Chapter 6.1 Living Medical etextbook A Digital Tool at the Point of Care From Projects In Knowledge Pulmonology Idiopathic Pulmonary Fibrosis @Point of Care IPF Case Study: Typical Presentation, Role of Surgical Lung Biopsy, and Acute Exacerbation Editor-in-Chief: Maria L. Padilla, MD Contributing Editor: Sakshi Dua, MD Contributing Editor: Kevin O. Leslie, MD Contributing Editor: Mary M. Salvatore, MD Medical Writer: Sara N. Fischer, PhD This independent CME/CE activity is supported by an educational grant from. This CME/CE activity has reached its termination date and no longer offers continuing education credit. Please note that expired CME/CE activities may not contain the most up-to-date information available. Introduction This case highlights a patient with typical presentation of idiopathic pulmonary fibrosis (IPF). According to the official American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) statement on IPF1 published in 2011, a surgical lung biopsy (SLB) is not considered necessary for a definitive diagnosis of IPF if imaging shows typical usual interstitial pneumonia (UIP) radiologic findings in an appropriate clinical setting. The importance of weighing the risk-benefit ratio of subjecting a patient to SLB should be considered. The concept of acute exacerbation of IPF (AEIPF) is discussed in this context and in general. Case Presentation Patient Assessment A 65-year-old male presents with the complaint of slowly worsening shortness of breath with exertion over the past 2 years. He has a dry cough without diurnal variation. The patientâ s exercise tolerance has slowly declined to a point where he feels short of breath when walking less than half a block on a flat surface. The patient has no significant past medical history with the exception of mild gastroesophageal reflux disease (GERD). The patient is not on any medications currently. He is an ex-smoker with a 40-pack-year history of smoking cigarettes, having quit smoking 3 years ago. He has no occupational exposures to dust, gases, fumes, or vapors. There is no significant family history of lung diseases. Upon examination the patient has Velcroâ -like rales in both lower lung fields. He has clubbing of his digits. A pulse oximeter shows 90% saturation (SpO2) on room air, which declines to 86% with ambulation in the office hallway. Routine labs show that his cell counts, electrolytes, liver function, and renal function are all within the normal ranges. Connective tissue disease serologies are performed and are found to be within normal limits (Table 1). -Table 1- Table 1. Connective Tissue Disease Serology Results -End Table- Pulmonary function tests reveal no obstructive defect, but a severe restrictive defect and severe gas exchange abnormality are present (Table 2). -Table 2-
Table 2. Pulmonary Function Test Results -End Table- Radiology The chest x-ray demonstrates the characteristic plain film findings of interstitial lung disease (Figure 1). Low long volumes are noted, which are characteristic of this restrictive lung disease. There is prominence of the interstitial markings with a peripheral basilar distribution. The costophrenic angles are involved and honeycombing is most readily appreciated on lateral projection in the posterior costophrenic angle. The known pulmonary artery enlargement and lymphadenopathy are suboptimally evaluated on this two-dimensional exam. -Figure 1- Figure 1. Chest X-ray Findings The radiographic guidelines1 for the computed tomography (CT) diagnosis of UIP include: subpleural, basal predominance, reticular abnormality, honeycombing with or without traction bronchiectasis, and absence of features listed as inconsistent with UIP pattern, including upper or midlung predominance, peribronchovascular predominance, extensive ground glass abnormality, profuse micronodules, discrete cysts, diffuse mosaic attenuation/airtrapping, and consolidation in the bronchopulmonary segment(s)/lobe(s). The CT scan is obtained in the supine position with a 1.25-mm collimation and a lung algorithm. No intravenous contrast was administered to the patient. Subpleural involvement, basal predominance, reticular abnormality, honeycombing with traction bronchiectasis, and absence of features listed as inconsistent with UIP pattern, particularly no significant ground glass opacity, are noted on CT (Figure 2). -Figure 2-
Figure 2. Supine CT Findings Prone CT images are beneficial for evaluating interstitial lung disease and differentiating it from dependent changes found on supine images (Figure 3). The pulmonary artery is enlarged, measuring 3.5 cm in transverse diameter. -Figure 3- Figure 3. Prone CT Findings In addition, there are prominent mediastinal lymph nodes, which often accompany interstitial lung disease (Figure 4). -Figure 4- Figure 4. Prone CT Findings Showing Prominent Mediastinal Lymph Nodes Pathology A decision is made to perform lung biopsies using video-assisted thoracoscopic surgery. Multiple wedge biopsies are performed from the right upper, middle, and lower lobes for pathologic examination (Figure 5). -Figure 5-
Figure 5. Initial Surgical Lung Biopsy Findings The SLBs all show similar changes. At very low magnification, the characteristic patchwork appearance of dense scarring alternating with normal lung is observed, which is an essential element to the diagnosis of UIP (Figure 5). The second most important feature to note is the presence of advanced honeycomb cystic remodeling (Figure 6), found commonly even in the earliest cases of UIP. These small groupings of mucous-filled cysts lined by respiratory columnar epithelium are surrounded by scarring on three sides, helping to distinguish microscopic honeycombing from chronic small airway remodeling, where mucous also may be seen in poorly demarcated partial cysts (eg, as seen in chronic hypersensitivity pneumonitis). -Figure 6- Figure 6. Microscopic Honeycomb Remodeling UIP must have zones of normal lung between areas of scarring, as illustrated in Figure 5. Another distinctive element of UIP is smooth muscle proliferation in subpleural scar tissue (Figure 7); this feature alone should always raise consideration of a UIP diagnosis in any case of pulmonary fibrosis. -Figure 7- Figure 7. Smooth Muscle Hyperplasia
The final element required for a diagnosis of UIP is the â œfibroblastic focusâ ï ½ (Figure 8), invariably present in UIP but not exclusive to this disease process. -Figure 8- Figure 8. Fibroblastic Focus of Usual Interstitial Pneumonia Diagnosis The patient is diagnosed with UIP based on histopathology, and a clinical-radiologic-pathologic diagnosis of IPF is established. Treatment The patient is discharged on postoperative day 3 on supplemental oxygen with plans for referral to a clinical trials coordinator for possible enrollment in a clinical trial. Plans are also made to refer the patient for lung transplant evaluation. Disease Course The patient returns for a post-op check 4 weeks later and is found to be in moderate respiratory distress. He notes that he has been feeling worse for the past 3 weeks with increasing shortness of breath and dry cough. The patient is unable to finish complete sentences without pausing for breath. The patient is tachypneic and SpO2 on room air is 79%. Lung exam shows diffuse coarse rales throughout both lung fields. Chest X-ray is immediately performed. A chest CT angiogram is obtained to rule out pulmonary thromboembolism. Chest CT obtained to evaluate respiratory distress demonstrates low lung volumes with peripheral basilar honeycombing. There are new diffuse ground glass opacities accentuating the previously seen traction bronchiectasis (Figure 9). -Figure 9- Figure 9. Chest CT Findings During Evaluation of Respiratory Distress
The patient requires intubation and mechanical ventilation due to acute respiratory failure. A bronchoscopic examination with bronchoalveolar lavage fails to reveal any infectious pathogens. Despite maximal supportive therapy, the patient succumbs to his illness on day 4 of his stay in the intensive care unit. An autopsy is performed and lung pathology shows acute injury superimposed on background fibrous remodeling of UIP, consistent with AEIPF (Figures 10 and 11). -Figure 10- Figure 10. Acute Exacerbation of IPF at Autopsy -Figure 11- Figure 11. Organizing Diffuse Alveolar Damage at Autopsy Discussion This case highlights several aspects of diagnostic considerations and disease course of patients with IPF. Patients with IPF are typically male, in the age range of 50 to 70 years.1 They typically present with slowly progressive chronic symptoms of dyspnea on exertion and dry cough.1 Risk factors include smoking and GERD.1 Familial IPF can present at a slightly earlier age.1 Physical examination findings of Velcroâ -like rales and digital clubbing aid in pointing towards the diagnosis. Chest X-ray often shows decreased lung volumes and increased interstitial markings, especially in basilar distribution with a peripheral predominance. HRCT scan of the chest is indispensible in evaluation, as a typical CT scan for UIP can obviate the need for SLB. The typical UIP pattern on HRCT includes1: 1. Subpleural and basal predominance
2. Reticular abnormality 3. Honeycombing with/without traction bronchiectasis 4. Absence of features inconsistent with UIP pattern (such as upper or mid-lung predominance, peribronchovascular predominance, extensive ground glass abnormality), profuse micronodules, mosaic attenuation/air trapping, or consolidation According to the official 2011 ATS/ERS/JRS/ALAT statement on IPF,1 SLB is not necessary to make a definitive diagnosis of IPF if imaging shows a typical UIP pattern of abnormalities in an appropriate clinical setting. SLB is reserved for patients who do not meet typical radiographic criteria for UIP. The typical histopathologic UIP pattern includes1: 1. 2. 3. 4. Evidence of marked fibrosis, architectural distortion, plus or minus honeycombing in a predominantly subpleural or paraseptal distribution Presence of patchy involvement of the lung parenchyma by fibrosis Presence of fibroblastic foci Absence of features against a diagnosis of UIP, suggesting an alternate diagnosis (such as organizing pneumonia, granulomas, marked interstitial inflammation, or airwaycentered changes) This patient had typical radiographic findings and in the absence of any known exposures to drugs or occupational dusts, which should have been adequate to establish the diagnosis of IPF once connective tissue disease was screened for. Given the large number of negative clinical trials, no known medication regimens have conferred a survival benefit to IPF patients. Median survival time is generally 2 to 3 years from the time of diagnosis.1 Clinical trial enrollment and lung transplant evaluation (in the absence of absolute contraindications) should also be offered to these patients. Additionally, after establishing a diagnosis, care is best provided by searching for and treating comorbidities, such as GERD and obstructive sleep apnea.1 Pulmonary rehabilitation is considered an essential part of care for IPF patients.1 Although the traditional view of the natural history of the IPF disease course is that of slowly progressive decline, in a small minority of patients (5%∠10%) there is an acute worsening of symptoms termed AEIPF (after ruling out conditions such as pneumonia, pulmonary thromboembolism, pneumothorax, and cardiac ischemia). The onset of worsening dyspnea and hypoxemia occurs over 1 month and is associated with diffuse bilateral alveolar opacities on chest X-ray. HRCT scan confirms alveolar filling process over a background of UIP changes. Histologically one sees acute (often diffuse alveolar damage) or organizing injury patterns superimposed on background lung showing advanced fibrosis and remodeling. When acute exacerbation of IPF occurs, the histopathology reflects acute injury (Figures 10 and 11), historically thought to only be only as â œdiffuse alveolar damage.â ï ½ In reality, other patterns of acute injury emerge in these patients, which is an important fact for pathologists to consider when reviewing lung biopsies where background fibrosis suggests UIP pattern lung pathology. AEIPF is a uniformly fatal condition with no known treatments.1 In this case, the stress of thoracic surgery may have precipitated AEIPF.1 This is a rare but serious complication of surgical lung biopsy. Hyperoxia, oxidative stress, and cytokine release have been considered as possible precipitating factors in this setting.2,3 Conclusion IPF typically presents in 50- to 70-year-old adults with slowly progressive dyspnea on exertion and dry cough. Patients with typical radiographic UIP pattern need not undergo SLB in the correct clinical setting to establish the diagnosis. Patients with IPF should be referred for clinical trial enrollment and lung transplant evaluation due to lack of established medical therapies known to enhance survival. AEIPF is a highly mortal complication with no known effective treatments. References 1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824. Ghatol A, Ruhl AP, Danoff SK. Exacerbations in idiopathic pulmonary fibrosis triggered by pulmonary and nonpulmonary surgery: a case series and comprehensive review of the literature. Lung. 2012;190:373-380. Yano M, Sasaki H, Moriyama S, et al. Post-operative acute exacerbation of pulmonary fibrosis in lung cancer patients undergoing lung resection. Interact Cardiovasc Thorac Surg. 2012;14:146-550. Copyright 1997-2018, Projects In Knowledge, Inc. All rights reserved. PROJECTS IN KNOWLEDGE is a registered trademark of Projects In Knowledge, Inc. LIVING MEDICAL ETEXTBOOK is a trademark of Projects In Knowledge, Inc. PROJECTS IN KNOWLEDGE 290 W. Mt. Pleasant Avenue, Suite 3150 Livingston, New Jersey 07039 (973) 890-8988