ABIM IM Board Review Interstitial Lung Diseases Nishant Gupta, MD, MS Director, ILD Program University of Cincinnati

Expect 4-5 questions on ILD

Airway versus interstitial abNMLities on histopathology

Detailed hx key in establishing the right dx Drug hx: Include recent and past exposures Include OTC meds and lipid formulations such as vaseline/mineral oils Common drugs associated with ILDs: Methotrexate - Cyclophosphamide Amiodarone - Radiation exposure Nitrofurantoin - Narcotics Sulfasalazine - Oxygen toxicity Bleomycin

Occupational History Thorough & detailed Long latency period between exposure and development of disease, so remember to ask about prior jobs Common occupational hazards linked with ILD: Inorganic dust inhalational injuries Silicosis Asbestosis Hard metal pneumoconiosis Coal workers pneumoconiosis Talc pneumoconiosis Berylliosis Siderosis

Other inhalational exposures Typically associated with hypersensitivity pneumonitis HP – can have an acute presentation, or a chronic, insidious, progressive course Environmental evaluation for suspected HP Pets and other domestic animals, especially birds Hobbies/recreational activities Hot tubs/saunas Leaks/floods indoors Water damage to carpets/furnishings Visible fungal growth Feather pillows, comforters, and bedding Similar symptoms in other occupants

Question 1 65yoM cc gradually worsening dyspnea on exertion, and chronic, dry cough. Sx’s progressive for 2 years. The patient had a 25 pack-year smoking hx but quit 5 years prior to the presentation. He has previously been diagnosed with COPD, and is on appropriate inhalers for management of his COPD. On examination, the patients vital signs are: Temp: 97.2 F, HR – 76bpm, BP - 134/82mmHg, Respiratory rate – 16 bpm, SaO2 86% on RA. Rest of his physical exam reveals the presence of clubbing and bibasilar, dry, end-inspiratory crackles in bilateral lung fields. You obtain a high-resolution chest CT scan which shows the following findings:

What is the underlying dx of this pt? Idiopathic pulmonary fibrosis (IPF) Interstitial lung disease secondary to undiagnosed connective tissue disease Chronic hypersensitivity pneumonitis CT findings not enough to make a conclusive diagnosis – need to obtain lung biopsy for a definitive diagnosis A - IPF

Definition of Idiopathic pulmonary fibrosis (IPF) IPF – chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP). The diagnosis of IPF requires: - Exclusion of other known causes of ILD (e.g environmental exposures, drug toxicity, connective tissue diseases etc.) - The presence of a UIP pattern on HRCT in pts not subjected to surgical lung biopsy - UIP pattern on histopathology in the right clinical setting (IPF = UIP always, but UIP = IPF always) Raghu G et al. Am J Respir Crit Care Med 2011; 183(6):788-824

Definite radiographic UIP pattern Radiographic evidence of UIP is enough to diagnose IPF in the right clinical setting Definite UIP pattern on HRCT is almost 100% specific for the presence of histopathological UIP on surgical lung bx Flaherty KR et al. Thorax. 2003 Feb;58(2):143-8 Definite radiographic UIP pattern Subpleural, basilar predominant abnormalities Reticulations are the primary abnormality Honeycombing with or without traction bronchiectasis Absence of features inconsistent with UIP such as ground glass attenuation, upper-mid lung predominance, discrete cysts, air trapping, consolidation etc. Raghu G et al. Am J Respir Crit Care Med 2011; 183(6):788-824

Traction bronchiectasis and honeycombing Absence of other features such as ground glass opacities Subpleural, basilar predominant reticular abnormalities

Temporal, and spatial heterogeneity, along with fibroblastic foci are the histopathologic hallmarks of UIP Normal lung Fibroblastic foci Patchy, subpleural fibrosis

Question 2 65yoM cc gradually worsening dyspnea on exertion, and chronic, dry cough. The patient had a 25 pack year smoking hx but quit 5 years prior to the presentation. On examination, the patients vital signs are: Temp: 97.2 F, HR – 76bpm, BP - 134/82mmHg, Respiratory rate – 16 bpm, SaO2 86% on RA. Rest of his physical exam reveals the presence of clubbing and bibasilar, dry, end-inspiratory crackles in bilateral lung fields. High-resolution chest CT reveals subpleural, basilar predominant reticular abnormalities along with honeycombing, characteristic of a UIP pattern.

Which of the following is the most appropriate medications to consider in this patient? Prednisone Prednisone and azathioprine Prednisone, azathioprine, and N-acetyl cysteine Pirfenidone D; C used to be standard but inc’d mortality

Pharmacological treatment of IPF Combination of prednisone, azathioprine, and N-acetylcysteine (NAC) used to be standard treatment regimen for patients with IPF PANTHER trial: Randomized, double-blind, placebo controlled trial of combined prednisone, azathioprine, and NAC versus NAC alone versus placebo Study stopped early after recruitment of 50% sample size (77 in combination group and 78 in placebo group) Increased rate of death in treatment group vs placebo (8 versus 1, p=0.01) Increased hospitalization in treatment group vs placebo (23 vs 7, p<0.001) N Engl J Med 2012; 366:1968-1977

Increased mortality and hospitalizations in patients with IPF treated with combined prednisone, NAC, and azathioprine Death Death and hospitalization N Engl J Med 2012; 366:1968-1977

Treatment with pirfenidone slows disease progression in IPF Pirfenidone – Oral antifibrotic drug Randomized, placebo-controlled, double-blind study, of patients with mild-moderate IPF (FVC 50-90% predicted, DLCO: 30-90% predicted) Primary outcome: Change in FVC or Death at Week 52 Treatment with pirfenidone reduced the rate of decline of FVC by approximately 50% (235mls decline in the pirfenidone group vs 428mls in the placebo group) Prespecified pooled analysis – reduced mortality among patients treated with pirfenidone vs placebo (hazard ratio, 0.52; 95% CI, 0.31 to 0.87; P = 0.01) King TE et al. N Engl J Med 2014;370:2083-92

Pirfenidone in IPF King TE Jr et al. N Engl J Med 2014;370:2083-2092.

Treatment with nintedanib slows disease progression in IPF Nintedanib: An intracellular inhibitor targeting multiple tyrosine kinases Two double-blind, randomized, double-blind, placebo-controlled, multicenter, phase 3 studies 1,066 patients with IPF randomized in a 3:2 fashion to receive nintedanib vs placebo Primary outcome: Decline in FVC at 52 weeks Treatment with nintedanib reduced the rate of decline of FVC by approximately 50% (115mls decline in the nintedanib group vs 240mls in the placebo group) ? Reduction in acute exacerbations of IPF (not seen in INPULSIS 1 but seen in INPULSIS 2) Richeldi L et al. N Engl J Med 2014;370:2071-82

Nintedanib in IPF Richeldi L et al. N Engl J Med 2014;370:2071-2082.

Question 3 62yoF cc fingers turning blue, and becoming numb in the cold weather. The complaints started a few weeks ago. She has otherwise been healthy and doesn’t have any significant past medical history. Her only medications include as needed alprazolam for anxiety. She has occasional heart-burn for which she takes as needed TUMS. She denies any pulmonary symptoms. Physical examination is mostly normal, except for puffy fingers in both hands. You are concerned about an auto-immune process and send lab work which reveals the following results: positive ANA in a nucleolar pattern with a titer of 1:1280, and positive Anti-Scl70 antibodies. A HRCT chest is performed that reveals the following findings:

Which of the following is true regarding ILD associated with scleroderma? UIP is the most common HRCT pattern in patients with scleroderma-related ILD Extent of ILD on HRCT does not carry prognostic significance for patients with scleroderma related ILD Mycophenolate mofetil is superior to cyclophosphamide in treating ILD associated with scleroderma Plasma levels of CXCL4 can predict development of ILD in patients with scleroderma D

NSIP is the most common ILD seen in patients with scleroderma Non-specific interstitial pneumonia (NSIP), especially fibrotic NSIP, is the dominant pattern of interstitial involvement in patients with scleroderma. In a cohort from UK, 77% (62 out of 80) of the patients with scleroderma ILD had NSIP on histopathology* The presence of Anti-centromere antibodies is linked with decreased incidence of pulmonary involvement, and improved survival in patients with systemic sclerosis** *Bouros D et al. Am J Respir Crit Care Med. 2002 Jun 15;165(12):1581-6 **McNearney TA et al. Arthritis Rheum 2007; 57:318. ** Ferri C et al. Medicine (Baltimore) 81: 139-53, 2002

Disease extent on HRCT predicts survival in patients with scleroderma Goh NS et al. AJRCCM 2008 Jun 1;177(11):1248-54

SLS-1: Small but significant improvement in FVC with cyclophosphamide Average FVC improvement in cyclophosphamide group at 1-year = 2.5% More side effects with cyclophosphamide Tashkin DP et al. N Engl J Med 2006;354:2655-66

SLS 2: Mycophenolate and cyclophosphamide have similar efficacy but cyclophosphamide has increased side effects Tashkin DP et al. Lancet Respir Med. 2016 Sep;4(9):708-19

CXCL4 is a novel biomarker that is specific to systemic sclerosis, and can predict the presence and progression of ILD and PH CXCL4: potent antiangiogenic chemokine, secreted by plasmacytoid dendritic cells, and may be responsible (in part) for the antiangiogenic and immune-dysregulatory features seen in patients with systemic sclerosis (SSc). Plasma levels of CXCL4 from patients with SSc compared with healthy controls, as well as other auto-immune conditions such as SLE, ankylosing spondylitis, and liver fibrosis. CXCL4 levels correlated with the presence and progression of pulmonary, and other, complications of SSc Van Bon L et al. N Engl J Med 2014;370:433-43

High levels of plasma CXCL4 in patients with SSc as compared to controls

Elevated CXCL4 levels predict the presence of pulmonary complications of SSc Van Bon L et al. N Engl J Med 2014;370:433-43

Question 4 39yoF cc new-onset left sided chest pain and dyspnea on exertion. Her symptoms worsen when she tries to take a deep breath. The patient is a never-smoker, denies any drug abuse. She has no significant past medical history, and is no medications. On physical examination, the patient’s vital signs are as follows: HR – 94bpm, BP – 134/78mmHg, Temp - 98°F, R – 20/minute. She appears in mild distress. Auscultation reveals decreased breath sounds on the left as compared to the right. Rest of the physical examination is unremarkable. Chest-x-ray performed in the ER reveals a left-sided spontaneous pneumothorax. After successful drainage of the pneumothorax, a CT chest is performed showing:

What is the most likely diagnosis? Primary spontaneous pneumothorax Lymphangioleiomyomatosis (LAM) Catamenial pneumothorax Pulmonary Langerhans cell histiocytosis (PLCH) B

Lymphangioleiomyomatosis A rare systemic neoplastic disease due to Tuberous sclerosis complex (TSC) mutations, seen almost exclusively in females HRCT features of LAM – uniform, round, thin-walled cysts in a diffuse distribution

Recurrent spontaneous pneumothoraces are common in patients with LAM 55-73% of patients with LAM develop at least one spontaneous pneumothorax in their lifetime On average patients with LAM suffer from more than 2 pneumothoraces prior to getting diagnosed with LAM The median age for pneumothorax in LAM is 35 years If managed conservatively, the recurrence rate of pneumothoraces in LAM is ~ 70% Pleurodesis is recommended following the initial pneumothorax in LAM as opposed to waiting for a recurrence Almoosa KF et al. Chest. 2006 May;129(5):1274-81

Treatment with mTOR inhibitors (sirolimus) can stabilize lung function in patients with LAM MILES: Randomized, double-blind, multicenter, placebo-controlled trial of sirolimus in patients with LAM McCormack FX et al. N Engl J Med. 2011 Apr 28;364(17):1595-606

Summary - IPF IPF – typically elderly males w/ hx smoking Radiological UIP is diagnostic of IPF in the right clinical setting and obviates the need for lung biopsy Treatment with prednisone, azathioprine, and NAC increases mortality in patients with IPF Treatment with pirfenidone or nintedanib slows disease progression in patients with IPF

Summary - Scleroderma NSIP is the most common interstitial abnormality in patients with scleroderma Extent of abnormality on HRCT is predictive of mortality in patients with scleroderma Mycophenolate – preferred first-line drug for scleroderma ILD based on better side effect profile and similar efficacy as compared to cyclophosphamide. CXCL4 levels are elevated in patients with systemic sclerosis, and correlate with the presence and progression of pulmonary fibrosis and pulmonary hypertension

Summary - Others Detailed occupational and exposure hx key in establishing the right dx – can be very helpful in cases of suspected ILDs, especially hypersensitivity pneumonitis Think about LAM in a young-middle aged female presenting with a spontaneous pneumothorax Perform pleurodesis after the first episode of pneumothorax in patients with LAM Treatment with sirolimus can stabilize lung function in patients with LAM