Case 1: Familial IPF

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

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

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

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

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

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

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

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

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

Serial PFTs 10/20/09 3/8/10 (Symptom onset) 5/26/10 FVC 1.15 0.91 0.92 41 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

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

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 )

Case 2: Inflammatory Bowel Disease (IBD)

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

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 105 R 14 Weight = 116 lb (52.617 kg) SpO2 = 97% on oxygen supplementation Pertinent findings Bibasilar rales, rare squeaks No clubbing

CT 12/19/05 Upper Lobes Carina

CT 12/19/05, Lower Lobes

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

Clinical Course 2006-2008 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

CT 5/20/08, Upper Lobes

CT 5/20/08, Carina

CT 5/20/08, Lower Lobes

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

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

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

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

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

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

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

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

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

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 2008-2010 management of disease with steroids, IS, IVIG, antioxidants, and macrolides leads to clinical stability

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

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

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;37:292-298. Douglas JG, et al. Respir Med. 1989;83:389-394.

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;37:292-298.

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

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

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