THE IPF EXPERT EXCHANGE

The Honeycomb Network

This is the first newsletter in the IPF educational program, which will bring you articles by Canadian respirologists who specialize in diagnosing and treating the idiopathic pulmonary fibrosis.

Dr. Fell is a respirologist, specializing in the diagnosis and treatment of idiopathic pulmonary fibrosis. Shes an Associate Professor of Medicine at the University of Calgary, the chair of the Canadian Thoracic Societys Pulmonary Fibrosis Interest Group and the Director of the University of Calgary Interstitial Lung Disease Program. She obtained her medical degree from the University of Toronto and completed her Internal Medicine residency and Respiratory Medicine fellowship training at the University of Calgary. She completed a Clinical Research Fellowship in Idiopathic Pulmonary Fibrosis at the University of Michigan. Her research interests include determining the clinical predictors of diagnosis and survival in patients with idiopathic interstitial pneumonias, clinical trials of novel therapeutic agents for patients with IPF, and improving the health-related quality of life for patients with fibrotic lung disease.

Idiopathic Pulmonary Fibrosis: understanding the natural history and epidemiology of this fatal disease
By Charlene D. Fell, BSc, MD, FRCP Learning objectives: 1. identify clinical phenotypes and heterogeneous natural history of IPF 2. recognize the need for early diagnosis
Idiopathic Pulmonary Fibrosis (IPF) is a specific form of chronic, progressive fibrosing disease of the lung. It is characterized by rapid deterioration in lung function, with a median survival from the time of diagnosis of only 2-5 years1, shorter than with many common malignancies. 2 The natural course of IPF is unpredictable. Some patients progress very rapidly while others remain relatively stable. For the majority of patients, periods of relative stability are punctuated by acute exacerbations of disease that result in substantial morbidity or death. A number of observational, translational and phase III clinical trials further our understanding of the natural history of IPF, allowing us to better manage the IPF patient. This newsletter will review the information covered in 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 and has the same goals: to identify clinical phenotypes and heterogeneous natural history of IPF, and to recognize the need for early diagnosis. What is Idiopathic Pulmonary Fibrosis?

IPF is a rare, debilitating, fatal disorder. The progressive scarring of the lungs and interstitium is nonreversible and often causes death by respiratory failure. Inflammation is also present in selected stages of IPF, however it is secondary in its importance to the fibrotic component. IPF occurs primarily in older adults (between the ages of 40 and 80) and is more common in men than in women.1,3 IPF has unknown etiology but is thought to result from an interaction of genetic and environmental factors. Gene mutations and polymorphisms are present in both sporadic and hereditary IPF. Cigarette smoking, chronic viral infection and gastroesophageal reflux are potential environmental risk factors.4
Accurate diagnosis of IPF can be life saving

Upcoming newsletters:
July 2013 Optimizing the IPF diagnosis: algorithms and multidisciplinary decision-making by Dr. Gerard Cox, MD, PhD, FRCPCI, FRCPC
September 2013 How recent randomized controlled trials inform clinical treatment of IPF: the therapeutic trials roller coaster ride by Dr. Charles K.N. 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:

Typical IPF symptoms include exertional dyspnea, dry cough, inspiratory bibasilar crackles, cyanosis and "clubbing" of the fingertips.5 The onset of symptoms is gradual. The most common initial symptoms unexplained exertional dyspnea and dry cough - are frequently misdiagnosed for asthma or COPD.6 A wrong or delayed diagnosis of IPF can be fatal to the patient, because it reduces the opportunity to stabilize disease progression and to refer the patient for lung transplantation assessment. In the upcoming July issue of this newsletter, Dr. Gerald Cox, MD PhD, Associate Professor at McMaster University, will discuss the optimal diagnosis of IPF, the algorithms and multidisciplinary decision-making. Overall, IPF should be suspected in any adult over the age of 40 who has an unexplained shortness of breath and dry cough. Testing4 by high resolution computed tomography (HRCT) will show the usual interstitial pneumonia (UIP) defined by 4 features: subpleural basal predominance, reticular abnormality, honeycombing with or without bronchiectasis and absence of features inconsistent with UIP pattern (See Figure 1). It is very important in the process of making the diagnosis of IPF to exclude all other causes of fibrotic lung disease and in particular UIP , such as domestic and occupational environmental exposures, connective tissue disease and drug toxicity. If HRCT scan results are inconclusive, the diagnosis can be confirmed by a surgical lung biopsy (See Figure 2). In this case, the risks versus benefits must be carefully considered.4
Estimated incidence and prevalence of IPF in Canada

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

The incidence and prevalence of IPF in Canada has not been studied, although several recent studies have evaluated the epidemiology of IPF in the US and the UK. The best US estimate is from a large retrospective study by Raghu et al.3 of health claims database that covered 3 million people in 20 states. Two definitions were used: broad and narrow. The broad definition of

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

TABLE 1. Incidence and prevalence of IPF in the US, per 100,000 persons
Broad definition Incidence Prevalence 16.3 42.7 Narrow definition 6.8 14.0

Raghu G, et al. Am J Respir Crit Care Med 2006;174(7):810-816.

TABLE 2. Total incidence and prevalence of IPF in Canada

Broad definition Incidence Prevalence 5,600 14,900 Narrow definition 2,300 4,800

Estimated based on US data from Am J Respir Crit Care Med 2006;174(7):810-816 and Statistics Canada 2011 Census Profile4.

FIGURE 1. HRCT of an IPF patient showing very typical subpleural reticulation with

clinical change and minimal ground-glass attenuation (patient of Dr. Charlene Fell).

progression, with a median survival from the time of diagnosis of only 2-5 years1 and estimated 5-year survival of 20-40%.10 This is more severe than with many chronic lung diseases and common malignancies such as colon cancer, leukemia and bladder cancer.2 When we consult

IPF included all patients who were assigned the ICD-9 diagnostic code for IPF by their doctors, regardless of whether patients had medical testing. This group may have included patients who had other forms of chronic progressive fibrosis and not only the IPF. The narrow definition included patients with ICD-9 code who had their IPF diagnosis confirmed by HRTC of the thorax or lung biopsy (transbronchular or surgical), hence this is a group of patients whom we understand to be more consistent with the diagnosis of IPF. The estimates per 100,000 persons are shown in Table 1. To derive a Canadian estimate, we applied this data to the 2011 Canadian census profile7 (See Table 2). Using the narrow definition, the incidence in Canada is about 2,300 cases and the prevalence is close to 5,000. Using the broad definition, the incidence in Canada is about 5,600 cases and the prevalence is close to 14,900. Since not all patients with IPF symptoms have their diagnosis confirmed by medical testing, the true situation is somewhere between the narrow and broad definition groups. An on-going Canadian study [by whom?] is using the same methodology evaluating healthcare claims using diagnostic codes and HRCT/biopsy results. The results of this study should become available in the next 2 years. On a different note, it is very important to use the right diagnostic codes in clinical practice, so that we can capture the patients in our research.
Mortality from IPF

A. Stable IPF, upper lung B. Stable IPF, lower lung

C. Acute exacerbation, upper lung D. Acute exacerbation, lower lung

FIGURE 3. HRCT of an IPF patient. (A, B) Stable IPF: the right upper and

IPF is an inevitably fatal lung disease. It is characterized by rapid

Pleural surface Dense area of subpleural fibrosis Areas of normal lung architecture

lower lung HRCT images show typical features of usual interstitial pneumonia pattern: peripheral and basal predominant reticular abnormality with traction bronchiectasis and subpleural honeycombing; a small amount of ground-glass abnormality is present. (C, D) Acute exacerbation: the right upper and lower lung of the same patient during an acute exacerbation of IPF show new, extensive ground-glass abnormality superimposed on the background of lung fibrosis. Collard HR, et al. Am J Respir Crit Care Med 2007; 176(7):636-643.

High power reveals fibroblastic foci

IPF patients in our clinic, we often use the cancer analogy to draw their attention to the seriousness of the disease. The overall survival of patients with IPF has been assessed in a number of retrospective studies. Nathan et al.9 retrospectively described 357 patients with IPF who were on a lung transplant waiting list, excluding those patients who received the transplant. The 50% survival in this 2011 study is just under 4 years, which is similar to the data from past studies, indicating that our improved understanding of IPF did not so far result in improved patient survival. Notably, the death rate from IPF is significantly increasing over time, as has been shown by a US study10 evaluating the number of IPFrelated deaths between 1992 and 2003. The etiology of this trend is not determined at this time.
Different phenotypes of IPF progression

FIGURE 2. Microscopic evaluation of a lung biopsy sample reveals a very particular

pattern: dense areas of subpleural fibrosis with areas of more normal lung tissue; high power microscopy shows fibroblastic foci with morphologic appearance characteristic for usual interstitial pneumonia (an IPF patient of Dr. M Kelly)

Ten years ago, we thought that IPF was a chronic slowly progressive disease, however recent data from large phase III randomised clinical

trials and large observational studies revealed that there are different phenotypes of IPF disease progression. While some patients are very stable and can remain stable for as long as 10-12 years, others experience a very rapid decline in lung function, with death occurring within 1-2 years after the diagnosis. The majority of patients, however, experience periods of relative stability, which are interjected by episodes of rapid deterioration caused by infection or another problem.6 Rapid deterioration episodes during the course of IPF - the incidence, risk factors, impact and causes - were evaluated in a 2011 retrospective study by Song et al.11 who described 461 patients, seen in their pulmonary fibrosis clinic from 1990 to 2009. The median follow-up period was 23 months. Rapid deterioration was defined as an acute deterioration in the pulmonary status within 30 days of patient presentation which resulted in worsening of symptoms, hospitalization and a new abnormality on chest HRCT. Acute exacerbation (AE) was defined by the Collard et al.12 criteria (which were published in 2007 in an attempt to standardize the AE diagnosis and bring uniformity to the studies). The AE diagnostic criteria are as follows:
previous or concurrent diagnosis of IPF unexplained worsening or development of dyspnea within 30 days prior to presentation with hypoxemia HRCT with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia pattern (See Figure 3) no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage (although in many instances, IPF patients undergoing an acute exacerbation are too ill to provide a sample) exclusion of alternative causes, including left heart failure pulmonary embolism identifiable cause of acute lung injury.

100 80 Survival % 60 40 20 0
Acute exacerbation Infection

12

18 24 Time (months)

30

36

FIGURE 4. The Kaplan-Meier survival curves (from rapid deterioration to death or

last follow up), comparing patients with acute exacerbation and infection. Song JW, et al. Eur Respir J 2011; 37(2):356-363.

hypertension and their physiology is unique in that their forced vital capacity is usually preserved. However, their diffusion capacity is dismal because there is little surface left for gas exchange. IPF patients with emphysema exhibited higher mortality compared to those with IPF without emphysema (See Figure 6). This dire prognosis seems to be at least partially associated with the development of severe pulmonary arterial hypertension.13
Rapid vs. slow progressors distinct biological types

Song et al.11 found that 35% of IPF patients experienced rapid deterioration. The most frequent cause of rapid deterioration was acute exacerbation (55% of cases), followed by an infection. The KaplanMeier survival curves (See Figure 4), from the time of rapid deterioration to the time of death or last follow up, show that survival of those who had AE and those with infection are virtually identical. The median survival was 2.2 months. When the patients were segregated into groups (See Figure 5), the Kaplan-Meier survival curves, from the time of initial IPF diagnosis to death or last follow-up, showed that patients with AE had the worst prognosis, and their rate of survival was dismal.11
TABLE 3. Incidence of acute exacerbation and rapid deterioration from all causes in IPF patients
Incidence 1-yr 3-yr Acute Exacerbation 14% 21% Rapid Deterioration 23% 35%

Another study by Selman et al.14 evaluated clinical and molecular features of rapid versus slow progressors with IPF. Patients were defined as rapid progressors if they had <6 months of symptoms upon presentation (26 patients) or slow progressors if they presented with >24 months of symptoms (88 patients). Microarrays, tissue protein verification and BAL analysis showed that rapid progressors appear to
100 80 Survival % 60 40
Stable IPF

Song JW et al. Eur Respir J 2011; 37(2):356-363.

20 0

Focal rapid deterioration Bilateral infection Acute exacerbation

In the overall IPF group in this study, the 1-year incidence of acute exacerbations was 14% and 3-year incidence was 20%. At the same time, the 1-year incidence of rapid deterioration from all causes was 23% and 3-year incidence was 35% (As shown in Table 3).11
Combined pulmonary fibrosis and emphysema

12

18 24 Time (months)

30

36

FIGURE 5. The Kaplan-Meier survival curves (from initial diagnosis to death or last

The presence of emphysema modifies the outcome of patients with IPF, expediting respiratory decline. Mejia et al.13 retrospectively evaluated 110 IPF patients and found that 28% had concurrent emphysema, and this was significantly associated with male gender and smoking. Emphysema often affects the upper zones of the lung while IPF affects the lower zones. These patients often have concurrent pulmonary

follow up), comparing patients with no rapid deterioration, focal rapid deterioration, bilateral infection and acute exacerbation. Patients with acute exacerbation had the worst prognosis, and their rate of survival was dismal. Song JW, et al. Eur Respir J 2011; 37(2):356-363

represent a distinct biological phenotype among patients with IPF. Rapid progressors were not patients presenting earlier or with milder disease but were similar in the degree of physiologic, radiologic and histopathologic abnormalities to slow progressors who presented at >24 months.

100 80 Survival % 60 40 20 0
P=0.014 (log-rank) IPF IPF / emphysema

progressive pulmonary fibrosis and usually die from respiratory distress. The immunoreactive A2BAR was mainly observed in alveolar epithelial cells and fibroblasts in rapid progressor lungs. Taken together, these results suggest a potential regulatory role for adenosine or its receptor in IPF.
Conclusions

20

40 Time (months)

60

80

FIGURE 6. The Kaplan-Meier survival curves for patients with IPF and IPF plus

emphysema. Survival time was significantly lower in the group of patients with IPF combined with emphysema. Meja M, et al. Chest 2009;136(1):10-15.

Rapid progressors were mostly male smokers. The Kaplan-Meier survival curve was significantly different for the 2 groups. For the rapid progressors, the median survival was 27 months (2.25 years). For the slow progressors, the median survival was 93 months (7.75 years). Global gene expression analysis performed in a subset of these patients identified 437 differentially expressed genes. The upregulation of several functional pathways became apparent in the lungs from rapid progressor patients. These pathways seem to reflect diverse molecular mechanisms mostly operating in alveolar epithelial and mesenchymal
Onset of symptoms Acute exacerbation Lung microinjuries Stable IPF Slow progressive course IPF / emphysema Rapid progressive course

IPF is a relentlessly progressive disease, causing lung deterioration and death. The epidemiology in Canada is unknown, but estimates suggest that prevalence is somewhere between 4,800 and 14,900 persons and incidence is between 2,300 and 5,600 new cases per year. The disease has a long asymptomatic period. Patients consult when the severity of lung deterioration reaches a threshold that is enough to provoke symptoms. Early diagnosis can be life saving to the patient. The natural history of IPF is heterogeneous, with different clinical phenotypes (See Figure 7).15 Some patients undergo a relatively slow and steady respiratory decline after diagnosis. Other patients progress very rapidly, yet others have periods of relative stability punctuated by episodes of rapid deterioration. There is definitely a link between smoking and IPF, although it is not entirely understood. Patients who progress very rapidly tend to be male smokers. These patients might also develop IPF combined with emphysema, which results in rapid decline in lung function. On another hand, patients experiencing acute exacerbations are most likely to have low forced vital capacity and be non-smokers. Genetic predisposition may play a role in IPF. Also, we think that IPF is initially caused by micro-injuries to the lungs, possibly from causes such as smoking, viral infection or chronic micro-aspiration of gastric contents, that prompts the fibrotic process. Our understanding of the natural history of IPF is evolving, and as we understand more about this disease from observational, translational and phase III clinical trials, it is becoming clear that IPF envelopes a spectrum of diseases with the same kind of underlying pathobiology.
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. American Cancer Society. Cancer Facts and Figures 2009. 3. 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.

Disease Progression

Asymptomatic period (months to years)

9 10

4. 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(6):788-824. 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. Statistics Canada. 2012. Census Profile. 2011 Census. Statistics Canada Catalogue no. 98-316-XWE. Ottawa. Released October 24, 2012. http://www12.statcan.gc.ca/censusrecensement/2011/dp-pd/prof/index.cfm?Lang=E (accessed November 20, 2012). 8. Bjoraker JA, Ryu JH, Edwin MK et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199-203. 9. Nathan SD, Shlobin OA, Weir N et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest 2011;140(1):221-229. 10. Olson AL, Swigris JJ, Lezotte DC et al. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med 2007;176(3):277-284. 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. Collard HR, Moore BB, Flaherty KR et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176(7):636-643. 13. Meja M, Carrillo G, Rojas-serrano J et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension. Chest 2009;136(1):10-15. 14. Selman M, Carrillo G, Estrada A, et al. Accelerated Variant of Idiopathic Pulmonary Fibrosis: Clinical Behavior and Gene Expression Pattern. PLoS ONE 2007;2(5):e482. 15. King TE, Pardo A and Selman M. Idiopathic pulmonary fibrosis. The Lancet 2011;378(9807):1949-1961.

Time (years)
FIGURE 7. Clinical phenotypes of IPF. The heterogeneous natural history pattern

in patients with IPF. The disease has a long (months to years) asymptomatic period. Patients consult when the severity of the lung lesions reaches a threshold that is enough to provoke symptoms. Some patients experience a relatively slow clinical and functional decline after diagnosis. Other patients have episodes of rapid deterioration (often caused by acute exacerbations) that precede and possibly initiate the terminal phase of their disease. Another group of patients experience rapidly progressive clinical course. Heavy smokers might develop IPF combined with emphysema, which results in rapid decline in lung function. Adapted from King TE, et al. The Lancet 2011;378(9807):1949-1961.

cells and include genes involved in cell motility, myofibroblast differentiation, oxidative stress, coagulation and development. Some genes, such as Smad6, were downregulated in rapid progressors. Although we can not rule out some effect of smoking, the differentially expressed genes among rapid and slow progressors found in this work differ from those described as associated to smoking. Of the genes increased in rapid progressors, one was the adenosine A2B receptor gene, which is involved in the differentiation of human lung fibroblasts to myofibroblasts - a key process in fibrotic remodelling. Interestingly, partially adenosine deaminase-deficient mice show upregulation of this receptor and exhibit spontaneous and