Idiopathic Pulmonary Fibrosis Diagnosis Treatment and Management ISCHR

Idiopathic Pulmonary Fibrosis: Diagnosis, Treatment, and Management ISCHR Conference March 5, 2016 Wendi R Mason, MSN, ACNP-BC Program Director Interstitial Lung Disease Program at Vanderbilt

Idiopathic Pulmonary Fibrosis A specific form of 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 UIP. Symptom onset to diagnosis is 1. 5 years Diagnosis to death is 3. 8 years

Case Study: JWM • 67 year old WM presented in early 2014 for shortness of breath concerning for IPF. Earlier had been dx’d with COPD and given inhalers More recently, had CT and nondiagnostic bronch Referred to our Center • Symptoms: shortness of breath with exertion; rare cough • ROS: • • • EENT: glasses, no dysphagia, + snores Card: no chest pain or pressure GI: reflux with OTC tums for relief Musculoskel: OA in right shoulder, right knee; no clubbing; Derm: no rash

IPF: Clinical Presentation Consider IPF in all adults with unexplained chronic exertional dyspnea which commonly presents with cough, bilateral crackles, and finger clubbing. Incidence increases with older age with typical presentation between 60 and 70 years old. A presentation younger than 50 years may be familial in nature. Slightly more men than women. Estimated 130, 000 persons in the US with IPF, with about 40, 000 cases diagnosed annually.

JWM: Past Medical History GERD HTN Hyperlipidemia Obesity (BMI 35. 4) Medications: • Coricidin prn • TUMS prn No macrodantin, bleomycin Reivew of outside records: CT chest – patchy areas of subpleural increased reticulation, suggestion of bronchiolectasis versus less likely early honeycombing, suggestion of ground glass opacities; distribution is subpleural with lower lung zone involvement. Concern for NSIP, less likely UIP, collagen-vascular disease vs HP vs. infection. Transbronchial biopsy – neg for tumor

IPF: Comorbidities Gastroesophageal Reflux Disease (GERD) Obstructive Sleep Apnea (OSA) Pulmonary Arterial Hypertension (PAH) Coronary Artery Disease (CAD) Hypothyroidism Obesity Emphysema

JWM: Social History Retired cement plant employee of 40+ years Started out doing repairs on machines, advanced to safety and training; usually wore masks and had abbreviated exposure to asbestos in walls. Currently drives a van locally Et. OH – 1 -2 beers a week No h/o illicit drugs Cigarette use for 2 weeks in high school Pets: 3 dogs, no birds Hobbies: races cars, rides motorcycles

IPF: Risks Although by definition, IPF is a disease of unknown etiology, there a number of risk factors: cigarette smoking (20+ pack years) environmental exposures (wood dust, metal dusts) certain viruses (EBV, CMV, HHV) GERD (acid and alkaline GER) familial

JWM: Family History Father – deceased 69 yo with CAD, MI Mother – deceased 75 yo with lung cancer, heavy smoker Brother – MI, renal failure, hyperlipidemia No cirrhosis No bone marrow disease No fibrotic lung disease

IPF: Genetic Factors Currently accounting for about 5% of the IPF population, familial forms of IPF occur where two or more members of the same primary biologic family are diagnosed. TERT TERC telomere length dyskeratosis congentia, anemias, liver diseases

JWM: Exam P 69, BP 116/82, RR 33, Wt 240 lbs, 95% RA at rest, afebrile ENT - tympanic membranes clear bilaterally; nares patent, oropharnyx is clear with grade IV mallampati airway Neck - no lymphadenopathy, trachea midline, no thyroid mass Lungs - bibasilar velcro crackles, lung sounds throughout, no wheezes CV - RRR with no murmur, S 3 or S 4 GI – abd is soft, nontender, nondistended, with bowel sounds throughout Musculoskeletal - no cyanosis, no clubbing, no edema Skin - no rashes or ecchymosis Neurologic – alert and oriented x 4, CN II-XII intact, strength intact, normal gait

JWM: Procedures Labs • • CBC, CMP, CPK - wnl ANA +, smooth, 1: 40 RF 3 Scl. Ab: < 0. 1 Pulmonary Function • • • FVC 2. 75 L 62% FEV 1 2. 35 L 69% FEV 1/FVC ratio 85 TLC 4. 14 L 61% DLCO 18. 5 m. L/mm. Hg/min 58% 6 Minute Walk Testing – walked 1050 feet with room air, no desaturation

JWM: Dx and Initial Plan Interstitial Lung Disease concerning for IPF by history and exam, restrictive pattern on PFTs: • Return for HRCT of chest and 2 D echocardiogram Referred to GERD clinic for evaluation: • Nexium 40 mg daily Elevated BMI: • Weight loss efforts through exercise and diet h/o snoring and disturbed sleep concerning for OSA: • Refer for NPSG Pneumovax

JWM: Return Appointment No change on history, physical exam Pulmonary Function: FVC 2. 68 L 61% FEV 1 2. 27 L 67% FEV 1/FVC ratio 85 TLC 57% Dl. CO 17. 6 m. L/mm. Hg 56% NPSG: AHI 20. 4, being set up for cpap titration Echocardiogram: Mild concentric LVH, with mildly dilated LA; LVEF > 55% No evidence to support pulmonary hypertension

JWM: Return Appointment HRCT of Chest • Diffuse areas of peripheral septal thickening involving all lobes of both lungs with sparing of the extreme lung apices • Several areas of bronchiectasis of lower lobes and RML. • Scattered areas of bronchiolectasis at the periphery • Evidence of early honeycombing at the lung bases • Minimal ground glass opacities seen at the bases • No significant air trapping • No pleural effusion • Changes are persistent on prone imaging and expiratory imaging. Consistent with UIP

IPF: HRCT Features of UIP HRCT is essential in diagnosing IPF, with the finding of honeycombing critical for a definitive diagnosis. Definitive UIP: subpleural, basal predominance reticular abnormality honeycombing with or without traction bronchiectasis absence of features associated with “inconsistent” Possible UIP Inconsistent UIP: upper or mid-lung predominance; peribronchovascular predominance, extensive ground glass, profuse micronodules, discrete cysts, diffuse mosaic attenuation or air-trapping in three or more lobes; consolidation in bronchopulmonary segments or lobes.

IPF: Histopathology Features of UIP Key findings on biopsy include: heterogeneous appearance at low magnification in which areas of fibrosis with scarring and honeycomb change alternate with area of less affected or normal parenchyma inflammation is usually mild subepithilial foci of proliferating fibroblasts and myofibroblasts (the “fibroblastic foci”) honeycomb change are usually cystic fibrotic airspaces that are frequently lined by bronchiolar epithelium and filled with mucus and inflammatory cells

IPF: Diagnostic Criteria A thorough medical, occupational/environmental and family history, physical examination, physiological testing, laboratory evaluation, and the presence of a UIP pattern on HRCT is sufficient for diagnosis. Diagnosis requires the following: 1. Exclusion of other known causes of ILD 2. The presence of a UIP pattern on HRCT 3. Specific combinations of HRCT and surgical lung biopsy UIP pattern Surgical lung biopsy is no longer essential. Diagnostic accuracy increases with clinical, radiologic, and histopatholgic correlation, or a multidisciplinary discussion (MDD).

JWM: Dx and Plan Idiopathic Pulmonary Fibrosis Treat with oral pirfenidone or nintedanib Not a candidate (currently) for lung transplant (weight, age) Comorbidities Hypertension and Hyperlipidemia • Refer to Cardiology HTN Clinic or PCP for management Obstructive Sleep Apnea • Schedule cpap titration Referred to GERD clinic for evaluation • Nexium 40 mg daily Obesity • Weight loss efforts through exercise and diet

IPF Treatments FDA Approved Oral Treatments Pirfenidone and Esbriet Non-Pharmaceutical Treatments Oxygen, Pulmonary Rehabilitation, Vaccines Clinical Drug Trials Lung Transplantation Palliative and Hospice Care

IPF Treatments: Oral Therapy Pirfenidone / Esbriet® Nintedanib / Ofev ® Reduced the proportion of patients with a 10% decline in FVC: 35% to 17% (a 48% change) Reduced the mean decline in m. L FVC: 240 m. L to 115 m. L (a 48% change) Increased stability evidenced by no decline in FVC: 10% to 23% (a 132% increase) Reduced the mean decline in m. L FVC: 428 m. L to 235 m. L (a 45% change) Increase in time to 1 st Acute Exacerbation: 9. 6 % to 3. 6 % (a 37. 5% change)

IPF Treatments: Oral Therapy Pirfenidone / Esbriet® Adverse Reactions: nausea (36%)(2% dc’d) other GI: abd pain, bloating, dyspepsia, vomiting, GERD, anorexia, weight loss fatigue (26%) photosensitivity (9%) liver enzymes (3. 8%) Nintedanib / Ofev ® Adverse Reactions: diarrhea (62%)(4. 5% dc’d) other GI: nausea, abd pain, bloating, dyspepsia, vomiting, GERD, anorexia, weight loss liver enzymes (14%) headache (8%) elevated bp (5%)

IPF Treatments: Oral Therapy Pirfenidone / Esbriet® Nintedanib / Ofev ® Risks: No fluoxetine No enoxacin Cipro 750 mg BID Hepatic Impairment? Use with caution in Child-Pugh Class A, B; do not use with Class C Renal Impairment? Use with caution Smoking causes decreased exposure to pirfenidone Risks: Arterial Thromboembolic Events MI 1. 6 % CVA Bleeding (nintedanib is a VEGFR inhibitor, therefore, use with caution with full anticoagulation therapy) Hepatic Impairment? Use with caution in Child-Pugh Class A; do not use with Class B, C

IPF Treatments: Oral Therapy Pirfenidone / Esbriet® Nintedanib / Ofev ® Oral treatment 267 mg Oral treatment 150 mg 3 capsules three times daily 1 capsule twice daily with food full dose 300 mg d titration to full dose 2403 mg daily Liver function monitoring: Initiation, monthly x 6 months, then quarterly Liver function monitoring: Initiation, monthly x 3 months, then quarterly

IPF Treatments: Non-Pharma Supplemental Oxygen Support Medicare requirements support desaturation to 88% or lower Pulmonary Rehabilitation Medicare requirements for restrictive patterns: FVC equal to or less than the values in a height-based chart (70 -71 inches -> 1. 75 L or less) DLCO < 10. 5 m. L/min/mm. Hg or < 40% ABGs according to charts based on altitude and comparing arterial PCO 2 and arterial PO 2. Vaccines influenza annually pneumonia PCV 13 (once) PPSV 23 (up to 3 doses q 5 years)

IPF Treatments: Clinical Trials AF-219 vs placebo BG 0001 vs. placebo CC-90001 (100 mg vs. 200 mg) FG-3019 vs. placebo Lebrikizumab vs. placebo Nintedanib +/- pirfenidone Pirfenidone + nintedanib Riociguat vs. placebo

IPF Treatments: Lung Txplnt Each Center in the US has specific guidelines for their programs. Indications for Transplant Referral for IPF at Vanderbilt: referral at the time of diagnosis TLC < 60% supplemental oxygen use secondary pulmonary hypertension clinical decline (> 10% loss of FVC in 6 months)

IPF Treatments: Lung Txplnt Absolute Contraindications: Active tobacco use Active substance abuse History of cancer within past 2 years beliefs prohibiting blood transfusions ventilator dependence (continuous cpap / endotrachial) history of HIV, chronic Hep. C, Burkholderiea cenocepacia infections severe comorbidities: DM with end organ damage (nephropathy, retinopathy) impaired renal function (GFR < 50) severe CAD: left main, three vessel impaired cardiac function CTD/Autoimmune causing sign renal, GI, esophageal, or liver dz Inadequate social support History of medical noncompliance

IPF Treatments: Lung Txplnt Relative Contraindications: osteoporosis with symptomatic fractures stented 1 or 2 vessel CAD previous chest wall surgery chronic narcotic use BMI < 17; BMI > 30 cancer within 2 -5 years Age > 69, age < 14 uncontrolled infection

IPF Treatments: Palliative Care The focus of palliative care is to reduce symptoms and provide comfort to patients. The primary goal is relief of suffering, both physical and emotional. Advanced directives and end-of-life care issues should be addressed.

IPF Management Natural History 10% Seemingly stable 80% Gradual decline 10 % Acute Exacerbation of IPF (acute decline after ruling out other causes of acute respiratory worsening) Those at increased risk of mortality at baseline presentation include those with increased dyspnea, DLCO < 40%, desat < 88% during 6 MWT, greater extent of honeycombing on HRCT, or pulmonary hypertension Those at increased risk of mortality longitudinally are those who lose > 10% FVC or > 15% in DLCO in 12 months, have increased dyspnea and/or hypoxemia, or worsening fibrosis on HRCT.

IPF Management: Symptoms Dyspnea oxygen therapy Fatigue pulmonary rehabilitation Cough benzonatate hydrocodone/chlorpheniramine syrup

IPF Management: Dz Progression Pulmonary Function Tests FVC DLCO 6 Minute Walk Test oxygen saturation on room air, or previously prescribed oxygen liter flow HRCT if PFTs change significantly

IPF Management: Comorbidities GERD PPI, even in asymptomatic GER Referral to GI PAH limited data on treatment of PAH due to IPF sildenafil may improve quality of life recommendation: reasonable treatment for some OSA cpap/bipap CAD/HTN referral to cardiology

JWM: Today Current Comorbidities: HTN/Hyperlipidemia OSA, excellent compliance with cpap GER basal cell carcinoma obesity (BMI 34. 9) Current Medications: Started pirfenidone on 12/2014; full dose maintained Started amlodipine, asa, and simvastatin by cardiologist GER controlled with omeprazole daily oxygen 4 L/min/nc with exertion

JWM: Today Pulmonary Function (01/28/2016) FVC 1. 97 L 49% DLCO 7. 94 m. L/min/Hg 33% One year prior (11/06/2014): FVC 2. 12 L / 52% [150 m. L or 7% loss] DLCO 11. 75 / 47% [32. 1% loss] 6 MWT 880 feet on 3 L with desat to 87% One year prior: 800 feet on 3 L with desat to 94%

JWM: Today, so… What now? - Decline in FVC by 7% in one year - Sharp decline in DLCO by > 15% in one year - 80 feet further in walk distance, however, reduced saturation with the increased effort. Treatment Plan: Continue pirfenidone at full dose Continue PPI, other comorbidity treatments Continue supplemental oxygen at 4 L Consider re-evaluation of pulmonary hypertension by echo Consider enrollment in clinical trial Enroll in Pulmonary Rehabilitation Weight loss Ensure vaccines remain up to date Not interested in Lung Transplant Consider introduction to Palliative Care Return in 3 months with PFTs, 6 MWT

wendi. mason@vanderbilt. edu 615 -343 -7068