Interstitial Lung Disease Anne McKay Consultant Respiratory Physician Queen Elizabeth University Hospital Glasgow

Outline Classification of ILD Clinical Presentation of ILD Symptoms Examination Initial investigations - X-rays, lung function, bloods Discuss common types of ILD Idiopathic pulmonary fibrosis Sarcoidosis Hypersensitivity pneumonitis

Classification of ILD

ATS Classification of Diffuse Parenchymal Lung Disease Infiltrative processes which involve the alveolar spaces or lung interstitium

Pragmatic Classification of ILD Commonest ILDs - idiopathic pulmonary fibrosis and sarcoidosis Adapted from Gulati. Prim Care Resp J 2011; 20 (2) 120

Initial Presentation and Investigation

Clinical Features of ILD Symptoms Cough Breathlessness – acute or chronic Fatigue Clinical Signs Crackles/creptitations in chest Finger clubbing Cyanosis Peripheral oedema

Initial Investigation

Initial Investigations CXR – bilateral interstitial changes

Initial Investigations Lung Function Tests Restrictive defect FEV1 to FVC ratio normal to high (both values reduced) CO gas transfer reduced Pred Actual % Pred FVC (l) 2.80 1.17 42 FEV1 (i) 2.39 1.04 44 FEV1/FVC (%) 80 89 - TLC (l) 4.57 1.75 38 DLCO (ml/mmHg/min) 23.3 6 26

Subsequent Investigations High Resolution CT chest (HRCT) Screening blood tests – any underlying cause Immunology screen – RF, ANA, ANCA Avian and aspergillus precipitans Serum angiotensin converting enzyme (ACE) level Arterial Blood Gases - Type 1 Respiratory Failure VATS lung biopsy Six minute walk test/ambulatory oxygen assessment Echocardiogram

Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic Pulmonary Fibrosis Definition: a specific form of chronic fibrosing interstitial pneumonia of unknown aetiology limited to the lung histopathological appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy other causes excluded (drugs, CTD) Characteristic radiological and lung function features (American Thoracic Society/European Respiratory Society, 2009)

Clinical Features of IPF Age of onset > 50, male > female Progressive breathlessness, productive cough, cyanosis Respiratory failure, cor pulmonale, pulmonary hypertension Fine bilateral end-inspiratory crackles Finger clubbing (2/3) usually a h/o cigarette smoking

Radiological Changes in IPF Predominantly at lung bases

CXR – irregular reticulonodular changes / honeycombing

High resolution CT Chest Early Advanced High resolution CT Chest subpleural reticular changes honeycombing traction bronchiectasis

Pathogenesis of IPF "repeated cycles" of epithelial activation/injury by some unidentified agent abnormal activation of epithelial cells lead to a dysregulated repair process inflammatory pathways also promote fibrosis induction of a Th2 type T cell response TGF-1β Abnormal epithelial repair at site of injury/inflammation leads to the formation of the fibroblastic foci

UIP Cobblestone surface of lung Fibroblastic foci and temporal Heterogeneity on histology Fibroblastic foci Normal lung Honeycomb Cysts

Treatment of IPF Anti-fibrotic agents - pirfenidone and nintedanib Approved for use in patients with FVC 50 – 80% predicted For many, therapy is mainly aimed at symptom control oxygen, diuretics, antibiotics, pulmonary rehabilitation Lung transplant for a few (age < 65)

Pirfenidone mechanism of action unclear ? suppresses fibroblast growth slows lung function decline mechanism of action unclear ? suppresses fibroblast growth Optimal dose 801 mg tds Side effects GI upset Photosensitivity ASCEND trial - King TE Jr et al, NEJM 2014; 370:2083

Nintedanib intracellular inhibitor of multiple tyrosine kinases Slows lung function decline (INPULSIS-1 and 2) Usual dose 150 mg bd Main side effect is GI upset especially diarrhoea Richeldi L et al, NEJM 2014; 370: 2071

Prognosis in IPF Median survival is 3 – 5 years from time of diagnosis 75% will die from respiratory illness 1 in 10 patients develop lung cancer Brett L, et al. AJCCM 2011, 183, 431-440

SARCOIDOSIS

Sarcoidosis Multi-system granulomatous disorder Unknown aetiology Non-caseating granulomas Unknown aetiology Commonly affects young adults Epidemiology UK prevalence 5 - 19/100,000 Peak incidence in 20s and 30s F > M

Sarcoidosis Antigen SARCOIDOSIS Genetic Factors Disordered Immune Regulation Genetic Factors Antigen SARCOIDOSIS

Other Factors Genetic factors Environmental factors Familial and racial clustering Associated with HLA-A1, HLA-B8 Environmental factors Mycobacteria Proprionobacterium acnes Fungi and viruses 15 times more common in Afro caribbeans, EBV, environmental agents

Clinical presentation Respiratory symptoms Abnormalities on CXR Fatigue and weight loss Peripheral lymphadenopathy Fever Skin and eye involvement Neurological symptoms

CXR – Bilateral HilarLymphadenopathy Erythema Nodosum CXR – Bilateral HilarLymphadenopathy EN ImageJamesHeilman, MD, Wikimedia Commons

Sarcoidosis - Diagnosis CXR – bilateral hilar lymphadenopathy, lung infiltrates CT chest (HR): nodular changes – subpleural or along bronchovascular bundles Lung Function Tests Normal Airflow obstruction Restrictive defect BHL and parenchymal sarcoidosis may be asymtpomatic Others have progressive breathlessness

Sarcoidosis - Diagnosis 2 Tissue Diagnosis Bronchoscopy → Transbronchial Lung Biopsy 90 % positive if chest disease Biopsy Mediastinal Lymph Nodes - EBUS Differential Diagnosis: Lymphoma, TB, Lung Cancer Blood Tests FBC – mild anaemia, raised ESR Serum biochemistry Hypercalcaemia Raised gammaglobulins Serum ACE TBLB - 50 % positive if extrapulmonary disease , NCNC anaemia, Raised Ca – mention Vit D

Respiratory Staging 0 – normal 1 – Bilateral hilar lymph (BHL) nodes alone 2 – BHL with pulmonary infiltrates 3 – Pulmonary infiltrates alone 4 – fibrosis Small proportion of patients progress to Stage 4 Stage 1 – 3 can be asymptomatic Some have progressive breathlessness Stage 1 2/3, Stage 2 ~ 25%, Stage 3 - rest

Stage 4 Sarcoidosis – Fibrotic Changes

Treatment Most patients do not require treatment Corticosteroids – if not improving or declining after 6 months 30 mg daily for 4 - 6 weeks then taper to 5 – 10 mg daily for a total of 12 months Methotrexate or azathioprine are common second-line drugs Mandatory treatment – eye, CNS, cardiac involvement or persistent hypercalcaemia

Prognosis Generally sarcoidosis has a very good prognosis Remittance within 2 years: Stage 1 – 66 % Stage 2 – 50 % Stage 3 – 33 % Less than 5 % of UK patients progress to respiratory failure and cor pulmonale High mortality in black americans upto 10 %

Hypersensitivity Pneumonitis

Hypersensitivity Pneumonitis Previously called extrinsic allergic alveolitis Hypersensitivity reaction to inhaled organic dust Commonest causes in UK: Farmer’s lung – Micropolyspora faeni Pigeon fancier’s lung – bloom/excreta 25% of cases no antigen identified

HP Clinical Features Acute illness: Examination – 3 – 9 hours after exposure Malaise, fever, anorexia, fatigue, headache Dry cough, breathless, wheeze Examination – increased respiratory rate and hypoxaemia bibasal crackles Chronically – progressive breathlessness, reduced exercise tolerance, weight loss

CXR in Acute Hypersensitivity Pneumonitis

HRCT Chest in Acute Hypersensitivity Pneumonitis Case courtesy of Dr Mark Holland , Radiopaedia.org, rID: 19551

Pathophysiology Acute non-specific diffuse pneumonitis Lymphocytic alveolitis – airway/aveolar oedema Non-caseating granulomata Circulating antibodies (IgG) to responsible antigen

Diagnosis Periodic or continuous exposure to a relevant antigen Appropriate changes in lung physiology and pathology Evidence of immunologic sensitisation to the suspected provoking agent

Treatment Withdrawal from causal agent Anti-inflammatory agents “short” courses of oral steroids Oxygen therapy Avoidance of further exposure

General Management of ILD Glasgow had an ILD MDT monthly Attended by Respiratory Consultants, ILD Clinical Nurse Specialist, Radiologist, Pathologist Discuss difficult cases and review cases where anti-fibrotic therapy might be appropriate

Summary The commonest interstitial lung diseases are idiopathic pulmonary fibrosis and sarcoidosis Pirfenidone and nintedanib are now available for the treatment of IPF. ILDs which respond to immunosuppressive treatment generally have a better prognosis An ILD MDT is helpful in the diagnosis and management of difficult cases

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