence to consolidations is seen in some areas. Also, traction bronchiectases and focal ground glass opacities are visible. No honeycombing is present and the main findings are not located to the subpleural layer (note the differences from UIP!) Travis et al. ATS/ERS Consent, AJRCCM 2013 For comparison: radiographic findings of stage IV sarcoidosis

A 69-year-old female patient. Lung fibrosis and deformation of the parenchymal structures that are more prominent in upper lung zones and centrally within the lung. Hilar retraction upwards is also prominent in such patients, though not well visible in solitary axial scans.

A. Altraja ©2017 Histopathological criteria for UIP pattern I Main criteria („definite UIP“, all 4 criteria required): • Evidence of marked fibrosis/architectural distortion, ± honeycombing in a predominantly subpleural/paraseptal distribution • Presence of patchy involvement of lung parenchyma by fibrosis • Presence of fibroblast foci • Absence of features against a diagnosis of UIP suggesting an alternate diagnosis

„Probable UIP“: • Evidence of marked fibrosis / architectural distortion, ± honeycombing • Absence of either patchy involvement or fibroblastic foci, but not both • Absence of features against a diagnosis of UIP suggesting an alternate diagnosis OR • Honeycomb changes only

„Possible UIP“ (all 3 criteria required): • Patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation • Absence of other criteria for UIP • Absence of features against a diagnosis of UIP suggesting an alternate diagnosis

„Not UIP Pattern“ (Any of the 6 criteria): • Hyaline membranes • Organizing pneumonia • Granulomas • Marked interstitial inflammatory cell infiltrate away from honeycombing • Predominant airway-centered changes • Other features suggestive of an alternate diagnosis

A. Altraja ©2017 Raghu et al., AJRCCM 2011 Autopsy findings of IPF: the outer surface of the lung • A 68-year-old male patient • About 6 months after onset of symptoms • Light protuberances visible under the visceral pleura: very non-specific phenomenon that does not refer to granulomas • The lungs turn rigid and the lung volumes shrink • This finding is bilateral and almost symmetrical, more pronounced in the lower parts of the lungs Autopsy findings of IPF: the section surface of the lung

• The same patient • The lungs turn rigid and the lung volumes shrink significantly • Honeycomb cysts and massive fibrosis are visible Autopsy findings of IPF: the section surface of the lung

• The same patient • The lungs turn rigid and the lung volumes shrink significantly • Honeycomb cysts and massive fibrosis are visible UIP (Usual Interstitial Pneumonia) as the histopathological finding in IPF

UIP (48×, hematoxylin and eosin (H&E) staining). The variability of the histopathological finding between the different parts of the lung biopsy specimen is characteristic. On the left: interstitial fibrosis with collagen deposits On the right and below in the middle: areas with preserved near-normal interalveolar septa Above: honeycombing (arrowheads): mucin-filled enlarged airspaces that are separated from each other by constricting connective tissue In the middle: fibroblast focus (arrow) with frank fibrosis and little inflammation

Katzenstein & Myers, Am J Respir Crit Care Med 1998 UIP (Usual Interstitial Pneumonia) as the histopathological finding in IPF UIP (300×, H&E staining). Characteristic fibroblastic focus (arrows) Fibroblastic foci are aggregates that consist of fusiform fibroblasts and paralleled hyperplastic alveolar cells Fibroblastic foci represent active fibrosis distinctly from the surrounding “collagenous” fibrosis

Katzenstein & Myers, Am J Respir Crit Care Med 1998 UIP as the histopathological finding in IPF The variability of the histopathological finding between the different parts of the lung biopsy specimen is characteristic. In the middle: interstitial fibrosis with collagen deposits: fibroblastic foci (arrows) surrounded by massive fibrosis and just quite little inflammation On the right and above in the middle: areas with relatively better preserved alveolar septa (H&E staining)

Fibroblastic focus (arrow) with surrounding fibrosis (H&E staining) A. Altraja ©2017 Combining HRCT and lung biopsy in the diagnosis of IPF HRCT finding Biopsy finding (if done) IPF diagnosis UIP UIP Yes “ Probable UIP Yes “ Possible UIP Yes “ Non-classifiable fibrosis Yes “ UIP is absent No Possible UIP UIP Yes “ Probable UIP Yes “ Possible UIP Probable “ Non-classifiable fibrosis Probable “ UIP is absent No Inconsistent with UIP UIP Possible “ Probable UIP No “ Possible UIP No “ Non-classifiable fibrosis No “ UIP is absent No

(Surgical) Lung Biopsy Biopsy UIP pattern Probable Possible Mitte- UIP not done UIP UIP klassifitseeritav features kopsufibroos are absent UIP IPF IPF IPF IPF IPF Not IPF pattern Possible ?* IPF IPF Probable Probable Not IPF HRCT UIP IPF* IPF* In- ? Possible Not IPF Not IPF Not IPF Not IPF consistent IPF* with UIP

*Some are IPF, some are not

A. Altraja ©2017 Raghu et al., AJRCCM 2011; Svensk Lungmedicinsk Förening, 2012 IPF: findings of bronchoscopy and BAL Bronchoscopy and BAL: • Not mandatory, if UIP-TPF is the most probable diagnosis clinically and radiographically; • In some expert centers, bronchoscopy and BAL are always performed as supplementary methods; especially in circumstances, where UIP-IPF is not that clear pre-study diagnosis • Neutrophils: correlated with the reticular HRCT finding (Wells et al. 1994) •Sometimes eosinophils • The total amount of cells indicates the activity of the disease (Schwartz et al. 1994) • If eosinophils >20% out of the cells  more probably eosinophilic lung disease • If lymphocytes prevail (>15%)  an alternative diagnosis may be more probable (a disease where the main pathogenesis is lymphoid (sarcoidosis, hypersensitivity pneumonitis, COP, NSIP, LIP, lymphomas etc.) A. Altraja ©2017 Raghu et al., AJRCCM 2011 Tasks of the multidisciplinary discussions (MDD) • The diagnosis of IPF is, by definition, multidisciplinary • Interactions between clinicians, radiologists and pathologists improve inter-observer agreement • Association with all diagnostic criteria of IPF/ILD: 1. Careful exclusion of alternative etiologies of ILD 2. The presence of a UIP pattern on HRCT in patients not subjected to (surgical) lung biopsy 3. Specific combinations of HRCT and lung biopsy •Especially when the radiologic and histopathologic patterns are discordant

• If not feasible or available on site, the patients should be referred to experienced clinical experts in ILD (Flaherty et al. 2007)

• Termed as the Gold Standard • Strong recommendation for MDD in the guidelines; low-quality evidence • Problematic access to and availability of experts for MDD • No consent with regard to details to be covered and algorithm/methodology how to proceed

• Some signals from the MDD are fuzzy • Dependence on the group dynamics: a social event, often not a purely objective event

A. Altraja ©2017 Raghu et al., AJRCCM 2011; Flaherty et al. AJRCCM 2007; Collard HR, ERS 2016 The biomarkers •Diagnostic biomarkers •Biomarkers for early detection of a disease •Markers of disease severity •Markers of disease progression •Markers of treatment effect •Primary vs. surrogate biomarkers •Surrogate BM: a marker that is a true substitute of the marker of the primary interest •Composite markers •An ideal biomarker should be reproducible over time at least in a stable disease

Agusti & Sin, Clin Chest Med 2014; Paone et al. Eur Rev Med Pharm Sci 2016 Other biomarkers in IPF • KL-6 (Krebs von den Lungen 6) • Lysyl oxidase-like protein 2 (LOXL2): responsible for cross-linking of collagen in the pathologic stroma: high serum level (≥800 pg/mL) represents high risk (Chien et al. ERJ 2014) • Increased serum CCL18 is associated with mortality in IPF (cutoff: 150 ng/mL; Prasse et al. 2009) • Anti-Hsp 70 autoantibodies increase mortality in IPF (Kahloon et al. AJRCCM 2013) • (Carbohydrate Antigen) CA 15-3 (n=20) • CA 125 correlates with FEV1% (p=0.0001) • CA 19-9 correlates with exercise capacity and PAP • CA 15-3 correlates with survival (p=0.04) • All tumor markers except CA 125, decrease significantly after lung transplantation in IPF, but not in COPD (CA 15-3 expressed most significant changes, p=0.001) (the patients were tested for not having a malignancy) • The serum level of CA 15-3 reflects the severity of IPF

• Growing repertoire of mutations (toll-interacting protein (TOLLIP), MUC5B etc.) • Signifying for event-based outcomes • Survival/prognosis • Response to treatment

A. Altraja ©2017 Differential diagnosis of IPF • The clinical signs and course of the disease are similar, in principle, wit other IIPs • Especially important alternatives include: •ILD due to known causes/etiologies, in particular ILD or UIP associated with systemic connective tissue diseases •Other pulmonary fibrotic conditions

• The histopathological finding of UIP is not specific of IPF! • UIP can also be present: •As a manifestation of connective tissue diseases (UIP- CTD): (systemic sclerosis, rheumatoid arthritis, asbestosis, hypersensitivity pneumonitis etc.) •Sometimes, also in other IIPs (especially in NSIP)

•Rheumatoid arthritis Extra-pulmonary Similar to IPF •Systemic sclerosis (scleroderma) findings: •Polymyositis/dermatomyositis •Lupus erythematosus skin, joints; laboratory •Sjögren’s syndrome findings •Bechet’ disease •Mixed systemic connective tissue diseases •Ankylosing spondylitis

Drug-related •Cytotoxic drugs History of drug May be similar to IPF •Antibiotics exposures •Others (see Pneumotox®) Finding of the main disease Pneumoconioses •Asbestosis Known exposures, Affection of the pleura clubbing

Hypersensitivity pneumonitis (HP) Known exposures, fine Fine granulation, crackles The HRCT finding has no subpleural concentration A. Altraja ©2017 The differential diagnosis of IPF II (Chan-Yeung & Müller, 1997)

Diseases that affect mainly the lungs History, status Imaging

Sarcoidosis Extra-pulmonary Hilar lymphadenopathy; in finding, mild dyspnea, stage IV, frank pulmonary little objective finding, fibrosis (upper-lobe no finding on auscult. predominance) Langerhans cell histiocytosis Spontaneous Cysts with relatively pneumothorax thicker walls, nodular pattern in upper and middle lung fields Lymphangioleiomyomatosis (LAM) Only in women, Thin-walled cysts spontaneous pneumothorax

Tuberous sclerosis (TS) Brain and kidney Thin-walled cysts involvement, Spont. pneumothorax

Carcinomatous lymphangitis Signs of the main Kerley B-lines disease Eosinophilic pneumonia Blood or BAL Bilateral consolidations eosinophilia COP or BOOP (Bronchiolitis Obliterans – General symptoms Limited alveolar infiltrates, Organizing Pneumonia) if with known similar to those of ground glass opacities etiology pneumonia

A. Altraja ©2017 Staging and prognostic markers of IPF • Classification into categories as “mild”, “moderate”, “severe” or “early” and “advanced” or “end-stage IPF” has been proposed on the basis of lung function data and the extent of the radiographic changes • Severe IPF: if FVC <50% and/or DLco <35% predicted • Demographic factors: males and patients in advanced age have worse prognosis • Breathlessness: correlates with the quality of life • mMRC, Borg’s scale, quality-of-life questionnaires, clinical-radiographic- physiological dyspnea score, UCSD dyspnea questionnaires etc. • Lung function: • A fall in FVC 5-10% per year may refer to worse prognosis • HRCT finding: honeycombing correlates well with FVC and DLco results (Lynch et al. 2005) • Composite indexes: for example: CPI (Composite Physiology Index): a predictor of mortality, based on the values of FEV1, FVC, and DLco (Wells et al., 2003): • CPI = 91 – (0.65×DLco%) – (0.53×FVC%) + (0.34×FEV1%) • 6 min. walk test (&MWT) • Histopathological finding: UIP vs. NSIP component, frequency of the fibroblastic foci • Pulmonary hypertension: significantly worse prognosis, if present • Emphysema: “combined pulmonary fibrosis and emphysema” (CPFE) • Biomarkers in serum and BAL fluid

A. Altraja ©2017 Raghu et al., AJRCCM 2011 GAP score for staging of IPF G („Gender“) • = 0, if female; = 1 if male A („Age“) • = 0, if ≤60 years; = 1, if 61-65 years; = 2, if >65 years P („Physiology“) • FVC % predicted: • = 0, if >75%; = 1, if 50-75%; = 2, if <50% • DLco % predicted • = 0, if >55%; = 1, if 36-55%; = 2, if ≤35%; = 3, if „not able to perform measurement“

• May have values between 0 and 8; predicts mortality

A. Altraja ©2017 Ley et al., AIM 2012 Variants of the natural course of IPF •A >10% fall in FVC or a >15% fall in DLco during the last 6–12 months refer to a rapidly progressive course Stable 80% Slowly progressive FVC % Exacerbation

60% Exacerbation Progressive with 40% Exacerbation exacerbations

20% Exacerbation Rapidly progressive

1 2 3 4 Time in years

A. Altraja ©2017 Modified from: Kim et al., 2006 Proc Am Thorac Soc Vol 3. pp. 285–292; Raghu et al., 2011 Variants of the course of IPF: before the diagnosis and after the start of the antifibrotic treatment

Radiographic changes

Patient referral, confirmation of the diagnosis

Treatment Treatment progression of the disease the of progression

Time (years) Cottin V et al. Eur Respir Rev. 2014 Ley B et al. Am J Respir Crit Care Med 2011 Acute exacerbation of IPF (AE-IPF): the definition

• An acute, clinically significant respiratory deterioration characterized by evidence of new, widespread alveolar abnormality

• Acute exacerbations are periodical in patients with IPF • The probability is approximately 5-10% per year

• The acute exacerbation can mimic other diseases • Acute cough, progressive dyspnea in <1 month • Weakness, fever, weight loss • Rapidly progressive hypoxemia, ARDS-like condition is possible

• Radiographically: • New bilateral progressive lung infiltrates: correspond morphologically to new fibroblastic foci; • New honeycomb cysts, as well as traction bronchiectases and bronchiolectases may appear • New peripheral, multifocal, or diffuse consolidations or areas of ground-glass opacities may appear

Raghu et al., AJRCCM 2011; A. Altraja ©2017 Ryerson et al. ERJ 2015 Radiographic findings in the acute exacerbation of IPF: chest X-ray • New progressive bilateral lung infiltrates, preferably in lower parts of the lungs • Multifocal, or diffuse bilateral consolidations or areas of ground-glass opacities • The findings are very similar to those of AIP (DAD and following active diffuse fibrosis)

A. Altraja ©2017 Radiographic findings in the acute exacerbation of IPF: CT (left panel) and HRCT (right panel) • New progressive bilateral lung infiltrates, preferably in lower parts of the lungs • Multifocal, or diffuse bilateral consolidations or areas of ground-glass opacities • The findings are very similar to those of AIP (DAD and following active diffuse fibrosis)

• 76-year-old female patient: the images have been done with 8-month interval • Multifocal bilateral consolidations have developed (right panel) • The findings are very similar to those of AIP (DAD and following active diffuse fibrosis)

A. Altraja ©2017 Radiographic findings in the acute exacerbation of IPF: HRCT • The same 76-year-old female patient: the scans are with 8-month interval • Fibrosis and ground glass opacities have been appeared bilaterally (developing fibrosis over diffuse alveolar damage (DAD)) • The findings are very similar to those of AIP (DAD and following active diffuse fibrosis)

• (A) Before the acute exacerbation: small peripheral reticular opacities with lower lobe predominance (superimposed by little emphysema) • (B) 4 months later: Multiple new ground glass opacities are visible on the background of reticular opacities and honeycombing

Travis et al. ATS/ERS Consent, AJRCCM 2013 Diagnostic criteria of the acute exacerbation of IPF (AE-IPF)

•Presence of previous or concurrent diagnosis of IPF •An acute worsening or development of dyspnea typically up to 1- month duration •High-resolution computed tomography (HRCT) with new bilateral ground-glass opacities and/or consolidation superimposed on a background pattern consistent with the pattern of usual interstitial pneumonia (UIP) •This condition/deterioration is not fully explained by cardiac failure or fluid overload

Acute respiratory deterioration in IPF (typically <1-month duration)

Yes Not an acute exacerbation: Extra-parenchymal cause identified? consider alternative diagnosis No (e.g. pneumothorax, pleural New, bilateral ground glass effusion, pulmonary embolism) Yes opacities/consolidation on CT (not fully Acute exacerbation of IPF: explained by cardiac failure or fluid overload)? •Triggered AE-IPF: e.g. No infection, post- procedural/postoperative, drug Not an acute exacerbation: consider toxicity, aspiration alternative diagnosis (e.g., infection, aspiration, drug toxicity, congestive •Idiopathic AE-IPF: no trigger heart failure etc.) identified

•Depends on the methods of the diagnosis and reporting •Incidence: 4-20 cases per 100 patients with IPF per year •Common mainly in advanced IPF, however, is possible in any IPF •Median survival <3 months •Mortality in shorter perspective 50% (90% among patients on mechanical ventilation)

•Chronic factors are involved (epithelial dysfunction and related fibroblast activation) and acute factors (acute stress and lung injury) •Genetic, environmental, and behavioral factors cause fibrotic phenotype of the injury with deposition of ECM components, scarring of the lung parenchyma, and remodeling of the lung •A certain acute event usually serves as a trigger (e.g. infection, (micro)aspiration, mechanical stretch) that in cases of fragile disposition causes extended damage to the lung (with interstitial edema and hyaline membranes in the initial phase, followed by rapid formation of connective tissue and fibrosis) •AE-IPF may activate the actions of the chronic factors (e.g. mechanical stress etc.)

A. Altraja ©2017 Collard et al. AJRCCM 2016 Histopathological findings in AE-IPF • The findings are approximately similar to the organization phase of acute interstitial pneumonia (AIP): formation of new fibroblastic foci

A. Altraja ©2017 Acute exacerbations of IPF: reasons and risk factors Not completely known, however, possible theories exist, based on research data: •All surgical manipulations on the lung (Incl. VATS-lung biopsy): due to stretch of the contralateral lung during its ventilation (Kondoh Y et al. Respir Med 2006) •Also in association with non-lung surgery •In some cases, simply as ”a manifestation of the course of IPF” •More frequent in patients with low FVC, DLco, and 6 min. walk distance = more in advanced IPF •More frequent in patients with recent rapid decline in FVC •More frequent in patients with hypoxemia already at the diagnosis of IPF; also in the presence of pulmonary hypertension •Viral infection: a frequent differential diagnostic problem - pneumonia or AE-IPF •Aspiration and silent aspiration: measurement of pepsin activity in BAL fluid (Lee JS et al. ERJ 2012; 39: 352) •Cryobiopsy (c-TBB), BAL •Chemotherapy, immunosuppression, and treatment with biologicals (mAbs) •Higher BMI, concomitant coronary disease, younger age, higher serum levels of KL-6 •Negative smoking history •More frequent in colder season

A. Altraja ©2017 Raghu et al., AJRCCM 2011; Ryerson et al. ERJ 2015, Collard et al. AJRCCM 2016 HRCT in a patient with IPF before an AE-IPF •A 70-year-old male patient, due to the presence of the HRCT pattern of „possible UIP“, VATS-lung biopsy was deemed necessary

A. Altraja ©2017 Acute exacerbations of IPF: incidence, treatment, and prognosis • Incidence: 4-20 cases per 100 patients with IPF per year • Common mainly in advanced IPF, however, is possible in any IPF • Median survival <3 months • Mortality in shorter perspective 50% (90% among patients on mechanical ventilation) The treatment of AE-IPF is a big unmet medical problem • Mechanical ventilation only with social indications or during waiting for extraordinary lung transplantation • ECMO: during waiting for extraordinary lung transplantation • Systemic glucocorticosteroids: no special evidence! • Lower-dose systemic glucocorticosteroids in milder cases (1 mg/kg) • Pulse treatment with systemic glucocorticosteroids (500-1000 mg for 3 days) followed by rapid decrease of the dose, stopping treatment by the end of the 1st month Other means of therapy: • No evidence basis: • Polymyxin B (immobilized) • Tacrolimus; rituximab, cyclosporin A

A. Altraja ©2017 Ryerson et al. ERJ 2015; Collard et al. 2007, 2016 Treatment considerations for IPF in conclusion • IPF has a rapid or unpredictable course and has 100% bad prognosis • After the diagnosis is there, a rapid commencement of treatment should follow in cases with no contraindications („Hit early and hit hard!“)

• Consider also the influence of the side effects of the treatment on the patient and thereby on the prognosis • Weigh the benefits the treatment can provide for the individual patients against the side effects: no desperate treatment in desperate situations! • Significantly advanced age, advanced IPF with end-stage lung fibrosis, probably low tolerance of the drugs, non- cooperating patient, numerous concomitant diseases that determine patients’ prognosis by themselves

A. Altraja ©2017 Principles of treatment of IPF • General measures: best supportive care for every patient (according to the criteria for COPD until data from specific investigations arrive) • Supplementary oxygen • Pulmonary rehabilitation (evidence basis is increasing) • Anti-reflux therapy and/or antacids: controversial data, not mandatory unless a clear independent indication exists apart from IPF • The need to recognize the terminal worsening: opiates etc. to relieve dyspnea symptomatically, waning from antifibrotic treatment • Disease-modifying medical treatment: • Directed to decelerating the progression of the pulmonary fibrosis: antifibrotic drugs: nintedanib and pirfenidone • Weigh the side effects of these drugs on the patient against their effects on the progression and prognosis of the disease • (Early) lung transplantation, if possible and accessible: timely referral to the center for evaluation (see the criteria!)

• Nintedanib (Ofev®), 150 (100) mg × 2 • Broad-spectrum tyrosine kinase inhibitor (TKI) for the receptors of the following growth factors: • FGF receptors 1 and 3) • PDGF receptors α and β • VEGF receptors 1, 2, and 3

• Pirfenidone (Esbriet®), (3×267 mg) × 3 • Inhibits collagen synthesis by TGF-β-stimulated IPF fibroblasts; also inhibits activation of T-cells and cytokine release • Reduces the production of TGF-β, TNF-α, and IL-1β

A. Altraja ©2017 Raghu et al., AJRCCM 2015 IPF-specific drugs: pirfenidone (Esbriet®) • Pirfenidone [5-methyl-1-phenyl-2-(1H)- pyridone]: antifibrotic agent • Esbriet®, original producer: InterMune/Roche

• Inhibits collagen synthesis by TGF-β- stimulated IPF fibroblasts; also inhibits activation of T-cells and cytokine release

• Reduces the production of TGF-β, TNF-α, and IL-1β • Prolongs the median survival of IPF patients for 2 times (King TE Jr et al. NEJM 2014)

A. Altraja ©2017 Raghu et al., 2011; Spagnolo et al., 2010; Azuma et al., 2012 How to use pirfenidone? • Is started with 267 mg ×3 during the 1st week, then, 2×267 mg ×3 during the 2nd week, and then, 3×267 mg ×3 thereafter • Together with food intake, if needed, by 1 capsule (267 mg) at a time, with 10-30 min. intervals • Metoclopramide for nausea and to prevent vomiting • Clinical control for efficacy with at least 3-month intervals (spirometry, diffusing capacity of the lung, 6MWT); HRCT with 6-month intervals • Pirfenidone is metabolized via CYP1A2: • Parallel use of CYP1A2 inhibitors (incl. fluvoxamine etc.) is therefore contraindicated • Caution is required also with parallel use of fluoxetin, amiodarone, fluconazole, chloramphenicol, and ciprofloxacin • Smoking and grapefruit juice slow down the effect of pirfenidone • Pirfenidone is hepatotoxic: • ALAT in serum: before commencement of pirfenidone, once monthly during the first 6 months, and further with 3-month intervals • Decrease the dose in cases of increased activity of ALAT in serum by ≤3-5 times above the upper limit of normal • In cases of higher values of S-ALAT, pirfenidone needs to be stopped (with possibility to resume later)

A. Altraja ©2017 Cederlund K et al. Vårdprogram för idiopatisk lungfibros. Svensk Lungmedicinsk Förening 2012 Nintedanib (Ofev®) • 1 capsule (150 or 100 mg) ×2 • Broad-spectrum tyrosine kinase inhibitor (TKI) for the receptors of the following growth factors: • FGF (Fibroblast Growth Factor) receptors 1 and 3 (FGFR 1/3) • PDGF (Platelet-Derived Growth Factor) receptors α and β • VEGF (Vascular Endothelial Growth Factor) receptors 1, 2, and 3 (VEGFR 1, 2, and 3)

• Therefore, nintedanib inhibits angiogenesis and has antineoplastic properties (anticoagulant treatment is a relative contraindication) • Diarrhea (overall prevalence >60%, but problematic in only <4%; for management: loperamide, rarely racecadotril etc.) • Increased activity of hepatic aminotransferases in serum

A. Altraja ©2017 Non-medical treatment of IPF and patient follow-up • Pulmonary rehabilitation • Well-documented efficacy • Long-term supplementary oxygen therapy (LTOT) • PaO2 <55 mmHg (the criteria for COPD are employed) • Lung transplantation: according to the current criteria for IPF • Palliative care for patients with end-stage IPF (opiates to control severe cough and dyspnea etc.) • Other means and follow-up: •Treatment of concomitant cardiovascular diseases •Increased risk of: •Pulmonary hypertension •Lung cancer •Pulmonary infections (chronic microaspirations, immunosuppressive treatment) •Pneumothorax •Pulmonary embolism •Gastroesophageal reflux A. Altraja ©2017 King, ILD, 5th ed. 2011; Raghu et al., 2011; 2015 Contemporary treatment of IPF: conclusions •Multidisciplinary team discussions to finalize the process of the diagnosis; together: •Pulmonologist (with the clinical and demographic data) •Thoracic radiologist (with on-site reproduction of 1…1.5 mm HRCT scans) •Pulmonary pathologist (with on-site projection of the specimens in parallel) •Other specialists if needed (rheumatologist etc. On the basis of invitation) •Treatment of IPF: •Nintedanib or(/and) pirfenidone (the mainstay of treatment) •Pulmonary rehabilitation •Antacids (contradicting recommendations •Lung transplantation (indications from 2015  „less strict“ in comparison to the previous (2006) version)

A. Altraja ©2017 Follow-up in IPF (for stable patients) • During the 1st month, out-patient control visits with 2-week intervals to discover the possible side effects of the treatments •Physical investigation •Liver function tests (ASAT, ALAT, γ-GT, bilirubin, bile acids etc.) •Full blood count, coagulometric indices •  During the 2nd and 3rd month, out-patient control visits with monthly intervals •  Further, with 3-month intervals, if the patient is stable in terms of treatment side effects • Lung function tests (spirometry with reversibility testing, transfer test, 6MWT) with 3-month intervals • HRCT: not more frequently that once per 6 months

Time

Referral for lung Progression of transplantation if IPF: criteria are met Monitoring every •Non- 3-6 months or pharmacological more frequently, if Referral for lung The treatment clinically indicated transplantation diagnosis •Pharmacotherapy of IPF •Concomitant Acute diseases: exacerbations: • Pulmonary •Treat accordingly hypertension (glucocorticosteroi ds etc.) • Other •Treatment of • Control of respiratory symptoms insufficiency

Continuous alertness with regard to clinical trials

A. Altraja ©2017 Raghu et al., AJRCCM 2011 Monitoring of the course of IPF: the indicators • What refers to the progression of IPF: worsening and/or addition of symptoms, decline in lung function indices, progression of fibrosis (on imaging) and/or acute worsening of the respiratory status (e.g. AE-IPF) Particular indicators: • FVC: relative decline (% decline in the values of % predicted) is better predictor of mortality than the decline in the diffusing capacity of the lung (DLco) (du Bois et al. AJRCCM 2011) • FVC: relative decline (%) from the initial absolute values (recorded at the diagnosis or during the previous visit) • Change in the 6 minute walk distance • Still, also the decline in the diffusing capacity of the lung (DLco) is indicative • Increase in the alveo-arterial difference in oxygen partial pressures (dAaO2) A. Altraja ©2017 Raghu et al., AJRCCM 2011; du Bois et al., ATS 2010 Monitoring of the course of IPF • Monitoring of worsening of symptoms • Composite measures: • Composite physiologic index (CPI): 91 – (0.65×DLco%) – (0.53×FVC%) + (0.34×FEV1%) (Wells et al. 2003) • Monitoring of worsening of oxygenation • Desaturation <88% during 6-minute walk test (6MWT) serves as a recommendation for using supplementary oxygen (ATS, 2002) • Monitoring of complications and concomitant diseases • Vigilance for pulmonary hypertension (PH-IPF represents group 3 PH) • Vigilance for lung cancer, coronary disease, pneumothorax, pulmonary embolism, and respiratory infections (all these serve as causes of death in patients with IPF, as well as have higher prevalence in the IPF population than in the general population) •Echocardiography •Serum NT-proBNP content •Vaccinations (against respiratory pathogens) A. Altraja ©2017 Raghu et al., AJRCCM 2011 Signs of the progression of IPF

Whatever out of the following: • Progressive dyspnea (objectively assessed) • Progressive, sustained decrease from baseline in FVC • The relative decline in FVC is more sensitive than the absolute change (Richeldi et al. 2012) • The minimal clinically important change in FVC is 2-6% over 6-12 months • The relative decline in FVC is better predictor of mortality than DLco (du Bois et al., AJRCCM 2011) • FVC is not suitable indicator, if combined pulmonary fibrosis and emphysema (CPFE) is the case • Progressive, sustained decrease from baseline in DLco (corrected for hemoglobin) • Progression of fibrosis from baseline on HRCT • Acute exacerbation • Death from respiratory failure

A. Altraja ©2017 Raghu et al., AJRCCM 2011; du Bois et al., AJRCCM 2011; Richeldi et al. 2012 Criteria for progression of IPF • >10% decline in FVC % predicted OR >15% decline in DLco % predicted during the last 6-12 months • The progression should be confirmed by repeated assessments with ≥4-intervals between the measurements

A. Altraja ©2017 Ley et al. AJRCCM 2011 Various indicators suggestive of progression of IPF • Symptoms • Increased dyspnea and cough • Decreased exercise capacity • Physical finding • Increase in areas, where velcro rales are audible • Worsening of the right heart failure • Peripheral edema • Augmentation of the II heart sound on the pulmonary artery • Worsening of the respiratory insufficiency • Cyanosis • Finger clubbing • Lung function • Hypoxemia and increased demand of the supplementary oxygen • Progressive decline in lung volumes (FVC) and diffusing capacity of the lung • Increase in the alveo-arterial difference in oxygen partial pressures (dAaO2) at rest or during exercise • Eventual hypercapnia • Radiographic findings • Progression of the interstitial opacification and reduction of the lung volumes • Progression of honeycombing • Dilatation of the heart silhouette • Occurrence or progression of pulmonary hypertension A. Altraja ©2017 King et al., 2011 Indicators of heightened risk of death in IPF • Indicators at baseline (at the diagnosis): •Level of dyspnea •DLco, <40% predicted •Desaturation ≤88% during 6MWT •Extent of honeycombing on HRCT •Presence of pulmonary hypertension •Indicators obtained during the course of IPF (longitudinal indices) •Progression of dyspnea (objective measured) •Decrease in FVC by >10% value •A relative change in FVC has better sensitivity for disease progression (Richeldi et al. 2012) •Decrease in DLco by >15% absolute value •Worsening of fibrosis assessed by HRCT

A. Altraja ©2017 Raghu et al., AJRCCM 2011; Richeldi et al., 2012 Prognosis of IPF • IPF predisposes for both small cell and non-small cell lung cancer and complicates implementation of all kinds of anti-cancer interventions, as well as worsens the treatment results • Survival is low (if untreated, it is worse than in most cancers), is dependent on factors that predict worse effect of treatment) • Mean survival 2-3 years from the diagnosis (data on patients without current anti-fibrotic treatments) • Median survival 3 years (Great Britain, Wells et al. 2008) • 5-year survival is about 20%, during the 5 year from the diagnosis, 50-80% of patients use to die (data from the era before availability of the antifibrotic treatments) • The probability of mortality rapidly increases with age • The mortality has increased from 1992 through 2003 (Olson et al. 2007) • Mortality (per 1,000,000 patients with IPF): • USA: 61.2 in male patients, 54.5 in female patients • Japan: 33.0 in male patients, 24.0 in female patients • Mortality in the patients with IPF is increased by: lung cancer, pulmonary embolism, and coronary disease (Hubbard et al., 2008)

Any of the following:

•Histopathological or radiographic evidence of UIP or fibrosing NSIP, regardless of lung function •Abnormal lung function: FVC <80% predicted or DLco) <40% predicted •Any dyspnea or functional limitation attributable to lung •disease •Any oxygen requirement, even if only during exertion •For inflammatory ILD, failure to improve dyspnea, oxygen requirement, and/or lung function after a clinically indicated trial of medical therapy

A. Altraja ©2017 Weill et al., JHLT 2015 indications (timing) of listing for lung transplantation Any of the following: •Decline in FVC ≥10% during 6 months of follow-up •(5% decline is associated with a poorer prognosis and may warrant listing) •Decline in DLco ≥15% during 6 months of follow-up •Desaturation to <88% or distance <250 m on 6-minute-walk test or >50 m decline in 6-minute-walk distance over a 6-month period •Pulmonary hypertension on right heart catheterization or 2- dimensional echocardiography •Hospitalization because of respiratory decline, pneumothorax, or acute exacerbation

A. Altraja ©2017 Weill et al., JHLT 2015 The influence of smoking and IPF: “Combined pulmonary fibrosis and emphysema” (CPFE) • Smoking and an organism susceptible for developing COPD is a sufficiently frequent combination CPFE = syndrome that involves the following: • Tobacco smoking (99% of the patients), male gender, mean age 65 years • Severe dyspnea • Disproportionately low diffusing capacity of the lung • Disproportionately well preserved spirometric lung volumes • Severe hypoxemia, at least during exercise • Bad prognosis, especially in the presence of pulmonary hypertension, lung cancer, other acute lung injury, or respiratory tract infections • Radiographically (HRCT scan is mandatory): • Characteristic centrilobular emphysema in the upper parts of the lung • Interstitial fibrosis in the lower parts of the lung • Strong propensity to the development of pulmonary hypertension (group 3, PH due to lung diseases and hypoxemia) • Strong propensity to cancerogenesis • Treatment of both diseases (emphysema-related COPD and IPF) is necessary

Cottin et al., Eur Respir J 2005; ; Jankowich & Rounds, Chest 2012 A. Altraja ©2017 Raghu et al., AJRCCM 2011 Reasons behind the little collapse-based obstruction in patients with CPFE Ordinary emphysema: high CPFE collapsibility of the Peribronchi(ol)ar Lung fibrosis exerts radial traction small conducting fibrosis to the conducting airways airways

Images from: The Netter PresenterTM Respiratory Edition, Version 1.0 “Combined pulmonary fibrosis and emphysema” (CPFE): radiographic finding (chest X-ray)

• A 72-year-old male patient • Characteristic centrilobular emphysema in the upper parts of the lungs • Relatively more interstitial fibrosis in the lower parts of the lungs A. Altraja ©2017 “Combined pulmonary fibrosis and emphysema” (CPFE): radiographic finding (HRCT)

• The same 72-year-old male patient • Characteristic centrilobular emphysema in the upper parts of the lungs • More interstitial fibrosis with honeycombing in the lower parts of the lungs

A. Altraja ©2017 Non-specific interstitial pneumonia (NSIP): the term and subclassification • Non-specific fibrosis and inflammation in the lung tissue that does not match UIP: temporally uniform finding (with regard to the evolutional stage of the inflammatory-fibrotic process) – all changes are of the same stage throughout the sample • NSIP is classically subdivided into fibrotic and cellular subtype, also, an intermediate, mixed NSIP, exists (Katzenstein & Fiorelli, 1994) • In NSIP, there is histopathologically chronic interstitial inflammatory infiltrate, with almost no fibroblastic foci or honeycombing • NSIP exists as an idiopathic interstitial lung disease (iNSIP), but is the most frequent type of pulmonary manifestations in systemic connective tissue diseases (CTD-NSIP) A. Altraja ©2017 Subclassification of NSIP Katzenstein & Fiorelli (1994) • I. Cellular (chronic interstitial inflammatory infiltrate, no fibroblastic foci or honeycombing) • III. Fibrotic (uniform fibrosis, temporal homogeneity, still harder to differentiate from UIP) • II. Mixed (closer to the fibrotic subtype due to the presence of fibrosis) • In clinical practice, cellular (I) and fibrotic (II and III) subtypes are widely in use

A. Altraja ©2017 Katzenstein & Myers, Am J Respir Crit Care Med 1998 NSIP: an alternative subclassification Based on clinical-pathological associations • NSIP/IPF (partial overlap of the traits) • Restrictive pattern, fine crackles, HRCT: resembles UIP, but much more ground glass opacities and less honeycombing; histopathologically more inflammatory cells; prognosis is the worst among the subtypes of NSIP, though significantly better than that of IPF) • NSIP/OP (partial overlap of NSIP and organizing pneumonia): • In HRCT: consolidations characteristic of COP (up to 10% of the lesions); BAL: mainly lymphocytes; nice responsiveness to glucocorticosteroids) • NSIP/HP (partial overlap of NSIP and hypersensitivity pneumonitis (HP)): • Clinically close to HP, possible involvement of a causative antigen, but absence of histopathological findings of HP

A. Altraja ©2017 Wells et al., BTS Guidelines: Thorax 2008 Non-specific interstitial pneumonia (NSIP): epidemiology • Incidence and prevalence not well known (Dacic & Yousem, 2003) • Historically, often confused with IPF in epidemiological studies • Peak incidence is varying between studies, being between 39-60 years of age (younger than patients with IPF!) • A slight female predominance, but this is also varying between reports (Nicholson et al., 2000; Flaherty et al., 2001) • A major part of the patients are current or former smokers

• Clinically, there are similarities with IPF: • Progressive dyspnea (on exertion) , dry cough, and bibasilar velcro rales on auscultation • Restrictive pattern of lung function decline

• In comparison to IPF: •The patients are younger: 40-50 years of age •The history of symptoms is somewhat shorter

• The most typical component is bilateral ground glass opacities • Irregular reticulations with traction bronchiectases are present in about 75% of cases • An absence of these findings in the subpleural layer (known as “subpleural sparing”) is characteristic of NSIP and enables to differentiate from UIP • Some honeycombing may exist, but this is usually absent in the initial stages of NSIP

• Consolidation is little and if present, it reflects the OP component and refers to a possibility of CTD-NSIP

• Fine reticular opacification • The opacification does not involve the very periphery („subpleural sparing“) • Honeycombing is absent • There is more ground glass opacification than that could be expected in idiopathic pulmonary fibrosis

Taylor & du Bois, IJTLD 2001 HRCT findings in NSIP • Courtesy of Dr. Janne Møller (Århus) • The opacification does not reach the very subpleural layer of the lung („subpleural sparing“)

• Bilateral confluent ground glass opacities with significant traction bronchiectases and volume restriction in the lower lobes • The peribronchovascular predominance with subpleural sparing is well visible on the axial image (A)

Travis et al. ATS/ERS Consent, AJRCCM 2013 CT findings in NSIP • A 74-year-old male patient • Fine reticular opacification is shown predominantly in the periphery • Honeycombing is absent • There is more ground glass opacification than that could be expected in IPF • The opacification does not involve the very periphery („subpleural sparing“)

A. Altraja ©2017 HRCT-findings in NSIP: a good response to treatment • The same 74-year-old male patient • Fine reticular opacification is seen predominantly in the periphery • Honeycombing is absent • There is more ground glass opacification than that could be expected in IPF • The opacification does not involve the very periphery („subpleural sparing“) • A good treatment effect with 4-month prednisolone (1.00.5 mg/kg)

A. Altraja ©2017 Idiopathic NSIP/IPF (according to the alternative classification) • The same 57-year-old female patient, rapidly progressive course • Interstitial fibrosis with honeycombing mainly in the lower parts of the lung • Too much ground glass opacities for IPF, also rapid course, female patient, younger age

• The same 57-year-old female patient with rapidly progressive disease • Non-segmental perfusion defects not suitable for pulmonary embolism/CTEPH • The ventilation-scan has appeared unsuccessful, because of the restricted lung volumes: deposition of the construct to the central airways only is visible

A. Altraja ©2017 Idiopathic non-specific interstitial pneumonia (iNSIP): the diagnostic criteria • Subacute or chronic, progressive dyspnea and dry cough • Absence of factors known to cause interstitial lung diseases (systemic connective tissue disease, environmental exposures (e.g. those that are characteristic of precipitating hypersensitivity pneumonitis) • As a rule, lung biopsy is needed for the diagnosis of NSIP • The finding of NSIP in the specimen(s) starts multidisciplinary evaluation (since NSIP is also a major pulmonary manifestation of systemic connective tissue diseases) • The histopathologic features include varying amounts of uniformly appearing interstitial inflammation and fibrosis • Most cases of NSIP have a predominantly fibrotic pattern • An isolated cellular NSIP is rare • For the diagnosis of NSIP, OP and honeycomb fibrosis should be inconspicuous or absent

• Varying amounts of uniformly appearing interstitial inflammation and fibrosis • Most cases of NSIP have a predominantly fibrotic pattern • An isolated cellular NSIP is rare • For the diagnosis of NSIP, OP and honeycomb fibrosis should be inconspicuous or absent

NSIP (120×, hematoxylin and eosin (H&E) staining). Thickening of the alveolar septa due to collagenous fibrosis and chronic inflammatory infiltrate Left above and right below: areas with extended collagen deposits are eosinophilic and contrasting from the neighboring regions, where darkly stained small lymphoid cells are found

Katzenstein & Myers, Am J Respir Crit Care Med 1998 Histopathological findings in NSIP

NSIP (120×, H&E staining). •Diffuse, equal thickening of the alveolar walls •The cellular infiltrate consists of mainly plasma cells and lymphocytes •Hyperplasia of the alveolar epithelial cells

Katzenstein & Myers, Am J Respir Crit Care Med 1998 Histopathological findings in NSIP

NSIP (300×, H&E staining). •Diffuse, equal thickening of the alveolar walls •The cellular infiltrate consists of mainly plasma cells and lymphocytes •Hyperplasia of the alveolar epithelial cells

Katzenstein & Myers, Am J Respir Crit Care Med 1998 Histopathological findings in NSIP

• Diffuse thickening of the alveolar walls, uniform fibrosis • Alveolar architecture is preserved • Honeycombing and fibroblastic foci are absent • Interstitial inflammation is scarce

Travis et al. ATS/ERS Consent, AJRCCM 2013 The presence of the radiographic and pathologic findings of NSIP is possible in many diseases

• Idiopathic NSIP (iNSIP) • Connective tissue diseases (CTD) (SSc, RA, DM/PM etc.) • Hypersensitivity pneumonitis (HP) • Toxic reactions to drugs • In some patients with familiar pulmonary fibrosis (FIP, FPF)

• Multidisciplinary team discussions are of paramount importance to make the correct final diagnosis

A. Altraja ©2017 Travis et al. AJRCCM 2008; Travis et al. ATS/ERS Consent, AJRCCM 2013 Treatment of non-specific interstitial pneumonia (NSIP): aspects • The cellular subtype responds better to treatments than does the fibrotic • The treatment conforms to the formerly used „triple therapy“ for IPF (azathioprine + prednisolone + N-acetylcysteine), however, regimens with solely systemic glucocorticosteroids are more often in use (initially 0.5-1.0 mg/kg prednisolone with dose reduction thereafter) • Response to systemic glucocorticosteroids is good (50-90%) • Duration of the treatment for at least 3-6 months; thereafter assessment of the results by means of clinical, radiographic, and lung function indices • The treatment is stopped, if the it remains without effect • If the treatment is efficacious, it may be continued • NSIP is a significant indication for lung transplantation

A. Altraja ©2017 Treatment of idiopathic NSIP accordingly to the subtype of the disease • Glucocorticosteroids with or without immunomodulators • No validated recommendations for drugs and indications and duration of treatment • NSIP/IPF: treatment could be similar to that of IPF (weaker evidence; the modern antifibrotic drugs are not yet allowed) • NSIP/COP: the recommendations concord with those of COP: • High-dose systemic glucocorticosteroids (initially, 1-1.5 mg/kg/24 h for 3 months, with further reduction of the dose; duration of the treatment is 6 months, there is heightened risk of relapse with shorter courses of treatment) • Methylprednisolone 500-1000 mg/24 h for 3 days, further prednisolone 20 mg/24 h, with dose reduction thereafter (Wells, 2001) • NSIP/HP: the treatment should resemble that of HP

This regimen was used to treat IPF until 2012: •Prednis(ol)one (start from 0.5 mg/kg/day, with dose reduction down to 10–20 mg/kg/day by the 3rd month of treatment •Azathioprine (start from 50 mg/day up to the maintenance dose of 2 mg/kg/day (max.150 mg/day) •High-dose N-acetylcysteine (NAC) (600 mg 3) continuously

• 67-year-old male patient • Slowly progressing dyspnea on exertion, cough, little mucoid sputum, and weight loss by 7 kg for 6 months from autumn 2003 • Having smoked 40 pack-years, finished in 1997 • On auscultation, bilateral end-inspiratory velcro rales referring to an alveolitis, but accompanied also by wheeze • Bilateral reticulonodular opacities on chest radiograms • On CT scans: peripheral, not completely symmetric ground glass opacities with little fibrosis and some traction bronchiectases with lower lobe predominance

A. Altraja ©2017 Non-specific interstitial pneumonia (NSIP): a case • The same 67-year-old male patient • Bilateral reticulonodular opacities on chest radiograms • On CT scans: peripheral, not completely symmetric ground glass opacities with little fibrosis and some traction bronchiectases with lower lobe predominance

A. Altraja ©2017 Idiopathic NSIP: histopathological findings of the patient • The same 67-year-old male patient • Temporally homomorphous finding throughout the specimen, with abundant cellular infiltration and absence of fibroblastic foci: the diagnosis is: Pneumonia interstitialis non-specifica (NSIP), variatio cellularia

A. Altraja ©2017 Prognosis of idiopathic NSIP • Significantly better than that of IPF, in all subtypes of NSIP • However, the prognosis is varying between patients: some patients improve, others remain stable or improve on treatment, but some evolve to end-stage fibrosis and may die of the disease • The median survival of patients with NSIP is generally 5-10 years • Depends on the fibrosis that is already present at diagnosis: 5-year survival is 70%, 10-year survival in cellular subtype 100%, in fibrotic subtype 35-90% (Collard & King, 2003) • In NSIP/IPF, 5-year survival is 45% (Nicholson et al., 2000) • In some NSIP patients, the survival is 2 years (rapid decline in DLco): • The histopathological finding of the UIP pattern is the risk factor here: present in up to 25% of NSIP of cases

• Desquamative interstitial pneumonia (DIP) • Cryptogenic organizing pneumonia (COP)

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013 How does smoking cause ILD? • Intensive accumulation of inflammatory cells (macrophages, neutrophils, Langerhans’ cells etc.) into the small airways, alveoli, and interstitium • The cause is the release of cytokines (GM-CSF) and inhibited apoptosis of the activated inflammatory cells • Release of profibrogenic growth factors (TGF-β1) • The role of nicotine (Jensen et al. FASEB J 2012): • Damage to the epithelial and endothelial cells • Stimulation of the release of TGF-β1 • Accumulation of inflammatory cells • Stimulation of the production of ROS • Intensifying od collagen synthesis  ECM remodeling • Telomere attrition  p53-mediated apoptosis (Armanios et al. 2009) • Dysregulation of autophagy (Margaritopoulos et al. 2013): • In the alveolar epithelium, elimination of toxic products and old cellular components, as well as their utilization as an alternative building material, is disturbed • Promotion of cell death

• One of the 2 smokers’ IIPs (in addition to RB-ILD) with macrophagal inflammation • Described also non-smokers (Craig et al. 2004), possible extension of childhood DIP (due to mutations in genes that code surfactant proteins) to the adulthood (Doan et al. 2008) • Also exposures to dusts, drugs • Gaucher’s disease

• 10-year survival about 70%, refractory to treatment only in little minority of patients

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013; Margaritopoulos et al. 2016 Desquamative interstitial pneumonia (DIP): epidemiology • 3-8% of ILDs (8% Mayo Clinic, <3% National Jewish Medical Research Center, Co, USA) (Bjøraker et al., 1998; King et al., 1999) • Peak incidence at the fourth-to-fifth decade • Male predominance (2:1) • No racial distribution (Persaud et al., 1967) • Infrequent disease: 3-8% of all ILD (Bjøraker et al. 1998; King et al. 1999) • In practice, DIP occurs almost exclusively in smokers, former smokers, or passive smokers

A. Altraja ©2017 Margaritopoulos et al. 2016 Desquamative interstitial pneumonia (DIP): the term and clinical manifestations •An independent separate disease (not a phase of RB-ILD, which develops to DIP with time) •Chronic progressive dyspnea with cough •The commonest age at the diagnosis is the third-to-fifth decade •Almost all patients are either smokers, former smokers, or passive smokers •Bibasilar end-inspiratory fine crackles •Clubbing in up to 50% of patients Lung function: •Restrictive pattern of the decline in ventilation function •Restrictive ventilation failure •Moderate decline in DLco: a quite exact indicator of the lung injury

A. Altraja ©2017 Margaritopoulos et al. 2016 Desquamative interstitial pneumonia (DIP): radiographic findings HRCT: • The main finding is bilateral, almost symmetric, diffuse ground glass opacifications, mainly (preferably) with peripheral (even subpleural) distribution in the middle and lower parts of the lungs; rarely also in the upper parts (where the findings do not dominate) → the difference from RB-ILD • Tractions of the airspaces characteristic of fibrosis are rare or absent; however, irregular lines with parenchymal distortion may be present in later phases of the disease • Cysts can be seen, but honeycombing is very rare and if present, it is very scarce

• The whole finding is relatively non-specific! • The main radiographic differential diagnosis is NSIP

A. Altraja ©2017 Margaritopoulos et al. 2016 Radiographic findings in DIP • A 54-year-old male patient, smoker with 38 pack-years • Non-specific bilateral opacifications • Presumably little fibrosis or even absence of fibrosis • FVC 3.71 L (74% predicted), FEV1 3.21 L (80%), FEV1/FVC 0.865, reversibility test negative; • DLco 44.3% predicted (normality limits 74-135%), Kco 58.2% (normality limits 76-131%), RV (residual volume) 68.4% predicted

• The same 54-year-old male patient • The main finding is diffuse ground glass opacifications, mainly with peripheral and lower lobe distribution • Tractions of the airspaces characteristic of fibrosis are absent • BAL: macrophages 35%, lymphocytes 2%, neutrophils 45%, eosinophils 17%, mast cells 1%; CD4:CD8 ratio: 0.5

A. Altraja ©2017 Desquamative interstitial pneumonia (DIP): histopathological finding • Surgical lung biopsy is needed for the diagnosis • Alveolar filling with „smokers’ macrophages“ • Chronic interstitial infiltration with macrophages • The cytoplasm of the macrophages has fine brownish inclusions that react positively for iron • These macrophages were mistakenly regarded as “desquamation” of the alveolar epithelial cells (because of that →“DIP”) • Slight-to-moderate thickening of the alveolar walls • Hyperplasia of the alveocytes, but the alveoli are well preserved • Histologically, the pattern is very uniform throughout the specimen

DIP (120×, H&E staining). Characteristic: •Filling of the alveoli with macrophages •Slight-to-moderate thickening of the alveolar walls •NB! Histologically, the pattern is uniform throughout the specimen

Katzenstein & Myers, Am J Respir Crit Care Med 1998 Histopathological findings in DIP

DIP (480×, H&E staining). •Filling of the alveoli with equally distributed macrophages •The macrophages have eccentric nuclei and slightly pigmented cytoplasm •Slight-to-moderate thickening of the alveolar walls due to some deposition of collagens •Frank alveocyte hyperplasia is present

Katzenstein & Myers, Am J Respir Crit Care Med 1998 Pathology of DIP • Alveolar filling with „smokers’ macrophages“ • Chronic interstitial infiltration with macrophages • Slight-to-moderate thickening of the alveolar walls • Hyperplasia of the alveocytes, but the alveoli are well preserved • The pattern is very uniform throughout the specimen

Photo: Dr. Alberto Cavazza Margaritopoulos et al. 2016 DIP: laboratory findings and the diagnosis BAL fluid: non-specific: • Increase in the total proportion of alveolar macrophages (irrelevant with regard to the diagnosis of DIP) • Slight increase in the amount of eosinophils and neutrophils The exact diagnosis is not possible without lung biopsy: • Radiology (ground glass opacifications) and the findings in BAL fluid are non-specific (Wells et al. 2007) • Slight DIP-like findings are present in many restrictive conditions, even the common transbronchial biopsy is not of major help due to the lack of specificity (Rao et al. 2008) • c-TBB may be of perspective

• First of all, differentiation is needed from RB-ILD, the other smoking-related IIPs • In DIP, the pigment-filled macrophages lie in the alveoli • In RB-ILD, the pigment-filled macrophages are located to the lumens of the respiratory bronchiole and around of them • Also, differentiation is necessary from other IIPs, especially from those with ground glass opacifications (e.g. from NSIP)

• In many cases, the disease is cured solely by smoking cessation • Glucocorticosteroid monotherapy, if the disease does not cure with smoking cessation (Hartman et al. 1996): •Positive treatment effect up to 60% of cases •Glucocorticosteroids are initiated with 0.5-1.0 mg/kg/24h by prednisolone •Thereafter, the dose is reduced by the end of the 2nd month of treatment •The duration of treatment is individual, but not less than at least 3 months •In up to 25% of patients, the disease may progress despite glucocorticosteroids → lung transplantation, if possible

• >70% patients have at least 5-year survival • Non-responsiveness to therapy is a rare problem • In some rare cases, DIP can progress to end-stage pulmonary fibrosis

A. Altraja ©2017 Margaritopoulos et al. 2016; Hartman et al. 1996 Respiratory bronchiolitis-interstitial lung disease (RB-ILD): general characteristics • The majority of the patients are heavy smokers, the disease develops on the basis of smoking (the other smokers’ IIP) • Presents with chronic, mild, but progressive dyspnea and cough • Bibasilar end-inspiratory fine crackles • Mixed, but predominantly restrictive pattern of ventilation dysfunction on spirometry • Accompanied by mild, but irreversible obstruction (difference from respiratory bronchiolitis (which presents with more obstruction) • Slight decrease in DLco • HRCT finding: • The main finding is ground glass opacities of low intensity and centrilobular nodules • Also, thickening of the wall of the peripheral bronchi and partial air trapping without a preponderance to concentrate to any part of the lung can be present

A. Altraja ©2017 Margaritopoulos et al. 2016 Respiratory bronchiolitis-interstitial lung disease (RB-ILD) • Histopathologically, RB is always present in smokers (Fraig et al. 2002) • Can be taken as a “natural” response to smoking … • that in few susceptible individuals develops further to interstitial lung disease (RB-ILD) • In clinical practice, RB-ILD is increasingly diagnosed without surgical lung biopsy in smokers with the following HRCT and BAL findings • The characteristic HRCT features are ground glass opacities and centrilobular nodules • BAL: • Presence of “smokers’ macrophages” • The absence of lymphocytosis, especially CD8+ cells • May resemble HP, but HP is not common among smokers and the absence of CD8+ lymphocytes speaks against HP • The mainstay of treatment is smoking cessation; in a vary small minority of patients, the disease persists after that

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013; Margaritopoulos et al. 2016 Respiratory bronchiolitis-interstitial lung disease (RB-ILD): epidemiology • Peak incidence at the third-to-fifth decade (30-50 years), but also found in young heavy smokers • Incidence and prevalence is poorly known (Dacic & Yousem, 2003) • A rare disease (<1% of respiratory bronchiolitis) • Occurs almost exclusively in heavy smokers or former heavy smokers • The disease can manifest also for years after smoking cessation • Slight male predominance • The disease is clinically and pathologically more severe in smokers, than in ex-smokers (Fraig et al., 2002, Wright et al. 1983)

A. Altraja ©2017 Respiratory bronchiolitis-interstitial lung disease (RB-ILD): radiology and the diagnosis Chest X-ray: • The images can be near-normal or with diffuse opacification of low intensity HRCT findings (correlate well with the macrophagal inflammation): • The main finding is centrilobular ground glass opacities of low intensity and centrilobular nodules • Also, thickening of the wall of the peripheral bronchi and partial air trapping without a preponderance to concentrate to any part of the lung can be present • Slight reticulation and mosaic attenuations bibasally • Slight upper lobe emphysema may be present (smokers!) • The diagnosis of RB-ILD is allowed to be clinical-radiographic (the clinical background with durable and heavy smoking, symptoms, objective and lung function findings, radiographic findings, and BAL findings)

A. Altraja ©2017 Wells et al. 2007; Bradley et al. 2008; Travis et al. 2013; Margaritopoulos et al. 2016 Respiratory bronchiolitis-interstitial lung disease (RB-ILD): a case • A 45-year-old female patient, having smoked ~25 pack-years: the chest X-rays are of near-normal appearance or show some emphysema

A. Altraja ©2017 Radiology of RB-ILD: HRCT • The HRCT findings correlate well with the macrophagal inflammation • The main finding is centrilobular ground glass opacities of low intensity and centrilobular nodules • Also, thickening of the wall of the peripheral bronchi and partial air trapping without a preponderance to concentrate to any part of the lung can be present • Slight reticulation and mosaic attenuations bibasally • Slight upper lobe emphysema may be present (smokers!)

Margaritopoulos et al. 2016

A. Altraja ©2017 Respiratory bronchiolitis-interstitial lung disease (RB-ILD): CT findings • Ground glass opacification of low intensity and partial air trapping without a preponderance to concentrate to any part of the lung • Thickening of the wall of the peripheral bronchi and centrilobular nodules

• A 57-year-old male patient • Smoking history of ~40 pack-years • Dry cough and decreased exercise tolerance

• RB-ILD in a female patient with a history of heavy smoking and progressive exertional dyspnea • Confluent areas of centrilobular ground glass opacifications • The chest X-ray is near-normal

T.E. King Jr, ILD 2003

A. Altraja ©2017 The diagnosis of RB-ILD and histopathological findings • Nowadays, the diagnosis is mainly clinical-radiographic (Wells et al. 2007; Bradley et al. 2008; Travis et al. 2013; Margaritopoulos et al. 2016)

• Bronchiolocentric disease • Pigment-filled macrophages within the alveolar ducts and bronchioli dilated due to the mucus retention • In the alveoli, the changes are less pronounced, but non- specific thickening of the alveolar walls could be observed • Very little, if any, interstitial fibrosis • With regard to macrophages, the finding is somewhat similar to that of DIP • The cytoplasm of the macrophages has fine, brown inclusions that react positively for iron („smokers’ macrophages“)

• 47-year-old heavy smoker; moderately intense ground glass opacities and centrilobular nodules (circles) • The bronchi have significantly thickened walls; emphysema is less pronounced • The BAL fluid contains 91% of macrophages Travis et al. ATS/ERS Consent, AJRCCM 2013 The histopathology of RB-ILD: most usually, no surgical lung biopsy is needed

• The same 47-year-old heavy smoker • Peribronchiolar accumulation of pigment-filled macrophages and emphysema (C) • Slight bronchiolar fibrosis along with the pigmented macrophages residing in the airways (D) Travis et al. ATS/ERS Consent, AJRCCM 2013 • Bronchiolocentric disease Pathology of RB-ILD • Pigment-filled macrophages within the alveolar ducts and bronchioli dilated due to the mucus retention • Non-specific thickening of the alveolar walls could be observed • Very little, if any, interstitial fibrosis • The cytoplasm of the macrophages has fine, brown inclusions that react positively for iron („smokers’ macrophages“)

Photos: Dr. Alberto Cavazza Margaritopoulos et al. 2016 Histopathological findings in RB-ILD • Pigment-filled macrophages within the alveolar ducts and bronchioli dilated due to the mucus retention (black arrow) • Cytoplasm of the macrophages is filled with brown pigment

A. Altraja ©2017 Respiratory bronchiolitis-interstitial lung disease (RB-ILD): treatment and prognosis • Smoking cessation is essential, as the disease can cure spontaneously as a result • Of the medicines, glucocorticosteroids as monotherapy (if smoking cessation is not of sufficient effect): • Response to glucocorticosteroids is very good: >90% of cases do respond • Glucocorticosteroids are initiated with 0.5-1.0 mg/kg/24h by prednisolone with reduction of the dose by the end of the 2nd month of treatment • The duration of treatment is individual, but not less than at least 3 months • In general, RB-ILD does not influence survival; >90% of patients have 5-years survival • No progression to end-stage pulmonary fibrosis (differently from DIP); but quicker decline in lung function has been observed (Portnoy et al. 2007)

• Cryptogenic organizing pneumonia (COP) • Acute interstitial pneumonia (AIP)

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013 Cryptogenic interstitial pneumonia (COP) • COP is always idiopathic • If connected with another disease (e.g. malignancy, connective tissue disease etc.: just „organizing pneumonia“ (”OP”); (formerly ”BOOP”) • CTD-OP: for example in RA, PM/DM etc. • Subacute disease, resembles ”decelerated” bacterial pneumonia

HRCT: • Characteristically, migrating subpleural, peribronchial, or band-like consolidations, usually together with ground glass opacifications • Perilobular opacifications and reversed halo (or atoll) sign may refer to COP • Scarce unilateral or bilateral pleural effusion in 10-30% of patients

• The real incidence of idiopathic COP is unknown • Prevalence is estimated to be 6…7/100 000 (Alasaly et al., 1995) • Mean age at the diagnosis: 50 years, but different age groups get ill with COP (20-80 years) • No gender difference in incidence or prevalence

A. Altraja ©2017 Cryptogenic interstitial pneumonia (COP): the term • Former term: “idiopathic BOOP” (Bronchiolitis obliterans – organizing pneumonia) • COP is an idiopathic lung disease, in which the granulation tissue proliferates into the alveoli, alveolar ducts, and small distal conducting airways (respiratory bronchioli) leaving the pulmonary interstitium relatively unaffected • When investigating lung biopsy material, organizing pneumonia (OP) can be found in numerous diseases: after infections, in systemic connective tissue diseases, as side effects of some drugs, in lung transplants etc.; sometimes also accompanied by findings characteristic of UIP etc. IIPs: in these occasions, this is not an idiopathic COP!

A. Altraja ©2017 Clinical manifestations of COP • Dry cough and dyspnea, sometimes weight loss from a few days to a few months • Fever is common, therefore, community-acquired pneumonia (CAP) is often misdiagnosed (a real pneumonia may (co)exist and cannot even be excluded however!): COP resembles clinical course of CAP that has been decelerated ~4-fold • End-inspiratory fine crackles • Clubbing is rare (some %) • In spirometry, restrictive pattern • Diffusing capacity of the lung is decreased in about 80% of cases

HRCT: • Bilateral focal or patchy areas of consolidation, more often subpleurally and peribronchially • “Air tapping” into the periphery – refers to the involvement of bronchioli (bronchiolar conductance) • Peribronchovascular foci and nodules, if present, are large, of irregular shape; subpleural nodules are also found • In some cases, intensive ground glass opacification is the leading finding • Honeycombing is almost never seen

• A 63-year-old female patient; after treatment of pneumonia, persistent fever, dyspnea, weakness, and weight loss • Bilateral alveolar opacifications are shown (left panel) that respond dramatically to 4- week treatment with glucocorticosteroids (right panel) A. Altraja ©2017 CT (left panel) and HRCT (right panel) findings in COP

• The same 63-year-old female patient; after treatment of pneumonia, persistent fever, dyspnea, weakness, and weight loss • A large consolidation is visible in the right upper lobe

• 50-year-old female patient; after treatment of pneumonia, persistent fever, dyspnea, weakness, and weight loss • An alveolar opacification (infiltrate) is shown in the right lung that improves with glucocorticosteroid treatment (6 months)

• A 60-year-old female patient, the clinical course initially resembled that of pneumonia, however, the decelerated course generated the suspicion of COP

• Temporally uniform finding of organizing pneumonia with weak chronic interstitial inflammation • Intraluminal organizing fibrosis appears in the distal airways (respiratory bronchioli, alveolar ducts, alveoli) • Confluent process, mainly OP that affects alveolar ducts and alveoli with or without bronchiolar intraluminal polyps • In some cases, a significant interstitial inflammation is present that equals with cellular NSIP • Architecture of the lung is generally well preserved in OP and honeycomb changes are almost never present

Travis et al. ATS/ERS Consent, AJRCCM 2013 A. Altraja ©2017 Histopathological finding in COP • A 63-year-old female patient. Temporally uniform finding of organizing pneumonia with weak chronic interstitial inflammation and Masson’s bodies (left panel). In the distal airways (respiratory bronchioli, alveolar ducts, alveoli), intraluminal organizing fibrosis appears (right panel).

• Depending on the concert of symptoms, their duration, and strength, COP can be confused with: •Community-acquired pneumonia •Other ILDs •Other forms of pulmonary fibrosis

• In cases of the histopathological finding of OP, it is necessary to exclude histopathological variants suggestive of other IIPs, because OP may be present as a “concomitant finding” together with those (UIP, NSIP, DAD, DIP, RB-ILD); if the latter is the case, OP is then a secondary phenomenon

A. Altraja ©2017 COP: the diagnosis • Transbronchial biopsy TBB (or preferably c-TBB) is highly recommended: a pathological finding of OP confirms the diagnosis • VATS-lung biopsy is needed in atypical cases • COP cannot be diagnosed solely by the histopathological finding

A. Altraja ©2017 Wells et al., BTS Guidelines: Thorax 2008; Travis et al. ATS/ERS Consent, AJRCCM 2013 COP: treatment and prognosis • Despite a minority of patients may cure spontaneously, treatment with systemic glucocorticosteroids is started, initially at 0.5-1.0 mg/kg/24h, with tapering the dose by the end of the 2nd month of treatment • The treatment should last for 6 months, shorter courses are associated with significant risk of relapse • About >80% of patients respond very well to glucocorticosteroids, the effect of treatment appears clinically already after few days • In some patients, the disease does not resolve despite longer treatment, residual fibrosis may develop with or without episodes of OP (”fibrosing OP” or NSIP) • In such patients, consolidation is often present during the course of the disease • This pattern is often seen in polymyositis and anti-synthase syndromes • In a small proportion of patients with COP (~5-10%), the disease progresses despite treatment, the disease then resembles IPF, whereas the effect of cyclophosphamide is uncertain

A. Altraja ©2017 Wells et al., BTS Guidelines: Thorax 2008; Travis et al. ATS/ERS Consent, AJRCCM 2013 Cryptogenic organizing pneumonia (COP): conclusions • Acute-to-subacute dyspnea, cough, and fever • Is “cryptogenic or idiopathic”, i.e. a certain background disease or condition is absent (in the presence of a such, the disease would be associated OP, not COP) • Confluent foci of inflammation of the terminal/respiratory bronchioli and/or the alveoli with proliferation of connective tissue that fills the airspaces • Excellent responsiveness to systemic glucocorticosteroids • Much better prognosis in comparison with IPF: 5-year survival is >90%

• Rapidly progressive hypoxemia, mortality ≥50%, no evidence- based treatment other than extraordinary lung transplantation • In those, who survive, the prognosis is good (like in ARDS), in some patients, however, progressive ILD develops (Ichikado et al. 2002) • The main differential diagnosis: ARDS due to known causes

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013 Acute interstitial pneumonia (AIP) • Synonym: Hamman-Rich syndrome • An acute from of IIPs that progresses to respiratory insufficiency and ends with death in some weeks or months • Clinically: cough and breathlessness from days to some weeks • Fever is common • Sometimes, a prodromal period that resembles a common viral infection is seen (myalgia, condition resembling upper respiratory tract infection) • The age of peaking incidence is 50s, men and women are equally affected • Diffuse alveogenic fine crackles are heard on auscultation • Restrictive pattern on spirometry (very seldom performed) • The causes of AIP are unknown; apoptosis of the alveolar epithelium in large areas of the lungs is thought: denudation of the basement membrane, a short exudative phase, followed by a rapid formation of connective tissue (a trial to ”repair the tissue defect”) • A strong connection to smoking! A. Altraja ©2017 Acute interstitial pneumonia (AIP): the radiology HRCT: • Areas of consolidation and ground glass opacification • Initially, in the basal parts, later everywhere in the lungs • Initially, the opacifications are focal, later, they become diffuse • Honeycombing is rare or absent (no time for that due to the rapid course and lethal exit) • During the exudative phase, bilateral, focal-to-confluent ground glass opacities are present, combined with areas of consolidation • In the organizing phase, distortion of the bronchovascular bundles and traction bronchiectases may be seem • The score of the HRCT changes is independently related to mortality in AIP

A. Altraja ©2017 Histopathological findings in AIP • Diffuse alveolar damage (DAD): there are 2 different stages: acute stage and organization Acute stage: • Edema, epithelial necrosis and desquamation, accumulation of fibrinous exudate and formation of hyaline membranes is also characteristic (too early/quick to be usually seen in biopsies) • The process typically diffuse and temporally uniform (in the specimens, all changes are in the same evolutionary phase) Organizing stage (usually present in biopsies, if taken) • Proliferation of type II pneumocytes, disappearance of alveolar exudate and hyaline membranes, proliferation of fibroblasts; thrombi in small and medium-sized vessels • Rapidly forming fibrosis, formation of connective tissue that, due to its contraction, causes cyst formation resulting in honeycombing-like changes • In AIP, the airspaces are lined with alveolar epithelium; in UIP, with bronchial epithelium! A. Altraja ©2017 Histopathological findings in AIP

AIP (120×, H&E staining). Characteristic: •Temporally uniform thickening of the alveolar walls and accumulation of the mononuclear cells •Although the magnitude of the airspaces and thickening of the interstitium vary throughout the specimen, the cellular component is constant

Katzenstein & Myers, Am J Respir Crit Care Med 1998 Histopathological findings in AIP

AIP (480×, H&E staining). Alveoli: •Thickening of the alveolar walls is associated with the presence of oval-to- fusiform fibroblasts and few little, vaguely distributed lymphocytes •Marked hyperplasia of alveocytes along the alveolar walls

Katzenstein & Myers, Am J Respir Crit Care Med 1998 The pathology of AIP in conclusion

• Acute and organizing diffuse alveolar damage (DAD) with hyaline membrane, not distinguishable from the histopathological finding of ARDS

In the organization stage (during which the biopsy, if any, is done): • The main finding includes diffuse proliferation of connective tissue, that leads to thickening of the alveolar walls • Frank pneumocyte hyperplasia • Hyaline membranes may already be absent • The developing background fibrosis may resemble UIP, in such cases, the finding may suggest, in turn, acute exacerbation of IPF • AIP may progress to a condition that either mimics fibrotic NSIP or develops to severe honeycombing

A. Altraja ©2017 Travis et al. ATS/ERS Consent, AJRCCM 2013 Acute interstitial pneumonia (AIP): differential diagnosis • Community-acquired pneumonia (CAP) • ARDS • Acute exacerbation of IPF (AE-IPF) • (IPF with) congestive heart failure • Pneumocystis jirovecii-related pneumonia • Rapidly progressive respiratory insufficiency due to other causes • In practice, the diagnosis of AIP is often not done, because, on the background of its rarity, there are usually not enough diagnostic „traditions“ to diagnose a condition other than ARDS • In conditions with rapidly progressive respiratory insufficiency that is not explained otherwise, lung biopsy is indicated, if possible due to the worsening clinical condition of the patient

• Not fully known (possibly, the same mechanisms that are operative in IPF and its acute exacerbations exacerbation) • Hypotheses for the pathogenesis (following to each other events): •Apoptosis of the alveolar epithelium (in a large, particular proportion of the lung) • The reasons are unknown: telomeric senescence of the alveolar epithelium following an exposure of a triggering factor? •Denudation of the alveolar basement membrane •Rapid exudation, short exudative phase •Uncontrolled “reparation” with formation of abundant connective tissue in the space of the former alveoli

A. Altraja ©2017 Acute interstitial pneumonia (AIP): treatment and prognosis • There is no evidence-based treatment option • Glucocorticosteroids and antibiotics have no effect • Antifibrotic agents? • Extraordinary lung transplantation • Casuistic cases of spontaneous cure • Relapses occur

• Mortality >50-60% • In those, who survive, the prognosis is good

• A strong connection with smoking! • Acute to subacute dyspnea and cough with rapid progression of the disease to respiratory insufficiency, fever may be typical • Absence of another cause known to lead to acute lung injury and respiratory insufficiency and (e.g. ARDS) • Lung biopsy can be rarely done because of patient’s condition: the finding is diffuse alveolar damage (DAD) • There is no treatment, the prognosis is very bad with short- term survival being <50% of cases • In cases of eventual spontaneous cure, the disease may relapse

• Idiopathic lymphoid interstitial pneumonia (LIP) • Other rare and unclassifiable conditions (idiopathic pleuroparenchymal fibroelastosis, rare histologic patterns, unclassifiable IIPs)

• The true incidence and prevalence are not known • Female predominance is clear • The mean age at the diagnosis is 56 years (Kohler et al., 1982)

A. Altraja ©2017 Idiopathic lymphoid interstitial pneumonia (LIP): • In a major proportion of patients presenting with LIP-like syndrome, there is a disease associated with a known cause (concomitant lymphoma, other malignancy, rheumatoid arthritis, Sjögren’s syndrome etc.) • Just a small proportion of such patients have idiopathic LIP • Clinically hart to differentiate from other IIPs • The patients are usually younger (30-50 a.) • Female predominance • The symptoms progress slowly, the leading symptoms include cough and dyspnea • Bibasilar inspiratory fine crackles on auscultation • Sometimes lymph node enlargement • Restriction on spirometry

A. Altraja ©2017 Lymphoid interstitial pneumonia (LIP): radiographic findings HRCT: • Diffuse ground glass opacification • Poorly defined centrilobular nodules • Thickened bronchovascular bundles • Cysts • Lymphadenopathy

A. Altraja ©2017 CT finding in lymphoid interstitial pneumonia (LIP) • A 56-year-old male patient. Bilaterally, almost throughout the lung parenchyma, diffuse ground glass opacification and parenchymal consolidation is visible • Poorly defined centrilobular nodules • Thickened bronchovascular bundles

A. Altraja ©2017 HRCT finding in lymphoid interstitial pneumonia (LIP) • The same 56-year-old male patient. Bilaterally, almost throughout the lung parenchyma, diffuse ground glass opacification and parenchymal consolidation is visible • Poorly defined centrilobular nodules • Thickened bronchovascular bundles

• In lung biopsies, there are interstitial infiltrates with varying, usually little involvement of the peribronchial tissue • The infiltrate consists of T-lymphocytes, plasma cells, and macrophages • Often, hyperplasia of the type II alveolar cells is accompanied • Lymphoid follicles are often present • Granulomas and slight fibrosis are rare

A. Altraja ©2017 Differential diagnosis in LIP • All parenchymal diseases of the lungs that may have lümfoidse infiltrates: •Castleman’s disease, nodular lymphoid hyperplasia, follicular bronchiolitis, hypersensitivity pneumonitis, cellular NSIP etc.: the clinical-histopathological diagnosis is essential •Together with follicular bronchiolitis, LIP may compose a special condition termed as “diffuse pulmonary lymphoid hyperplasia” •Out of systemic connective tissue diseases, LIP is a pulmonary manifestation of primary Sjögren’s syndrome (SS), LE, and RA

A. Altraja ©2017 Treatment and prognosis of idiopathic LIP • Systemic glucocorticosteroids with or without immunomodulating treatment: response to treatment is presumably good, there is not a 100% confidence, however

• The clinical course of the disease can be variable and unpredictable • The majority of patients will stabilize and cure: 5-year survival is about 60% • In the minority, the disease may progress to pulmonary fibrosis that leads to death via respiratory insufficiency

• Clinically, chronic, progressive dyspnea and cough with rapid progression of the disease to respiratory insufficiency; fever may be present • An autoimmune disease or immunodeficiency syndrome is absent • Dense interstitial lymphoid infiltrate is present • Response to treatment is not always clear • Prognosis is nevertheless good in general • Progression to either pulmonary fibrosis or malignant lymphoma remain as the problems