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ORIGINAL ARTICLE
Current Australasian practice for diagnosis and management of idiopathic pulmonary fibrosis: Where are we now? LAUREN K. TROY,1,2 SALLY A. CHAPMAN,3,4 FIONA LAKE,5 MARGARET L. WILSHER,6,7 LIARNA B. HONEYSETT,1,4 SACHA MACANSH4 AND TAMERA J. CORTE1,2,4 1
Department of Respiratory Medicine, Royal Prince Alfred Hospital, 2Sydney Medical School, University of Sydney, Sydney, New South Wales, 3Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, 4Australian IPF Registry Steering Committee, Lung Foundation Australia, Brisbane, Queensland, 5School of Medicine and Pharmacology, SCGH Unit, University of Western Australia, Perth, Western Australia, Australia, 6Green Lane Respiratory Services, Auckland City Hospital, and 7Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
ABSTRACT Background and objective: Recent international consensus statements have refined evidence-based guidelines for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). This study sought to investigate how closely these guidelines are adhered to and to compare current practices with those of a similar cohort 15 years ago. Methods: A questionnaire on IPF diagnosis and management was distributed to respiratory physicians practising in Australia and New Zealand, in 2012–2013, and results were compared with a similar survey conducted in 1999. Results: A total of 172 and 144 questionnaires were completed in 1999 and 2012–2013, respectively. The most important investigations in both survey populations were high-resolution computed tomography scans, spirometry, diffusing capacity for carbon monoxide, chest X-ray, static lung volumes and autoimmune serology. In 1999, physicians were more likely to perform arterial blood gases, bronchoalveolar lavage and transbronchial lung biopsy. In the 2012–2013 cohort, 6-min walk tests and pulse oximetry were more widely utilized. Treatment choices differed considerably between the two survey populations. In 1999, the majority would offer a steroid-based regimen, whereas most would not use any specific treatment or would refer for trial participation in 2012–2013. Conclusions: Approach to IPF diagnosis and management is not uniform and has changed over 15 years. Surveyed respiratory physicians were generally practising in accordance with clinical guidelines, although significant variation in practice was identified in both cohorts. This study identifies the need to standardize care of IPF patients across Australia and New Zealand. Correspondence: Lauren Troy, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2050, Australia. Email: ltroy@ med.usyd.edu.au Received 24 May 2014; invited to revise 20 August and 24 December 2014; revised 18 November 2014 and 1 January 2015; accepted 2 January 2015 (Associate Editor: Toby Maher). Article first published online: 22 March 2015 © 2015 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE This is the first study looking at Australian and New Zealand management of IPF, comparing two physician surveys conducted 15 years apart. Significant variation in practice was identified in both cohorts. With increasing understanding of disease pathogenesis and emerging therapeutic options, a guideline-based, standardized approach is needed.
Key words: clinical decision making, disease management, idiopathic pulmonary fibrosis, pulmonary fibrosis, practice. Abbreviations: 6MWT, 6-min walk test; BAL, bronchoalveolar lavage; CPET, cardiopulmonary exercise test; DLCO, diffusing capacity for carbon monoxide; DTPA, Tc-99m diethylene triamine penta-acetic acid scan; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MDT, multidisciplinary team; SpO2, oxyhaemoglobin saturation, measured on pulse oximetry; TBLB, transbronchial lung biopsy; TSANZ, Thoracic Society of Australia and New Zealand; UIP, usual interstitial pneumonia.
INTRODUCTION The past two decades have seen significant changes in the way physicians diagnose, investigate and manage idiopathic pulmonary fibrosis (IPF). This chronic, progressive form of lung fibrosis confers a poor prognosis, with a median survival of 2–3 years from diagnosis.1 Diagnosis can be challenging, particularly where clinical and/or radiological features are atypical. Treatment options remain limited, although two large recent Phase 3 trials of antifibrotic therapy have yielded positive results, bringing new hope for disease sufferers. Recently published international guidelines address some of the uncertainties surrounding IPF diagnosis.1,2 The current classification schema refines Respirology (2015) 20, 647–653 doi: 10.1111/resp.12512
648 the diagnostic algorithm and discusses levels of confidence with regards to radiologic and histopathological findings. Confirmation of IPF requires exclusion of other causes of interstitial lung disease (ILD), along with the presence of the usual interstitial pneumonia (UIP) pattern on highresolution computed tomography (HRCT). In those without definite radiological UIP, a surgical lung biopsy with characteristic findings of UIP is necessary for conclusive diagnosis of IPF. Multidisciplinary team (MDT) discussion is now considered the gold standard approach for distinguishing IPF from other ILD.2,3 We hypothesized that the approach to IPF patients across Australia and New Zealand was varied between centres and respiratory physicians. To better understand the prevailing strategies used for the diagnosis, management and follow up of IPF patients, a questionnaire was circulated to physician members of the Thoracic Society of Australia and New Zealand (TSANZ). We sought to compare responses with a previous similar questionnaire, distributed in 1999.
METHODS In 2012–2013, Australian and New Zealand Respiratory Physicians were invited to participate in a survey on IPF management. This was an initiative of the Australian IPF Registry Steering Committee, a national database established by the Lung Foundation Australia in 2012. The questionnaire was based on a previous questionnaire issued to TSANZ members in 1999 (S. Chapman, G. Ryan, R. Scicchitano, M. Wilsher, F. Lake, unpub., 2000), with permission from investigators. Ethics approval was obtained through the Royal Prince Alfred Ethics Review Committee; Protocol No X12-0055 & LNR/12/RPAH/89.
2012–2013 survey A cross-sectional questionnaire was distributed to an estimated 400 specialists between April 2012 and March 2013, in both paper and electronic format (using online tool SurveyMonkey, Palo Alto, CA, USA). The questionnaires are available in the online supplement. Four broad domains were assessed through specific questions, capturing participant demographics and various aspects of investigation and management of patients suspected of having IPF: (i) ‘Background information’ questions addressed the physicians’ type of practice, location, years of experience and estimated numbers of ILD patients seen per month; (ii) the ‘Investigations and monitoring’ section used a four-point Likert scale4 to identify the investigations used in the work-up of patients with suspected IPF. Provided examples were ranked as ‘routinely done’, ‘sometimes done’, ‘seldom done’ or ‘not available’. (iii) The third section, ‘Management of patients investigated for probable IPF’ asked respondents to choose which histopathological, radiologic and clinical features would influence them to use immunosuppressive therapy, where there was diagnostic uncertainty. They were asked to record their therapy of choice in such cases. And (iv) in the Respirology (2015) 20, 647–653
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‘Management of patients with confirmed or definite IPF’ section, specific therapy preferences were recorded. Finally, physicians were asked how frequently they referred patients to MDT, transplantation and palliative care services.
1999 survey Three hundred fifty physicians received this questionnaire by mail. The first two sections, ‘Background information’ and ‘Investigations and monitoring’ were similar to those of the 2012–2013 questionnaire, with minor differences relating to the trending investigations of each era, such as echocardiography in 2012–2013 and gallium scan in 1999. The questions in the final two sections related to a hypothetical case, describing a patient with the ‘typical’ clinical and radiological findings of IPF (as outlined in the online supplement). Statistical analysis Paper responses were entered into an Excel spreadsheet. Electronic, online responses were exported from SurveyMonkey to Microsoft Excel (version 2007). Data were analysed using STATA version 13 (STATA, College Station, TX, USA). Proportions of responses were compared using the chi-squared test. P-values less than 0.05 were considered significant throughout.
RESULTS Background information In the 2012–2013 questionnaire, 144 questionnaires were completed (48 online and 96 in paper format), giving an estimated response rate of ∼36%. Respondents were primarily tertiary hospital specialists (73%), with less representation from private practice (13%), specialists in non-teaching hospitals (9%) and those engaged mainly in research (5%). The majority of physicians were based in capital cities of Australia and New Zealand (75%), with the remainder in major urban or rural centres. Twenty-eight per cent had an academic interest in ILD. The clinical experience of respondents was wide ranging, with most (59%) graduating within 20 years of the survey. In 1999, 172 questionnaires were completed, with a response rate of 49%. Most respondents had between 10 and 30 years clinical experience. Compared with the contemporary cohort, significantly fewer specialists worked in teaching hospitals (56%) and fewer had a research interest in ILD (18%). Table 1 includes demographic data of each survey cohort. Investigations and monitoring of IPF patients In the 2012–2013 questionnaire, the preferred routine investigations for patients suspected of having IPF were: HRCT (99%), spirometry (99%), diffusing capacity for carbon monoxide (DLCO; 97%), oxyhaemoglobin saturation (SpO2), measured on pulse oximetry; 93%), chest X-ray (93%), static lung volumes (86%) and autoimmune serology (84%). Forty-one per cent © 2015 Asian Pacific Society of Respirology
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IPF management: changes over 15 years Table 1 Physician demographics Demographic information
2012–2013 n (%)
1999 n (%)
Table 2 Routine investigations for patients with suspected IPF Investigations
Main practice type Specialist in teaching hospital Specialist in other hospital Private practice Research/administration Practice location† Capital city Major urban or rural area Years since graduation from medical school Less than 10 10–19 20–29 30 or more Academic appointment Research interest in ILD Number of ILD patients seen per month‡ 0–5 6 or more
104 (72) 13 (9) 19 (13) 8 (6)
98 (57)* 27 (16) 37 (21) 10 (6)
108(75) 36 (25)
116(81) 28 (19)
36 (25) 48 (33) 28 (19) 32 (22) 74 (51) 41 (28)
13 (7)* 62 (36) 65 (38)* 32 (19) 75 (46) 31 (18)*
59 (61) 37 (39)
113 (66) 59 (34)
*P < 0.05. † Location information available in 144 of 172 respondents in 1999 survey. ‡ Patient number information available in 96 of 144 respondents in 2012–2013 survey. ILD, interstitial lung disease.
of physicians routinely arranged 6MWT, and 39% regularly utilized echocardiography. Bronchoalveolar lavage (BAL) or transbronchial lung biopsies (TBLB) were performed routinely by 9% and 1%, respectively, with 48% and 32% of physicians utilizing these occasionally. Only 6% would routinely recommend surgical lung biopsy; however, 52% would refer for this investigation on occasion. Investigations seldom employed or not available included cardiopulmonary exercise testing (CPET), Tc-99m diethylene triamine penta-acetic acid (DTPA) imaging and right heart catheterization. Physicians preferred to monitor patients with serial DLCO, 6MWT, spirometry, HRCT and SpO2. Three-monthly follow-up was the most common practice. In contrast, in 1999, the most utilized investigations were chest X-ray (100%), spirometry (99%), HRCT (98%), DLCO (95%), autoantibody serology (82%), (comprising of antinuclear antibodies and rheumatoid factor) and static lung volumes (81%). BAL and TBLB were performed more routinely in 1999 than in 2012–2013 (21% and 18%, respectively). Referral patterns for surgical biopsy were similar in each cohort. In 1999, more physicians utilized CPET (9%), and fewer used 6MWT (14%). Table 2 shows the routinely used investigations in each survey population. The frequency of utilizing specific investigations is shown in Figures 1a (2012–2013) and 1b (1999). In regards to the case study, 56% of respondents would proceed to lung biopsy for diagnostic confirmation. Of these, 61% favoured a surgical biopsy and 39% would © 2015 Asian Pacific Society of Respirology
Chest X-ray High-resolution CT Spirometry Static lung volumes Diffusing capacity Arterial blood gas SpO2 CPET 6-min walk test Autoimmune serology Bronchoalveolar lavage Transbronchial lung biopsy Surgical lung biopsy DTPA scan Echocardiogram Right heart catheter Sleep study Gallium scan ESR CRP CRP
2012–2013 n (%) 129 (90) 141 (99) 137 (95) 118 (82) 140 (97) 42 (30) 128 (93) 3 (2) 59 (41) 116 (81) 13 (9) 2 (1) 9 (6) 6 (4) 54 (38) 0 (0) 9 (6) — — — —
1999 n (%) 172 (100)* 168 (98) 170 (99)* 140 (81) 164 (95) 97 (56)* 116 (67)* 16 (9)* 24 (14)* 141 (82) 37 (21)* 31 (18)* 11 (6) 7 (4) — — — 2 (1) 123 (72) 57 (33) (33)
*P < 0.05. CPET, cardiopulmonary exercise test; CRP, C-reactive protein; CT, computed tomography; DTPA, Tc-99m diethylene triamine penta-acetic acid scan; ESR, erythrocyte sedimentation rate; IPF, idiopathic pulmonary fibrosis; SpO2, oxyhaemoglobin saturation.
perform TBLB. Physicians preferred to follow suspected or confirmed IPF patients on a monthly basis.
Treatment of IPF patients In the 2012–2013 questionnaire, most physicians would not offer any treatment or would refer patients with definite IPF for clinical trial participation. However, a substantial proportion of respondents (33%) would commence corticosteroids and/or azathioprine. Smaller numbers would prescribe the antioxidant N-acetyl cysteine (9%) or cyclophosphamide (2%). Treatment preferences for definite IPF are shown in Table 3. The clinicians whose treatment preferences were discordant with best evidence were more likely to be working outside of the tertiary care setting than those who were following evidencebased practice (42%, compared with 18%, P = 0.003). They were also more likely to have been practising for 20 years or more (60%, compared with 37%, P = 0.01). There was no difference between the proportions in each group of those with specific research interest in ILD. Physicians were more likely to commence immunosuppressive therapy when HRCT features suggesting a diagnosis other than IPF were present, particularly if disease was clinically severe or progressive. Specific radiologic findings that influenced this decision included ground glass opacification, mosaic Respirology (2015) 20, 647–653
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LK Troy et al. Table 3
Treatment for definite IPF
Treatment options†
2012–2013 n (%)
Referral to clinical trial No treatment Oral prednisone IV methylprednisolone Azathioprine N-acetyl cysteine Cyclophosphamide Other
76 (53) 65 (45) 47 (33) 14 (10) 23 (19) 24 (17) 5 (3) 3 (2)
†
More than one response allowed. IPF, idiopathic pulmonary fibrosis; IV, intravenous.
Figure 2 Referral patterns for patients with idiopathic pulmonary fibrosis (IPF) (2012–2013). , A = always; , B = often; , C = sometimes; , D = rarely; , E = never. Figure 1 Frequency of investigations used in diagnosing idiopathic pulmonary fibrosis in (a) 2012–2013 and (b) 1999. CPET, cardiopulmonary exercise test; CRP, C-reactive protein; CT, computed tomography; DTPA, Tc-99m diethylene triamine pentaacetic acid scan; ESR, erythrocyte sedimentation rate; SpO2, oxyhaemoglobin saturation. , A = routinely do it; , B = sometimes; , C = seldom; , D = investigation not available.
attenuation, nodules and atypical fibrosis distribution. When asked to state the percentage of ground glass change in the radiograph that would necessitate treatment, the responses were wide ranging, from 10% to 80%. The majority of respondents, however, did not quantify the amount. On histopathology, the presence of a lymphocytic infiltrate, granulomata and predominantly airway-centred changes would commonly lead to immunosuppressive therapy initiation. The favoured option was prednisone, on its own, or in combination with azathioprine, cyclophosphamide or mycophenolate mofetil. In assessing treatment response, approximately 40% of the cohort looked for improvement in sympRespirology (2015) 20, 647–653
toms, pulmonary function tests and/ or radiology. The remainder gauged a therapeutic response as seeing stability in these parameters. In 1999, the majority of physicians (75%) would commence treatment for the hypothetical patient, irrespective of referral for lung biopsy. Most would start prednisone as monotherapy or in combination with other immunosuppressive agents.
Referral of IPF patients In 2012–2013, physicians reported their referral patterns to subspecialist services (Fig. 2). Most of the cohort would ‘sometimes’ refer to subspecialist ILD clinics or MDT meetings (34%), or lung transplantation units (52%). Forty-three per cent would ‘often’ refer patients to palliative care services.
DISCUSSION This is the first study to comprehensively review physician practice in two distinct epochs of IPF © 2015 Asian Pacific Society of Respirology
IPF management: changes over 15 years
management. Our study informs as to the approach to diagnosis, investigation and treatment of Australian and New Zealand IPF patients in 2012–2013 and 1999. The majority of surveyed physicians in the 2012–2013 cohort adhered to international guidelines. Many of the observed differences over time reflect the changing landscape of evidence in this field.
Diagnostic methods Technological advances have brought HRCT to the forefront in diagnosing IPF, and in many cases these findings will obviate the need for surgical lung biopsy. In the hypothetical case of the earlier survey, the described pattern on HRCT would be in keeping with ‘definite UIP’. According to the current algorithm, this would be sufficient for a confident diagnosis of IPF, avoiding the need for invasive procedures.1,2 It is possible that the majority of 1999 respondents would proceed to biopsy because of a low degree of confidence in the available diagnostic information. In 1999, HRCT had poorer resolution and less precision than current imaging. Accordingly, HRCT was of lower importance than the plain chest radiograph in the published diagnostic algorithm for ILD in 1999.5 Also evolving in recent years is the role of the MDT with specific expertise in IPF and other ILD. This process where clinicians, pathologists and radiologists collaborate dynamically is now considered the gold standard for diagnosing IPF, having been shown to reduce observer biases and improve diagnostic confidence.1–3,6 As stipulated in international guidelines, it is important that all patients with suspected IPF be reviewed at such a forum, particularly patients with atypical features in which diagnosis is sometimes difficult. The MDT discussion is also an important step for those patients considered appropriate for clinical trial participation. Despite the strengths of this approach, 25% of the present-day respondents would rarely or never utilize the MDT even though many practised within the tertiary referral setting. This may be due to limited access or perhaps a perception of loss of autonomy in decision making. Particular investigations favoured in the past are no longer performed routinely due to low diagnostic yield. The sensitivity and specificity of TBLB and BAL in UIP are insufficient for these to be routinely recommended.7–10 Their greatest utility is when an alternative diagnosis such as sarcoidosis or opportunistic infection is suspected. Treatment preferences Although most respondents in the current survey were practising in accordance with best evidence, there were points of deviation. Despite lack of efficacy, and evidence of harm, many would still trial first-line corticosteroid therapy or other immunosuppressants in patients with definite IPF. This highlights lack of diagnostic confidence in some cases. Speculatively, it may also reflect the unwillingness of some to ‘do nothing’ for a progressive disease, particularly in those patients ineligible for trials or transplantation. © 2015 Asian Pacific Society of Respirology
651 It is worth noting that the subject of ‘acute exacerbations’ in IPF was not specifically addressed in either survey. In the earlier survey, the vogue was to treat fairly aggressively with immunosuppressive therapy, often with escalation if early response was not seen. Many, however, commented that in the absence of objective response, they would wean or discontinue this approach. When gauging response, opinion differed back then, as it does now, on whether improvement or stability in lung function was the therapeutic target. In 1999, the British Thoracic Society Diffuse Parenchymal Lung Disease Guidelines acknowledged the paucity of high quality evidence in treating IPF.5 Recommended first-line therapy was prednisone, with or without azathioprine or cyclophosphamide. The evidence for this was limited by inclusion of heterogeneous disease populations in earlier clinical trials.11,12 In the intervening years between questionnaires, the IFIGENIA trial showed a small but significant benefit with the combination of prednisone, azathioprine and N-acetyl cysteine.13 So-called ‘triple therapy’ was compared with combination prednisone and azathioprine, without inclusion of a placebo group. Despite the limitations of this study, triple therapy became standard IPF therapy in some centres. In early 2012, prior to the circulation of the contemporary survey, interim findings of the PANTHER-IPF trial revealed increased mortality in the group receiving triple therapy compared with placebo.14 This resulted in early termination of this intervention arm and discontinuation of this regimen in clinical practice. Importantly, it is probably the most conclusive evidence that anti-inflammatory therapy is not useful in IPF. Early in 2014, evidence has emerged in the use of antifibrotic therapies, pirfenidone and nintedanib, with others still the subject of ongoing trials.15–19 As it stands, the 2011 international IPF consensus statement contains some recommendations that are already obsolete. Updated American Thoracic Society/European Respiratory Society guidelines are in draft stage and are certain to include the newer agents with proven benefit in management algorithms. On a practical level, access to these drugs is limited for most patients in Australia and New Zealand at the present time, but this is likely to change in the future. As was hypothesized, the 2012–2013 survey revealed that there were variations in practice that sometimes controverted best available evidence. This was particularly seen in those working outside of the teaching hospital setting. Previous surveys of North American and British chest physicians have also highlighted diversity in IPF treatment approaches.20–22 These studies were conducted prior to publication of recent evidence against immunosuppression, although it is apparent that many were already moving away from this strategy.14 The referral patterns of the 2012–2013 respondents are also informative. Having already discussed the reasons for variable access of the MDT, it is relevant to mention the role of transplant versus palliation. These two seemingly opposing treatment approaches Respirology (2015) 20, 647–653
652 may be simultaneously considered for patients with IPF. Age, burden of comorbidities and individual preference will often render this group marginal transplant candidates.
Surveillance and prognosis Epidemiological data from well-defined IPF populations have revealed that desaturation during 6-min walk test (6MWT), extensive honeycombing on HRCT and pulmonary hypertension at baseline are indicators of poorer prognosis.23–26 Trends in forced vital capacity and DLCO can assist in the timing of transplantation or palliative care referral.24,25 The current guideline recommendation for following pulmonary function tests and 6MWT every 3–6 months was followed by the majority of 2012–2013 respondents. The 1999 cohort may have favoured a more frequent appraisal to assess for treatment response and potential toxicities. Limitations We acknowledge limitations within this study. Suboptimal response rates in both surveys indicate the findings may not accurately reflect clinical practices. Particularly in the 2012–2013 survey, physicians working outside of the tertiary hospital setting were under-represented, and there was a significant proportion with academic interest in this area. As with any surveyed population, there are likely to be inherent biases in those willing to complete the questionnaires. The disparity in the two populations made direct comparisons of practices difficult. There were also questions that differed between surveys. Alterations were made to preserve the relevance of the current questionnaire to contemporary practice. As the aim of this study was to provide a descriptive narrative, direct comparison was not considered important for some areas. Finally, some adjunctive therapies were not explored, including domiciliary oxygen, pulmonary rehabilitation, vaccinations and antireflux therapy. These would be important inclusions in subsequent questionnaires, along with updated pharmacological strategies. Standardization of diagnosis and management of IPF: A call for local guidelines? As in many other complex disease processes, a holistic, evidence-based approach to IPF is essential. This study has demonstrated disparity in approach to both diagnosis and management of IPF across Australia and New Zealand at two separate time points. It is imperative that physicians are aware of recent changes in the field and practice variations that potentially compromise patient outcomes point towards a clear need for standardization of care across centres. Local guidelines that reflect the spectrum of patient demography, access to specialist clinics with MDT, local health legislation and available therapeutic options are an important step, and likely to resonate Respirology (2015) 20, 647–653
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with Australian and New Zealand physicians and other stakeholders. Additionally, well-designed education programmes for respiratory physicians, trainees and allied health professionals, incorporating remote-access technology, will help to disseminate best practice principles. Public advocacy and patient education will also help to reduce barriers to timely care. Finally, the impact of such measures should be elicited through further surveys, with audit of practice the best means of highlighting areas of deficiency. In conclusion, there is a lack of uniformity for the diagnosis and management of IPF patients in Australia and New Zealand, as assessed at two different time points in this study. Much has changed in the way physicians diagnose and manage IPF. With a new treatment paradigm on the horizon, it will be interesting to compare the current survey responses with those of a future cohort of physicians in the coming years. There is a clear need to standardize the approach to diagnosis and treatment of IPF patients. Local guidelines may help to address some of the divergence from current best-evidence practice.
Acknowledgements The authors would like to express sincere gratitude to the Lung Foundation Australia staff who assisted with survey distribution, to the members of the Australian IPF Registry Steering Committee with their assistance in survey design, and finally to the physicians who donated their time to fill in the questionnaires.
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Supplementary Information Additional Supplementary Information can be accessed via the html version of this article at the publisher’s web-site: Supplementary Appendix S1 1999 survey. Supplementary Appendix S2 2012–2013 survey.
Respirology (2015) 20, 647–653
ORIGINAL ARTICLE
Current Australasian practice for diagnosis and management of idiopathic pulmonary fibrosis: Where are we now? LAUREN K. TROY,1,2 SALLY A. CHAPMAN,3,4 FIONA LAKE,5 MARGARET L. WILSHER,6,7 LIARNA B. HONEYSETT,1,4 SACHA MACANSH4 AND TAMERA J. CORTE1,2,4 1
Department of Respiratory Medicine, Royal Prince Alfred Hospital, 2Sydney Medical School, University of Sydney, Sydney, New South Wales, 3Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, 4Australian IPF Registry Steering Committee, Lung Foundation Australia, Brisbane, Queensland, 5School of Medicine and Pharmacology, SCGH Unit, University of Western Australia, Perth, Western Australia, Australia, 6Green Lane Respiratory Services, Auckland City Hospital, and 7Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
ABSTRACT Background and objective: Recent international consensus statements have refined evidence-based guidelines for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). This study sought to investigate how closely these guidelines are adhered to and to compare current practices with those of a similar cohort 15 years ago. Methods: A questionnaire on IPF diagnosis and management was distributed to respiratory physicians practising in Australia and New Zealand, in 2012–2013, and results were compared with a similar survey conducted in 1999. Results: A total of 172 and 144 questionnaires were completed in 1999 and 2012–2013, respectively. The most important investigations in both survey populations were high-resolution computed tomography scans, spirometry, diffusing capacity for carbon monoxide, chest X-ray, static lung volumes and autoimmune serology. In 1999, physicians were more likely to perform arterial blood gases, bronchoalveolar lavage and transbronchial lung biopsy. In the 2012–2013 cohort, 6-min walk tests and pulse oximetry were more widely utilized. Treatment choices differed considerably between the two survey populations. In 1999, the majority would offer a steroid-based regimen, whereas most would not use any specific treatment or would refer for trial participation in 2012–2013. Conclusions: Approach to IPF diagnosis and management is not uniform and has changed over 15 years. Surveyed respiratory physicians were generally practising in accordance with clinical guidelines, although significant variation in practice was identified in both cohorts. This study identifies the need to standardize care of IPF patients across Australia and New Zealand. Correspondence: Lauren Troy, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2050, Australia. Email: ltroy@ med.usyd.edu.au Received 24 May 2014; invited to revise 20 August and 24 December 2014; revised 18 November 2014 and 1 January 2015; accepted 2 January 2015 (Associate Editor: Toby Maher). Article first published online: 22 March 2015 © 2015 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE This is the first study looking at Australian and New Zealand management of IPF, comparing two physician surveys conducted 15 years apart. Significant variation in practice was identified in both cohorts. With increasing understanding of disease pathogenesis and emerging therapeutic options, a guideline-based, standardized approach is needed.
Key words: clinical decision making, disease management, idiopathic pulmonary fibrosis, pulmonary fibrosis, practice. Abbreviations: 6MWT, 6-min walk test; BAL, bronchoalveolar lavage; CPET, cardiopulmonary exercise test; DLCO, diffusing capacity for carbon monoxide; DTPA, Tc-99m diethylene triamine penta-acetic acid scan; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MDT, multidisciplinary team; SpO2, oxyhaemoglobin saturation, measured on pulse oximetry; TBLB, transbronchial lung biopsy; TSANZ, Thoracic Society of Australia and New Zealand; UIP, usual interstitial pneumonia.
INTRODUCTION The past two decades have seen significant changes in the way physicians diagnose, investigate and manage idiopathic pulmonary fibrosis (IPF). This chronic, progressive form of lung fibrosis confers a poor prognosis, with a median survival of 2–3 years from diagnosis.1 Diagnosis can be challenging, particularly where clinical and/or radiological features are atypical. Treatment options remain limited, although two large recent Phase 3 trials of antifibrotic therapy have yielded positive results, bringing new hope for disease sufferers. Recently published international guidelines address some of the uncertainties surrounding IPF diagnosis.1,2 The current classification schema refines Respirology (2015) 20, 647–653 doi: 10.1111/resp.12512
648 the diagnostic algorithm and discusses levels of confidence with regards to radiologic and histopathological findings. Confirmation of IPF requires exclusion of other causes of interstitial lung disease (ILD), along with the presence of the usual interstitial pneumonia (UIP) pattern on highresolution computed tomography (HRCT). In those without definite radiological UIP, a surgical lung biopsy with characteristic findings of UIP is necessary for conclusive diagnosis of IPF. Multidisciplinary team (MDT) discussion is now considered the gold standard approach for distinguishing IPF from other ILD.2,3 We hypothesized that the approach to IPF patients across Australia and New Zealand was varied between centres and respiratory physicians. To better understand the prevailing strategies used for the diagnosis, management and follow up of IPF patients, a questionnaire was circulated to physician members of the Thoracic Society of Australia and New Zealand (TSANZ). We sought to compare responses with a previous similar questionnaire, distributed in 1999.
METHODS In 2012–2013, Australian and New Zealand Respiratory Physicians were invited to participate in a survey on IPF management. This was an initiative of the Australian IPF Registry Steering Committee, a national database established by the Lung Foundation Australia in 2012. The questionnaire was based on a previous questionnaire issued to TSANZ members in 1999 (S. Chapman, G. Ryan, R. Scicchitano, M. Wilsher, F. Lake, unpub., 2000), with permission from investigators. Ethics approval was obtained through the Royal Prince Alfred Ethics Review Committee; Protocol No X12-0055 & LNR/12/RPAH/89.
2012–2013 survey A cross-sectional questionnaire was distributed to an estimated 400 specialists between April 2012 and March 2013, in both paper and electronic format (using online tool SurveyMonkey, Palo Alto, CA, USA). The questionnaires are available in the online supplement. Four broad domains were assessed through specific questions, capturing participant demographics and various aspects of investigation and management of patients suspected of having IPF: (i) ‘Background information’ questions addressed the physicians’ type of practice, location, years of experience and estimated numbers of ILD patients seen per month; (ii) the ‘Investigations and monitoring’ section used a four-point Likert scale4 to identify the investigations used in the work-up of patients with suspected IPF. Provided examples were ranked as ‘routinely done’, ‘sometimes done’, ‘seldom done’ or ‘not available’. (iii) The third section, ‘Management of patients investigated for probable IPF’ asked respondents to choose which histopathological, radiologic and clinical features would influence them to use immunosuppressive therapy, where there was diagnostic uncertainty. They were asked to record their therapy of choice in such cases. And (iv) in the Respirology (2015) 20, 647–653
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‘Management of patients with confirmed or definite IPF’ section, specific therapy preferences were recorded. Finally, physicians were asked how frequently they referred patients to MDT, transplantation and palliative care services.
1999 survey Three hundred fifty physicians received this questionnaire by mail. The first two sections, ‘Background information’ and ‘Investigations and monitoring’ were similar to those of the 2012–2013 questionnaire, with minor differences relating to the trending investigations of each era, such as echocardiography in 2012–2013 and gallium scan in 1999. The questions in the final two sections related to a hypothetical case, describing a patient with the ‘typical’ clinical and radiological findings of IPF (as outlined in the online supplement). Statistical analysis Paper responses were entered into an Excel spreadsheet. Electronic, online responses were exported from SurveyMonkey to Microsoft Excel (version 2007). Data were analysed using STATA version 13 (STATA, College Station, TX, USA). Proportions of responses were compared using the chi-squared test. P-values less than 0.05 were considered significant throughout.
RESULTS Background information In the 2012–2013 questionnaire, 144 questionnaires were completed (48 online and 96 in paper format), giving an estimated response rate of ∼36%. Respondents were primarily tertiary hospital specialists (73%), with less representation from private practice (13%), specialists in non-teaching hospitals (9%) and those engaged mainly in research (5%). The majority of physicians were based in capital cities of Australia and New Zealand (75%), with the remainder in major urban or rural centres. Twenty-eight per cent had an academic interest in ILD. The clinical experience of respondents was wide ranging, with most (59%) graduating within 20 years of the survey. In 1999, 172 questionnaires were completed, with a response rate of 49%. Most respondents had between 10 and 30 years clinical experience. Compared with the contemporary cohort, significantly fewer specialists worked in teaching hospitals (56%) and fewer had a research interest in ILD (18%). Table 1 includes demographic data of each survey cohort. Investigations and monitoring of IPF patients In the 2012–2013 questionnaire, the preferred routine investigations for patients suspected of having IPF were: HRCT (99%), spirometry (99%), diffusing capacity for carbon monoxide (DLCO; 97%), oxyhaemoglobin saturation (SpO2), measured on pulse oximetry; 93%), chest X-ray (93%), static lung volumes (86%) and autoimmune serology (84%). Forty-one per cent © 2015 Asian Pacific Society of Respirology
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IPF management: changes over 15 years Table 1 Physician demographics Demographic information
2012–2013 n (%)
1999 n (%)
Table 2 Routine investigations for patients with suspected IPF Investigations
Main practice type Specialist in teaching hospital Specialist in other hospital Private practice Research/administration Practice location† Capital city Major urban or rural area Years since graduation from medical school Less than 10 10–19 20–29 30 or more Academic appointment Research interest in ILD Number of ILD patients seen per month‡ 0–5 6 or more
104 (72) 13 (9) 19 (13) 8 (6)
98 (57)* 27 (16) 37 (21) 10 (6)
108(75) 36 (25)
116(81) 28 (19)
36 (25) 48 (33) 28 (19) 32 (22) 74 (51) 41 (28)
13 (7)* 62 (36) 65 (38)* 32 (19) 75 (46) 31 (18)*
59 (61) 37 (39)
113 (66) 59 (34)
*P < 0.05. † Location information available in 144 of 172 respondents in 1999 survey. ‡ Patient number information available in 96 of 144 respondents in 2012–2013 survey. ILD, interstitial lung disease.
of physicians routinely arranged 6MWT, and 39% regularly utilized echocardiography. Bronchoalveolar lavage (BAL) or transbronchial lung biopsies (TBLB) were performed routinely by 9% and 1%, respectively, with 48% and 32% of physicians utilizing these occasionally. Only 6% would routinely recommend surgical lung biopsy; however, 52% would refer for this investigation on occasion. Investigations seldom employed or not available included cardiopulmonary exercise testing (CPET), Tc-99m diethylene triamine penta-acetic acid (DTPA) imaging and right heart catheterization. Physicians preferred to monitor patients with serial DLCO, 6MWT, spirometry, HRCT and SpO2. Three-monthly follow-up was the most common practice. In contrast, in 1999, the most utilized investigations were chest X-ray (100%), spirometry (99%), HRCT (98%), DLCO (95%), autoantibody serology (82%), (comprising of antinuclear antibodies and rheumatoid factor) and static lung volumes (81%). BAL and TBLB were performed more routinely in 1999 than in 2012–2013 (21% and 18%, respectively). Referral patterns for surgical biopsy were similar in each cohort. In 1999, more physicians utilized CPET (9%), and fewer used 6MWT (14%). Table 2 shows the routinely used investigations in each survey population. The frequency of utilizing specific investigations is shown in Figures 1a (2012–2013) and 1b (1999). In regards to the case study, 56% of respondents would proceed to lung biopsy for diagnostic confirmation. Of these, 61% favoured a surgical biopsy and 39% would © 2015 Asian Pacific Society of Respirology
Chest X-ray High-resolution CT Spirometry Static lung volumes Diffusing capacity Arterial blood gas SpO2 CPET 6-min walk test Autoimmune serology Bronchoalveolar lavage Transbronchial lung biopsy Surgical lung biopsy DTPA scan Echocardiogram Right heart catheter Sleep study Gallium scan ESR CRP CRP
2012–2013 n (%) 129 (90) 141 (99) 137 (95) 118 (82) 140 (97) 42 (30) 128 (93) 3 (2) 59 (41) 116 (81) 13 (9) 2 (1) 9 (6) 6 (4) 54 (38) 0 (0) 9 (6) — — — —
1999 n (%) 172 (100)* 168 (98) 170 (99)* 140 (81) 164 (95) 97 (56)* 116 (67)* 16 (9)* 24 (14)* 141 (82) 37 (21)* 31 (18)* 11 (6) 7 (4) — — — 2 (1) 123 (72) 57 (33) (33)
*P < 0.05. CPET, cardiopulmonary exercise test; CRP, C-reactive protein; CT, computed tomography; DTPA, Tc-99m diethylene triamine penta-acetic acid scan; ESR, erythrocyte sedimentation rate; IPF, idiopathic pulmonary fibrosis; SpO2, oxyhaemoglobin saturation.
perform TBLB. Physicians preferred to follow suspected or confirmed IPF patients on a monthly basis.
Treatment of IPF patients In the 2012–2013 questionnaire, most physicians would not offer any treatment or would refer patients with definite IPF for clinical trial participation. However, a substantial proportion of respondents (33%) would commence corticosteroids and/or azathioprine. Smaller numbers would prescribe the antioxidant N-acetyl cysteine (9%) or cyclophosphamide (2%). Treatment preferences for definite IPF are shown in Table 3. The clinicians whose treatment preferences were discordant with best evidence were more likely to be working outside of the tertiary care setting than those who were following evidencebased practice (42%, compared with 18%, P = 0.003). They were also more likely to have been practising for 20 years or more (60%, compared with 37%, P = 0.01). There was no difference between the proportions in each group of those with specific research interest in ILD. Physicians were more likely to commence immunosuppressive therapy when HRCT features suggesting a diagnosis other than IPF were present, particularly if disease was clinically severe or progressive. Specific radiologic findings that influenced this decision included ground glass opacification, mosaic Respirology (2015) 20, 647–653
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Treatment for definite IPF
Treatment options†
2012–2013 n (%)
Referral to clinical trial No treatment Oral prednisone IV methylprednisolone Azathioprine N-acetyl cysteine Cyclophosphamide Other
76 (53) 65 (45) 47 (33) 14 (10) 23 (19) 24 (17) 5 (3) 3 (2)
†
More than one response allowed. IPF, idiopathic pulmonary fibrosis; IV, intravenous.
Figure 2 Referral patterns for patients with idiopathic pulmonary fibrosis (IPF) (2012–2013). , A = always; , B = often; , C = sometimes; , D = rarely; , E = never. Figure 1 Frequency of investigations used in diagnosing idiopathic pulmonary fibrosis in (a) 2012–2013 and (b) 1999. CPET, cardiopulmonary exercise test; CRP, C-reactive protein; CT, computed tomography; DTPA, Tc-99m diethylene triamine pentaacetic acid scan; ESR, erythrocyte sedimentation rate; SpO2, oxyhaemoglobin saturation. , A = routinely do it; , B = sometimes; , C = seldom; , D = investigation not available.
attenuation, nodules and atypical fibrosis distribution. When asked to state the percentage of ground glass change in the radiograph that would necessitate treatment, the responses were wide ranging, from 10% to 80%. The majority of respondents, however, did not quantify the amount. On histopathology, the presence of a lymphocytic infiltrate, granulomata and predominantly airway-centred changes would commonly lead to immunosuppressive therapy initiation. The favoured option was prednisone, on its own, or in combination with azathioprine, cyclophosphamide or mycophenolate mofetil. In assessing treatment response, approximately 40% of the cohort looked for improvement in sympRespirology (2015) 20, 647–653
toms, pulmonary function tests and/ or radiology. The remainder gauged a therapeutic response as seeing stability in these parameters. In 1999, the majority of physicians (75%) would commence treatment for the hypothetical patient, irrespective of referral for lung biopsy. Most would start prednisone as monotherapy or in combination with other immunosuppressive agents.
Referral of IPF patients In 2012–2013, physicians reported their referral patterns to subspecialist services (Fig. 2). Most of the cohort would ‘sometimes’ refer to subspecialist ILD clinics or MDT meetings (34%), or lung transplantation units (52%). Forty-three per cent would ‘often’ refer patients to palliative care services.
DISCUSSION This is the first study to comprehensively review physician practice in two distinct epochs of IPF © 2015 Asian Pacific Society of Respirology
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management. Our study informs as to the approach to diagnosis, investigation and treatment of Australian and New Zealand IPF patients in 2012–2013 and 1999. The majority of surveyed physicians in the 2012–2013 cohort adhered to international guidelines. Many of the observed differences over time reflect the changing landscape of evidence in this field.
Diagnostic methods Technological advances have brought HRCT to the forefront in diagnosing IPF, and in many cases these findings will obviate the need for surgical lung biopsy. In the hypothetical case of the earlier survey, the described pattern on HRCT would be in keeping with ‘definite UIP’. According to the current algorithm, this would be sufficient for a confident diagnosis of IPF, avoiding the need for invasive procedures.1,2 It is possible that the majority of 1999 respondents would proceed to biopsy because of a low degree of confidence in the available diagnostic information. In 1999, HRCT had poorer resolution and less precision than current imaging. Accordingly, HRCT was of lower importance than the plain chest radiograph in the published diagnostic algorithm for ILD in 1999.5 Also evolving in recent years is the role of the MDT with specific expertise in IPF and other ILD. This process where clinicians, pathologists and radiologists collaborate dynamically is now considered the gold standard for diagnosing IPF, having been shown to reduce observer biases and improve diagnostic confidence.1–3,6 As stipulated in international guidelines, it is important that all patients with suspected IPF be reviewed at such a forum, particularly patients with atypical features in which diagnosis is sometimes difficult. The MDT discussion is also an important step for those patients considered appropriate for clinical trial participation. Despite the strengths of this approach, 25% of the present-day respondents would rarely or never utilize the MDT even though many practised within the tertiary referral setting. This may be due to limited access or perhaps a perception of loss of autonomy in decision making. Particular investigations favoured in the past are no longer performed routinely due to low diagnostic yield. The sensitivity and specificity of TBLB and BAL in UIP are insufficient for these to be routinely recommended.7–10 Their greatest utility is when an alternative diagnosis such as sarcoidosis or opportunistic infection is suspected. Treatment preferences Although most respondents in the current survey were practising in accordance with best evidence, there were points of deviation. Despite lack of efficacy, and evidence of harm, many would still trial first-line corticosteroid therapy or other immunosuppressants in patients with definite IPF. This highlights lack of diagnostic confidence in some cases. Speculatively, it may also reflect the unwillingness of some to ‘do nothing’ for a progressive disease, particularly in those patients ineligible for trials or transplantation. © 2015 Asian Pacific Society of Respirology
651 It is worth noting that the subject of ‘acute exacerbations’ in IPF was not specifically addressed in either survey. In the earlier survey, the vogue was to treat fairly aggressively with immunosuppressive therapy, often with escalation if early response was not seen. Many, however, commented that in the absence of objective response, they would wean or discontinue this approach. When gauging response, opinion differed back then, as it does now, on whether improvement or stability in lung function was the therapeutic target. In 1999, the British Thoracic Society Diffuse Parenchymal Lung Disease Guidelines acknowledged the paucity of high quality evidence in treating IPF.5 Recommended first-line therapy was prednisone, with or without azathioprine or cyclophosphamide. The evidence for this was limited by inclusion of heterogeneous disease populations in earlier clinical trials.11,12 In the intervening years between questionnaires, the IFIGENIA trial showed a small but significant benefit with the combination of prednisone, azathioprine and N-acetyl cysteine.13 So-called ‘triple therapy’ was compared with combination prednisone and azathioprine, without inclusion of a placebo group. Despite the limitations of this study, triple therapy became standard IPF therapy in some centres. In early 2012, prior to the circulation of the contemporary survey, interim findings of the PANTHER-IPF trial revealed increased mortality in the group receiving triple therapy compared with placebo.14 This resulted in early termination of this intervention arm and discontinuation of this regimen in clinical practice. Importantly, it is probably the most conclusive evidence that anti-inflammatory therapy is not useful in IPF. Early in 2014, evidence has emerged in the use of antifibrotic therapies, pirfenidone and nintedanib, with others still the subject of ongoing trials.15–19 As it stands, the 2011 international IPF consensus statement contains some recommendations that are already obsolete. Updated American Thoracic Society/European Respiratory Society guidelines are in draft stage and are certain to include the newer agents with proven benefit in management algorithms. On a practical level, access to these drugs is limited for most patients in Australia and New Zealand at the present time, but this is likely to change in the future. As was hypothesized, the 2012–2013 survey revealed that there were variations in practice that sometimes controverted best available evidence. This was particularly seen in those working outside of the teaching hospital setting. Previous surveys of North American and British chest physicians have also highlighted diversity in IPF treatment approaches.20–22 These studies were conducted prior to publication of recent evidence against immunosuppression, although it is apparent that many were already moving away from this strategy.14 The referral patterns of the 2012–2013 respondents are also informative. Having already discussed the reasons for variable access of the MDT, it is relevant to mention the role of transplant versus palliation. These two seemingly opposing treatment approaches Respirology (2015) 20, 647–653
652 may be simultaneously considered for patients with IPF. Age, burden of comorbidities and individual preference will often render this group marginal transplant candidates.
Surveillance and prognosis Epidemiological data from well-defined IPF populations have revealed that desaturation during 6-min walk test (6MWT), extensive honeycombing on HRCT and pulmonary hypertension at baseline are indicators of poorer prognosis.23–26 Trends in forced vital capacity and DLCO can assist in the timing of transplantation or palliative care referral.24,25 The current guideline recommendation for following pulmonary function tests and 6MWT every 3–6 months was followed by the majority of 2012–2013 respondents. The 1999 cohort may have favoured a more frequent appraisal to assess for treatment response and potential toxicities. Limitations We acknowledge limitations within this study. Suboptimal response rates in both surveys indicate the findings may not accurately reflect clinical practices. Particularly in the 2012–2013 survey, physicians working outside of the tertiary hospital setting were under-represented, and there was a significant proportion with academic interest in this area. As with any surveyed population, there are likely to be inherent biases in those willing to complete the questionnaires. The disparity in the two populations made direct comparisons of practices difficult. There were also questions that differed between surveys. Alterations were made to preserve the relevance of the current questionnaire to contemporary practice. As the aim of this study was to provide a descriptive narrative, direct comparison was not considered important for some areas. Finally, some adjunctive therapies were not explored, including domiciliary oxygen, pulmonary rehabilitation, vaccinations and antireflux therapy. These would be important inclusions in subsequent questionnaires, along with updated pharmacological strategies. Standardization of diagnosis and management of IPF: A call for local guidelines? As in many other complex disease processes, a holistic, evidence-based approach to IPF is essential. This study has demonstrated disparity in approach to both diagnosis and management of IPF across Australia and New Zealand at two separate time points. It is imperative that physicians are aware of recent changes in the field and practice variations that potentially compromise patient outcomes point towards a clear need for standardization of care across centres. Local guidelines that reflect the spectrum of patient demography, access to specialist clinics with MDT, local health legislation and available therapeutic options are an important step, and likely to resonate Respirology (2015) 20, 647–653
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with Australian and New Zealand physicians and other stakeholders. Additionally, well-designed education programmes for respiratory physicians, trainees and allied health professionals, incorporating remote-access technology, will help to disseminate best practice principles. Public advocacy and patient education will also help to reduce barriers to timely care. Finally, the impact of such measures should be elicited through further surveys, with audit of practice the best means of highlighting areas of deficiency. In conclusion, there is a lack of uniformity for the diagnosis and management of IPF patients in Australia and New Zealand, as assessed at two different time points in this study. Much has changed in the way physicians diagnose and manage IPF. With a new treatment paradigm on the horizon, it will be interesting to compare the current survey responses with those of a future cohort of physicians in the coming years. There is a clear need to standardize the approach to diagnosis and treatment of IPF patients. Local guidelines may help to address some of the divergence from current best-evidence practice.
Acknowledgements The authors would like to express sincere gratitude to the Lung Foundation Australia staff who assisted with survey distribution, to the members of the Australian IPF Registry Steering Committee with their assistance in survey design, and finally to the physicians who donated their time to fill in the questionnaires.
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Supplementary Information Additional Supplementary Information can be accessed via the html version of this article at the publisher’s web-site: Supplementary Appendix S1 1999 survey. Supplementary Appendix S2 2012–2013 survey.
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