THE IPF EXPERT EXCHANGE

The Honeycomb Network

This is a newsletter series in the continuing educational program designed to bring you articles by leading Canadian specialists who are experts in fibrosing diseases.

Dr. Gerard Cox is a respirologist and Professor of Medicine at McMaster University. He is past-President of the Canadian Thoracic Society as well as Director of the Division of Respirology at the Firestone Institute for Respiratory Health, at St. Josephs Healthcare Hamilton (FIRH-SJHH). In addition to general respirology, Dr. Cox has a special interest in interstitial lung diseases such as pulmonary fibrosis and sarcoidosis. In association with Dr. Martin Kolb, he runs a dedicated clinic at FIRHSJHH, caring for patients with these uncommon disorders. Dr. Coxs research interests focus on mechanisms of disease and development of novel strategies for diagnosis and therapy based on improved understanding of how respiratory diseases arise.

Idiopathic Pulmonary Fibrosis: optimizing the diagnosis and multi-disciplinary decision making
By Gerard Cox, MD, MB, FRCPCI, FRCPC Learning objectives: 1. Recognize the need for early diagnosis 2. Explain the current diagnostic algorithm for IPF 3. Explain the importance of a multi-disciplinary approach to diagnosis
Idiopathic Pulmonary Fibrosis (IPF) is characterized by progressive deterioration in lung function, due to fibrosis and inflammation, with a median survival from the time of diagnosis of only 2-5 years.1 Early diagnosis is important for optimal disease management, whether through clinical treatment or timely patient referral for lung transplantation assessment. There are well established criteria for the diagnosis of IPF. Some patients however do not present with clear findings, in which case multi-disciplinary decision making has been shown very effective for arriving at correct diagnosis.2 This newsletter will discuss the diagnostic process and provide tools for differentiating IPF from other interstitial pneumonias. The information is based on the Section 1 Accredited Group Learning Activity co-developed with the Canadian Thoracic Society and presented at the Canadian Respiratory Conference in Quebec City in April 2013.

Upcoming newsletters:
IPF: understanding the natural history and epidemiology of this fatal disease by Dr. Charlene D.

Fell, BSc, MD, FRCP

How recent randomized controlled trials inform clinical treatment of IPF: the therapeutic trials roller coaster ride by Dr. Charles K.N.

Early diagnosis of IPF can prolong life IPF is a chronic, debilitating, fatal disorder of unknown etiology. It is characterized by the deposition of extracellular matrix which causes an architectural distortion of the lungs and interstitium, with minimal associated inflammation.3 The onset of symptoms is gradual, with an asymptomatic period lasting from months to years. However, once the symptoms manifest themselves, the disease progression is often very rapid, causing death by respiratory failure within 2-5 years.1 The rapid onset of symptoms limits the opportunity for clinical treatment, hence an early accurate diagnosis of IPF can be life saving to the patient. The 2011 American Thoracic Society Clinical Practice Guidelines provide a comprehensive, evidence-based, treatment matrix which includes recommendations for and against specific treatment strategies.4 These include clinical options, such as control of acid reflux and long-term oxygen therapy. Pirfenidone is the only pharmaceutical product that has obtained regulatory approval in Canada for the treatment of adults with mild to moderate IPF. Also, timely referral for lung transplantation can significantly prolong a patients life. In the fall issue of this newsletter series, Dr. Charles K.N. Chan, MD, FRCPC, FCCP, FACP, Professor and Vice-Chair of Medicine at the University of Toronto, will review the management of IPF patients, including a discussion of recent clinical data, pharmacological treatment and limitations of the existing ATS/ ERS treatment guidelines. Recognizing IPF is a challenge The onset of IPF is gradual. The initial symptoms are often limited to exertional dyspnea and dry cough, which are followed by inspiratory bibasilar crackles, fatigue, cyanosis and clubbing of the fingertips.5 The similarity of symptoms to other common diseases, such as asthma, COPD and congestive heart failure, make it challenging to recognize IPF in clinical practice.6 It is important to suspect IPF in any adult over the age of 40 who presents with an unexplained shortness of breath and dry cough. When IPF is advanced, there may be evidence of pulmonary hypertension and congestive heart failure.7 Causes, epidemiology and natural history Despite extensive investigation, the cause of IPF remains unknown. However, an interplay of genetic and environmental factors has been implicated in the disease development. Gene mutations and polymorphisms are present in both hereditary and sporadic IPF. Environmental factors linked to IPF include cigarette smoking, chronic viral infection and gastroesophageal reflux.4 The epidemiology of IPF in Canada is unknown, but estimates suggest that the prevalence is between 4,800 and 14,900 cases and the incidence is between 2,300 and 5,600 new cases per year.8,9,10

Chan, MD, FRCPC, FCCP, FACP If you wish to receive the newsletters by email, wish to subscribe or unsubscribe, or have any questions, please contact:

Anna Liachenko, MSc 514-435-7860 anna@z-zinc.com

Sponsored by an unrestricted educational grant from InterMune. Based on Section 1 Accredited Group Learning Activity co-developed with the Canadian Thoracic Society.

TABLE 1. HRCT criteria for the UIP pattern

De nite UIP pattern (all 4 features)
n

Possible UIP pattern (all 3 features)

n

Inconsistent with the UIP pattern (any of the 7 features)

n

Subpleural basal predominance Reticular abnormality Honeycombing with or without traction bronchiectasis Absence of features listed as inconsistent with the UIP pattern (see the 3rd column)

Subpleural basal predominance Reticular abnormality Absence of features listed as inconsistent with the UIP pattern (see the 3rd column)

Upper lung or midlung predominance Peribronchovascular predominance Extensive ground-glass abnormality (extent > reticular abnormality) Profuse micronodules (bilateral, predominantly upper lobes) Discrete cysts (multiple, bilateral, away from areas of honeycombing) Diffuse mosaic attenuation/air trapping (bilateral, in 3 lobes) Consolidation in bronchopulmonary segments/lobe

Am J Respir Crit Care Med 2011; 183:788-824.

The natural course of IPF is unpredictable.4,6 Some patients decline rapidly, experiencing severe symptoms (so-called rapid progressors with unstable IPF). Other patients may live with milder symptoms for a number of years (so-called slow progressors with stable IPF). Many patients experience either gradual progression or periods of relative stability of symptoms, which are suddenly interjected by episodes of progressive deterioration, often due to an acute exacerbation or infection. More than 50% of patients who are hospitalized with progressive deterioration die in hospital.6,11 For an in-depth discussion of epidemiology and natural history of IPF, see the next issue of this newsletter, authored by Dr. Charlene D. Fell, BSc, MD, FRCP, Associate Professor of Medicine at the University of Calgary and Chair of the Canadian Thoracic Societys Pulmonary Fibrosis Interest Group. Differential diagnosis of Interstitial Lung Disease IPF is part of a group of entities called interstitial lung diseases (ILDs).12 Differentiating IPF from other types of ILDs is a key factor in the diagnostic process. ILDs are a heterogeneous group of more than

Interstitial Lung Diseases

Exposure-related: n Occupational n Environmental n Avocational n Medication Idiopathic interstitial pneumonia Connective tissue disease: n Scleroderma n Rheumatoid arthritis n Sjogren Sarcoidosis Other: n Vasculitis/Diffuse alveolar hemorrhage n Langherhans cell histiocytosis n Eosinophilic pneumonias n Neuro bromatosis n LAM

150 diseases that differ significantly with respect to cause, prevention, therapy and prognosis. Pulmonary fibrosis is the final stage of many different ILDs, including ILDs with a known cause and a subset of ILDs called interstitial pneumonias. IPF is one type of idiopathic interstitial pneumonia.12 Figure 1 shows the different types of ILDs. The first step in the differential diagnosis of IPF is exclusion of any known causes of pulmonary fibrosis, such as occupational and environmental exposures (e.g. radiation, asbestos, ground-stone, metal dust and silica dust) and medication toxicity (e.g. from nitrofurantoin, amiodarone, bleomycin, cyclophosphamide or methotrexate).1 A comprehensive history of all respiratory risk factors and exposures in the past and present should include assessment of occupations, drug therapies, treatments, hobbies, and travel.12 Unfortunately, many patients do not have a clear recollection of the timing or extent of their exposures, making it impossible to establish in many cases whether the exposure was indeed sufficient to cause pulmonary fibrosis. Notably, family history is of special interest in this context, because a considerable number of patients with ILDs have hereditary traits.12 Other differential diagnostic considerations, described in Figure 1, include connective tissue diseases (rheumatoid arthritis and scleroderma/systemic sclerosis), sarcoidosis, chronic hypersensitivity pneumonitis and a number of rare diseases such as pulmonary Langerhans cell histiocytosis, vasculitis and eosinophilic pneumonias. When identifiable causes of ILDs are present, the patient does not have idiopathic pulmonary fibrosis (See Figure 2). Approach to diagnosing IPF Once IPF is suspected based on a patients history and known causes of ILD are excluded, the diagnosis is confirmed by a pulmonary function test and high resolution computed tomography (HRCT).7 Pulmonary function abnormalities in IPF reveal evidence of a restrictive ventilatory defect and an impaired gas exchange. HRCT showing usual interstitial pneumonia (UIP) defined by 4 specific features confirms the IPF diagnosis (See Figure 3). The features are subpleural basal predominance, reticular abnormality, honeycombing with or without bronchiectasis and absence of features inconsistent with the UIP pattern (See Table 1). When all 4 HRCT features are present, in conjunction with the clinical presentation and pulmonary function testing indicative of ILD, further testing is not required.7 The challenge arises when HRCT does not show the clear typical pattern of IPF or when the patients disease history is inconsistent with IPF. At this point, another look at the occupational history as well as serology is warranted. The sensitivity of HRCT is significantly lower than its positive predictive value, thus, in the absence of a characteristic HRCT pattern, the diagnosis of IPF is not ruled out. When HRCT does not show a clear IPF pattern, the potential presence of occult connective tissue diseases (CTDs) or collagen vascular diseases, which can mimic idiopathic interstitial pneumonias, should be considered.13 With the exception of systemic lupus erythematosus, all CTDs may imitate chronic idiopathic interstitial

Idiopathic pulmonary brosis Desquamative interstitial pneumonia Nonspeci c interstitial pneumonia Respiratory bronchiolitis interstitial lung disease Cryptogenic organizing pneumonia Lymphocytic interstitial pneumonia

FIGURE 1. Classification of ILDs. In the diagnosis of IPF, known causes of ILDs must

be excluded. Am J Respir Crit Care Med 2002; 165:277-304.

Diagnostic algorithm
Suspected IPF

Lung biopsy to diagnose IPF: size does matter (1X Magni cation)
TBBx VATS Bx

Identi able cause for ILD? (CTD, drugs, exposures, ...)

YES

NO
Chest HRCT Consistent with UIP Inconsistent with UIP Surgical lung biopsy

Not UIP

UIP

FIGURE 4. Comparison of transbronchial lung biopsy (TBBx) samples and

UIP Possible UIP / Probable UIP Non classi able brosis

samples obtained through a video-assisted thoracic surgery biopsy (VATS Bx).

Multi-disciplinary discussion

IPF

IPF / Not IPF

Not IPF

FIGURE 2. Diagnostic algorithm for IPF. IPF = idiopathic pulmonary fibrosis;

ILD = interstitial lung disease; HRCT = high resolution computed tomography; UIP = usual interstitial pneumonia. Am J Respir Crit Care Med 2011; 183:788-824.

pneumonias and may at times present without extra-pulmonary manifestations.13 The presence of CTDs is assessed by immunological testing. Traditionally, autoantibody tests focused on the rheumatoid factor, however we are now able to measure a number of potentially relevant serologic markers (See Table 2). Diagnosis of CTD provides the patient with a much more favorable prognosis than the diagnosis of IPF. The challenge that needs to be resolved in the future is how to diagnose and treat patients with positive serology but no connective tissue symptoms.

2 mm and therefore are very difficult to interpret. Even with multiple samples, sampling errors can occur.7 Also, IPF is not uniform across the pulmonary lobes. Dense areas of subpleural fibrosis are interspersed with areas of more normal lung tissue. Hence, TBBx samples may contain normal lung tissue even in the presence of pulmonary fibrosis.7 Overall, TBBx is usually more useful in finding other causes of ILD (e.g. granulomatous disease, lymphangitis carcinomatosis, eosinophilic granuloma) than in confirming a diagnosis of IPF. Figure 5 shows microscopy of surgical lung biopsy specimens demonstrating a UIP pattern. A careful assessment of risks (increased in the presence of hypoxia and severe reduction in vital capacity) and benefits is necessary due to significant morbidity and mortality associated with the surgical lung biopsy procedure.4 While it is definitely more accurate than TBBx, VATS Bx is also subject to sampling error and inconclusive results because of non-uniformity of the IPF disease pattern.
TABLE 2. Serologic testing
n

ANCA RF, CCP ANA SSA, SSB Jo-1, CPK, aldolase RNP Scl-70

GPA RA SSc, SLE, UCTD Sjogren Myositis, a-synthethase MCTD SSc

Connective tissue disease may present without extra-pulmonary manifestations

High-resolution computed tomography (HRCT) images demonstrating usual interstitial pneumonia (UIP) pattern and possible UIP pattern. (A) UIP pattern, with extensive honeycombing: HRCT image shows basal predominant, peripheral predominant reticular abnormality with multiple layers of honeycombing (arrows). (B) Possible UIP pattern: image shows peripheral predominant, basal predominant reticular abnormality with a moderate amount of ground glass abnormality, but without honeycombing. Am J Respir Crit Care Med 2011; 183:788-824.
FIGURE 3.

For patients presenting with IPF symptoms, no identifiable causes of ILDs, and showing pulmonary function testing indicative of IPF, negative serology for CTD, and unclear HRCT pattern, it is recommended to perform lung biopsy; either transbronchial biopsy (TBBx) or surgical [open or video-assisted thoracic surgery (VATS)]. In IPF, the microscopic evaluation of biopsy sample will reveal fibroblastic foci with morphologic appearance characteristic of UIP. TBBx has limitations due to sample size. Figure 4 compares histological samples from TBBx and a VATS Bx. The TBBx sample sizes are only

Multi-disciplinary decision making The diagnosis of IPF is based on clearly defined criteria, and it is simple and straightforward in some patients. The algorithm described in this newsletter (See Figure 2) provides a step-wise approach for a progressive decision making. However, at each stage, results may be unclear or conflicting in some patients. In many cases, establishing an accurate diagnosis of IPF is still a challenging process. Studies consistently show that the accuracy of IPF diagnosis is improved with a multi-disciplinary approach involving a respirologist, radiologist and pathologist experienced in interstitial lung disease.4,14,15 These multi-disciplinary discussions do not have to have any specific formalized structures to be effective but should focus on both what is known about the patient as well as what information is not available. Potential for sampling error and adequacy of the HRCT technique should also be addressed. The multi-disciplinary discussion forums are especially useful in cases of inadequate clinical information or contradictions, for example inadequate radiologic data, non-diagnostic biopsy, or the existence of a

TABLE 3. Combination of high-resolution computed tomograpy and surgical lung biopsy for the diagnosis of IPF (requires multi-disciplinary discussion)
HRCT pattern Surgical lung biopsy pattern (when performed) UIP Probable UIP Possible UIP Nonclassi able brosis Not UIP Possible UIP UIP Probable UIP Possible UIP Nonclassi able brosis Not UIP Inconsistent with UIP UIP Probable UIP Possible UIP Nonclassi able brosis Not UIP Diagnosis of IPF

UIP

YES

Community physicians were more likely to make the diagnosis of IPF and were also more likely to disagree with each other about the diagnoses. Those physicians who saw very few patients with ILD were more likely to make the diagnosis of IPF where it was not warranted. On the other hand, academic physicians were more concordant among themselves about the diagnoses. Interactions between clinicians, radiologists, and pathologists improved inter-observer agreement at both community and academic sites. The study provided a recommendation that, wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options. Conclusions IPF is characterized by progression from the time of diagnosis, with a narrow window of opportunity to implement treatment and slow down disease progression. Our patients deserve an early and accurate diagnosis of their disease as this facilitates optimal management. A clear algorithm for diagnosing IPF has been developed. Some patients present with clear findings, and making confident diagnosis is simple. In other cases, the patient history and test results may be unclear or contradictory, posing a challenge to the treating physician. Multi-disciplinary discussion forums that facilitate collaboration between respirologists, radiologists and pathologists experienced in lung diseases is the gold standard for diagnosing IPF. When doubts exist and it is feasible, it is recommended for patients to be referred to clinics with special expertise in idiopathic pulmonary fibrosis and interstitial lung diseases.
REFERENCES: 1. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165:277-304. 2. Sharma S. Diagnosing idiopathic pulmonary fibrosis. To biopsy or not to biopsy. Curr Opin Pulm Med 2012; 18(5):528-529. 3. Wuyts WA, Thomeer M, Demedts MG. Newer modes of treating Interstitial Lung Disease. Curr Opin Pulm Med 2011; 17(5):332336.

No Yes Probable No Possible No

Am J Respir Crit Care Med 2011; 183:788-824.

4. Raghu G, Collard HR, Fernando, 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; 183:788824. 5. Ley B, Collard HR, Talmadge E et al. Clinical course and prediction of survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2011; 183(4):431-440. 6. Kim DS, Collard HR, King TE. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 2006; 3:285-292. 7. Olson AL, Swigris JJ. Idiopathic Pulmonary Fibrosis: diagnosis and epidemiology. Clin Chest Med 2012; 33:41-50. 8. Fell CD. Idiopathic Pulmonary Fibrosis: understanding the natural history and epidemiology of this fatal disease. The IPF Expert Exchange - The Honeycomb Network.

FIGURE 5. Surgical lung biopsy specimens demonstrating the UIP pattern.

(A) Scanning power microscopy showing a patchy process with honeycomb spaces (thick arrow), some preserved lung tissue regions (thin arrow), and fibrosis extending into the lung from the subpleural regions. (B) Adjacent to the regions of more chronic fibrosis (thick arrow) is a fibroblast focus (asterisk), recognized by its convex shape and composition of edematous fibroblastic tissue, suggestive of recent lung injury. Am J Respir Crit Care Med 2011; 183:788-824.

9. Raghu G,Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006; 174(7):810-816. 10. Statistics Canada. 2012. Census Profile. 2011 Census. Statistics Canada Catalogue no. 98-316-XWE. Ottawa. Released October 24, 2012. http://www12.statcan.gc.ca/ census-recensement/2011/dp-pd/prof/index.cfm?Lang=E (accessed November 20, 2012). 11. Song JW, Hong SB, Lim SM, Koh Y and Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011; 37(2):356-363. 12. Behr J. Approach to the diagnosis of Interstitial Lung Disease. Clin Chest Med 2012; 33:1-10. 13. Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases mimicking idiopathic interstitial pneumonias. Eur Respir J 2008; 31(1):11-20. 14. Flaherty KR, Andrei AC, King TE Jr et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am J Respir Crit Care Med 2007; 175(10):1054-1060. 15. Flaherty KR, King TE Jr, Raghu G et al. Idiopathic interstitial pneumonia: what is the effect of multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 2004; 170:904-910.

major discrepancy between clinical, radiologic, and pathologic findings (See Table 3). Other issues complicating the diagnosis are alterations in the radiologic or histologic findings due to previous therapy, different histologic information in different lobes or coexistence of multiple histologic patterns, for instance the UIP pattern in one lobe and eosinophilic pneumonia in another lobe. A recurring situation requiring discussion is when the HRCT pattern is not consistent with UIP, but lung biopsy samples favor a diagnosis of UIP. Clinical and radiologic outcomes over follow-up are very informative in these cases, as the illness is likely to behave like IPF but with a better than average prognosis. An interesting study by Flaherty KR et al.14 evaluated diagnostic agreement between academic and community-based physicians when diagnosing patients with diffuse parenchymal lung diseases.