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

2. Expect 4-5 questions on ILD

4. Airway versus interstitial abNMLities on histopathology

5. 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

6. 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

7. 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

8. 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:

10. 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

11. 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):

12. 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 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):

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

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

15. 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.

16. 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

17. 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:

18. 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:

19. 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:

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

21. 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:

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

23. 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:

25. 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

26. 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 Jun 15;165(12):1581-6
**McNearney TA et al. Arthritis Rheum 2007; 57:318.
** Ferri C et al. Medicine (Baltimore) 81: , 2002

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

28. 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:

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

30. 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

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

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

33. 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:

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

36. 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

37. 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 May;129(5):

38. 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 Apr 28;364(17):

39. 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

40. 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

41. 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