1. Case 1: Familial IPF

2. Case Presentation: Familial IPF
56-year-old Hispanic female with a family history of aortic aneurysm underwent a routine chest CT to assess her aorta
No respiratory symptoms
Medical history
h/o SVT
Type 2 diabetes mellitus
Hypertension
Iron-deficiency anemia
Hypothyroidism
Medications: atorvastatin; metformin; levothyroxine; irbesartan; aspirin
Habits: Lifetime non-smoker; non-drinker
No unusual pets or exposures
Family history of lung disease

3. Maternal Family Tree Grandmother Uncle
Deceased, ILD, Presumed Sarcoidosis
Mother
Sarcoidosis, Deceased,
ruptured AAA
Brother
ILD Presumed Sarcoidosis
Sister
Good Health
Presumed Sarcoidosis
PATIENT
Deceased MVA
Deceased in infancy
Deceased,
confirmed IPF
Aunt MI

4. CT CT (not HRCT) obtained on 10/23/07 is shown on the following slide
CT shows ill-defined reticular opacities (arrows)
Because the scan is not high-resolution, some of the abnormalities appear to be of ground-glass opacity, but this is not likely the case
The abnormality involves all levels shown, including the upper lobes
The CT findings are consistent with UIP and IPF
Because ground-glass opacity may be present, NSIP must also be considered

6. Clinical Course
Patient remained asymptomatic and continued to work as an HR specialist
About 3 months prior to evaluation, the patient noticed the onset of some mild DOE while going up stairs and sometimes while getting dressed. This was also associated with the onset of a dry cough
Saw pulmonologist
Obtained a CT of the chest
Recommended a VATS biopsy, based on the family history of IPF and “presumed” sarcoidosis

7. CT
CT 2 years later (next slide) shows progression of the ill-defined opacities which are diffuse and strikingly peripheral in distribution; they are likely reticular in nature
The abnormality remains consistent with UIP and IPF, or NSIP, but would be very unusual with sarcoidosis
Sarcoidosis typically results in small or large nodular opacities, which are peribronchial and subpleural in distribution, and predominate in the upper lobes

9. SLB Reveals UIP: Image A
Fibrosis (F)
Microscopic
honeycombing F
Normal
Lung F
Fibroblast Foci (ff) F F

10. Temporal Heterogeneity in UIP: Image B
Fibroblast
Foci (ff)

11. Fibroblast Focus: Image C
Type 2 cells ff
The fibroblast focus (ff) is made up of a parallel arrangement of immature fibroblasts covered by a thin layer of pink-appearing reactive type 2 cells (t2). Note the coarse fibrosis (F) underlying the fibroblast focus. F

12. Histopathologic Findings
At low magnification (Image A), coarse fibrosis appears to surround areas of more normal lung. All of the features required for a diagnosis of UIP are illustrated in this image. The alternating zones of fibrosis (F) and normal lung (N) are accentuated by fibroblast foci (ff). Endstage microscopic lung remodeling referred to as “microscopic honeycombing” (mh) is nearly always present in UIP
Temporal heterogeneity in UIP (Image B). The transitions from fibrosis to normal lung are nicely illustrated. A few fibroblast foci (ff) are evident
The fibroblast focus in Image C has a parallel arrangement of immature fibroblasts covered by a thin layer of pink-appearing reactive type 2 cells (t2). Note the coarse fibrosis (F) underlying the fibroblast focus

13. Serial PFTs 10/20/09 3/8/10 (Symptom onset) 5/26/10 FVC 1.15 0.91 0.9241 32 33
FEV1
1.02
0.78
0.88
FEV1% 44 38
TLC
4.01
3.68
1.83
TLC% 87 80 40
DLCO
7.5
7.9
6.5
DLCO% 34 28

14. Clinical Course Referred to ILD clinic 6MWT on room air
Resting SpO2 = 100
Walked 417 meters on room air, desaturation to 93%
Borg score = 4
HR increased from 80 to 105, recovered to 91 one minute after exercise
Diagnosis of familial IPF confirmed
Possible that family members with “presumed” sarcoidosis could have had IPF instead
Work-up for potential lung transplantation recommended and initiated

15. Familial IPF Summary
Familial IPF accounts for less than 5% of total IPF cases
It is characterized by two or more cases of idiopathic interstitial pneumonia in first-degree relatives
Autosomal dominance with reduced penetrance is likely
Not all of the genes associated with familial pulmonary fibrosis are known. Mutations have been identified in about 10% of individuals with familial pulmonary fibrosis
Surfactant protein C
TERT (telomerase reverse transcriptase)
TERC (telomerase RNA component )

16. Case 2: Inflammatory Bowel Disease (IBD)

17. Case Presentation
78-year-old female in relatively good health presented in 2005 with diarrhea, abdominal pain, and fever
Colonoscopy revealed inflammatory colitis (ulcerative colitis) and she was treated with mesalamine
Two months later she developed fever, diarrhea, and flu-like illness associated with cough and bibasilar crackles on physical examination
Chest radiograph revealed minimal increase in chronic interstitial markings
A diagnosis of therapy-related pneumonitis was established clinically
Mesalamine was discontinued and budesonide enemas substituted

18. Case Presentation Medical History Examination
Ex-smoker, 7.5 pack-years
Fistula repair 20 years before
History of psoriasis
Family history of Crohn’s disease
Examination
Physical exam
BP 149/81 P R 14
Weight = 116 lb ( kg)
SpO2 = 97% on oxygen supplementation
Pertinent findings
Bibasilar rales, rare squeaks
No clubbing

19. CT 12/19/05
Upper Lobes
Carina

20. CT 12/19/05, Lower Lobes

21. CT 12/19/05 Upper lobe tubular bronchiectatic changes
Surrounding lung with hazy opacities
Patchy areas of similar appearance in lower lobes

22. Clinical Course
Recurrent febrile episodes associated with abdominal pain and profuse mucousy diarrhea
In January 2008, she presented with cough, phlegm expectoration, dyspnea on effort, hypoxemia, fatigue, and malaise
No associated fever, chest pain, arthralgias, or hemoptysis
She was treated with moxifloxacin and low-dose corticosteroids
She improved but did not regain fully her previous functional status
Dyspnea on exertion progressed
Repeat CT scan in May 2008 showed progressive changes: increased interstitial markings and diffuse ground-glass opacities

23. CT 5/20/08, Upper Lobes

24. CT 5/20/08, Carina

25. CT 5/20/08, Lower Lobes

26. Radiology Summary CT findings CXR (data not shown)
Ground glass densities
Bands of interstitial changes
Focal honeycombing
Traction bronchiectasis
Peribronchial inflammation
Distribution: not predominantly peripheral
CXR (data not shown)
Increased interstitial markings
Relatively well-maintained lung volumes

27. Clinical Course 2008
Pulmonary function, O2 saturation, and HRCT were abnormal
Test results for collagen vascular disease, vasculitis (ANCA), and HP were negative
Mild hypogammaglobulinemia
6/25/08 VATS lung biopsy
Date
FVC
FEV1
TLC
DLCO
Vol, L
% pred
4/25/07
2.1 86
1.69
102 73 55
5/20/08
1.68 71
1.39 79 70 34
6/11/08
1.81 76
1.55 88 35

28. Peribronchial Chronic Inflammation and Bronchiolar Metaplasia of Adjacent Alveolar Spaces
Medium power image of small airway
Image courtesy of Dr. MB Beasley

29. Chronic Inflammation and Remodeling; Bronchiolar Metaplasia
Higher power view of small airway
Image courtesy of Dr. MB Beasley

30. Foamy Macrophages in Alveolar Spaces Suggest Airway Obstruction
Image courtesy of Dr. MB Beasley

31. Subpleural Architecture: Focal Fibrosis and Emphysema
Image courtesy of Dr. MB Beasley

32. Histopathology Sampling Findings Review by independent pathologist
Right upper, middle, and lower lobe
Wedge biopsies
Findings
Chronic interstitial pneumonia
Focal granulomatous inflammation
Interstitial fibrosis
Review by independent pathologist
Diagnosis confirmed
Process is accentuated around bronchioles suggesting HP or infection such as mycobacteria
No serologic evidence of HP
No growth of mycobacteria detected

33. Clinical Course 2008-2010 Corticosteroid treatment, improved condition
Relapse of respiratory symptoms and radiographic findings with lowering of corticosteroids
Activity of IBD associated with respiratory symptoms
Pulmonary exacerbations managed with
Immunosuppressive agents
IVIG infusions
Periodic antibiotics
Chronic macrolide treatment
Mucolytics
Increased doses of corticosteroids

34. PFT Update
Date
FVC
FEV1
TLC
DLCO
Vol, L
% pred
4/25/07
2.1 86
1.69
102 73 55
5/20/08
1.68 71
1.39 79 70 34
6/11/08
1.81 76
1.55 88 35
4/28/10
2.07 83
1.74 94 48
7/21/10
1.89 75
1.53 54
Decline of PFTs on 7/21/10 coincided with activity of IBD, prednisone dose increased

35. Clinical Course Summary
2005 initial presentation
Resolution of acute symptoms but persistence of abnormal CT
2007 exacerbation of pulmonary symptoms
Treatment of IBD and pulmonary manifestations with steroids
2008 exacerbation – VATS biopsy
Treatment with corticosteroids, immunosuppressive agents (IS), macrolides
management of disease with steroids, IS, IVIG, antioxidants, and macrolides leads to clinical stability

36. Case Summary
Onset of pulmonary disease after many years of inflammatory bowel disease
Pulmonary disease manifested initially with mesalamine treatment
Lung disease is airway-centered but with evidence of ILD
Response and stabilization with multidrug therapy

37. Pulmonary Aspects of IBD
Pulmonary manifestations more common in ulcerative colitis than Crohn’s
Airways more commonly involved than parenchyma
Pulmonary symptoms usually follow IBD diagnosis

38. Pulmonary Aspects of IBD
Symptoms1,2
Present in 44–48% of patients with IBD
Cough, phlegm expectoration, wheezing, and dyspnea
Association with asthma and IBD-Asthma more severe in this setting
PFT abnormalities
Most common: decreased diffusing capacity
Airway reactivity may be present (detected with methacholine challenge)
Songür N, et al. J Clin Gastroenterol. 2003;37:
Douglas JG, et al. Respir Med. 1989;83:

39. Pulmonary Aspects of IBD: HRCT
Abnormalities in 53% of patients with IBD1
Air trapping, GGO, peripheral reticular opacities, and cysts
Nodules
Bronchiectasis
COP and ILD patterns may also be detected
Songür N, et al. J Clin Gastroenterol. 2003;37:

40. Pulmonary Aspects of IBD
Bronchiectasis
Most common pulmonary manifestation of IBD (in ~66% of patients with airway manifestation)
Exacerbations may occur in close proximity to colonic resection
Small airways less frequently involved than larger airways
With small airway involvement, bronchiolitis is the most common finding
Can be associated with granuloma formation
IBD pulmonary manifestations may be confused with HP or infection
Upper airways are least frequently involved
Parenchymal involvement
Histologic patterns reported: chronic organizing pneumonia, HP, desquamative interstitial pneumonia, NSIP, fibrosing lung disease

41. Pulmonary Aspects of IBD: Histology
Features
Microscopic granulomas sometimes present
Nodules (may be necrobiotic)
Airway-centered inflammatory process
Bronchiectasis
Histologic patterns similar to the idiopathic interstitial pneumonias can also be seen
The predilection for airway involvement and the degree of associated inflammation contrasts with UIP in cases with parenchymal manifestations

42. IBD Summary
Thoracic manifestations of inflammatory bowel disease are frequent and underdiagnosed
Bronchiectasis and airway abnormalities most common
Pulmonary function studies: decreased diffusing capacity
Pathology: interstitial and airway inflammation, granulomas may be present
IBD therapy may induce lung disease
Sulfasalazine
Mesalamine
Methotrexate
Treatment of IBD-associated lung disease
Corticosteroids
Immunosuppressive agents
Disease-modifying agents to treat IBD