EDITORIAL

INTERSTITIAL LUNG DISEASES |

Insights into idiopathic pulmonary

fibrosis in the real world
Vincent Cottin1 and Wim Wuyts2

Affiliations: 1Dept of Pulmonary Medicine and National Reference Center for Rare Pulmonary Diseases,
Competence Center for Pulmonary Arterial Hypertension, Louis Pradel Hospital, Hospices Civils de Lyon,
Claude Bernard Lyon 1 University, Lyon, France. 2Unit for Interstitial Lung Diseases, Dept of Pulmonary
Medicine, University Hospitals Leuven, Leuven, Belgium.

Correspondence: Vincent Cottin, National Reference Center for Rare Pulmonary Diseases, Louis Pradel
Hospital, 28 Avenue Doyen Lepine, F-69677 Lyon, France. E-mail: vincent.cottin@chu-lyon.fr

@ERSpublications
Prospective cohorts such as INSIGHTS-IPF are complementary to clinical trials in idiopathic
pulmonary fibrosis http://ow.ly/NLvfX

Idiopathic pulmonary fibrosis (IPF) is a relentless fibrotic disorder leading to an irreversible damage of the
lungs, chronic respiratory failure, and death after a median of 3 years following the diagnosis [1]. The
landscape in IPF has recently been profoundly modified in a number of ways. The disease process, once
considered as a chronic inflammation and treated with anti-inflammatory and immunosuppressive drugs,
is now viewed as uncontrolled wound healing resulting from injury to the alveolar epithelium [2].
Epidemiological studies have showed that IPF is more common than previously appreciated in the elderly
population [3], with rising prevalence and mortality [4, 5]. The role of tobacco smoking is better
appreciated [6]. The underlying genetic predisposition to IPF is progressively unveiled [7]. International
evidence-based guidelines [8] have clarified the diagnostic approach and criteria, making large clinical
studies possible, with the joined efforts of academic centres, the pharmaceutical industry, clinicians, and
patients. Two antifibrotic drugs, pirfenidone and nintedanib [9–12], were recently demonstrated to reduce
the progression of disease in a well-designed randomised controlled trials, and are now available to treat
this dreadful disease. However, much remains to be done, before progression of IPF is controlled and the
disease can be cured.
Despite the tremendous progress made, paradoxically limited information is available with regard to the
natural course of disease outside clinical trials, which are admittedly biased toward selection of generally
less severe disease, patients with fewer comorbidities, optimised follow-up, and most typical presentation
of disease allowing inclusion. It has been shown, in a number of settings other than IPF, that patients
included in clinical trials are not representative of the broader population of patients diagnosed and
treated in the community throughout the world [13–15]. Many relevant questions cannot be addressed in
clinical trials. Therefore, there is a need to complement data from trials by large prospective cohorts or
registries that are more representative of healthcare management and the course of the disease. Several
perspectives have recently emphasised the need to join efforts and to collect both data and biological
material to support clinical research in the field [16, 17].
In this issue of the European Respiratory Journal, BEHR et al. [18] report on the first analysis of a
prospective multicentre observational study, called INSIGHTS-IPF (Investigating Significant Health Trends
in IPF) and is being conducted in Germany, in which 502 consecutive patients (including 171 newly
diagnosed) were enrolled in 19 centres. IPF was diagnosed according to the current international
definition [8, 19]. The mean disease duration was 2.3±3.5 years. Although the size of the cohort is already
important, inclusion is continuing.

Received: March 05 2015 | Accepted: March 06 2015

Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
Copyright ©ERS 2015

16 Eur Respir J 2015; 46: 16–18 | DOI: 10.1183/09031936.00036815

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 INTERSTITIAL LUNG DISEASES | V. COTTIN AND W. WUYTS

The authors should be commended for this important contribution to the field, with prospective inclusion,
quality assurance of data, and analysis by a steering committee that is independent of the sponsor. Of note,
we consider that the terminology of cohort would be more appropriate to qualify this study than that of
registry, as IPF cases were probably not exhaustively included in Germany. One possible weakness of the
study is that the diagnosis of IPF and decision to include into the cohort were based on an individual
physician’s decision and without multidisciplinary discussion for the majority of cases. Although cases were
not centrally reviewed, therefore with some potential for inclusion of overlapping diagnosis, the study findings
nevertheless are likely to reflect IPF as managed by interstitial lung disease (ILD) expert centres in Germany.
The main findings of this first analysis of the INSIGHTS-IPF cohort were that the functional severity of
disease at diagnosis was greater than in recent randomised controlled trials. The proportion of patients
who had some exposure to asbestos or to birds (56 and 19 out of 502 patients, respectively) was
unexpectedly high and requires further exploration. Comorbidities were found at a high rate, illustrating
differences between observational cohorts and randomised controlled trials. Interestingly, the proportion of
patients who had a lung biopsy was surprisingly high, including some patients with a pattern of usual
interstitial pneumonia at high resolution computed tomography, for whom biopsy may not be necessary.
Only 44% of patients received pirfenidone, the only approved therapy in Europe at the time of the study,
including 37% of whom had pirfenidone prescribed in combination with N-acetylcysteine or prednisone
despite the absence of evidence for combination therapy. A significant number of patients received
corticosteroids, the use of which is discouraged by current guidelines. These findings imply that further
educational efforts are needed to best adapt practice to state of the art knowledge and recommendations,
similar to the results of a recent survey in France [20].
What can we further expect from IPF observational cohorts? It is fair to consider that lessons learned from
the study by BEHR et al. [18] only represent the tip of the iceberg, and much more can be expected in
coming years. As we have witnessed in the field of pulmonary arterial hypertension, cystic fibrosis, lung
transplantation, lymphangioleiomyomatosis and others, prospective cohorts now represent the preferred
tool to evaluate the patients’ characteristics and to dissect subgroups or phenotypes that may have clinical
relevance. In IPF, much can be learned from cohorts regarding evolution, and onset and impact of
complications (acute exacerbations of fibrosis, pulmonary hypertension, lung cancer, etc.). Whereas
randomised controlled trials aim at including the most homogeneous patient groups possible in order to
maximise the chance of adequately measuring the effect size, prospective cohorts capture the heterogeneity
of a disease (IPF and ILD in general are highly heterogeneous conditions) reflecting the management of
patients in the “real world” and best describe the natural course of disease. IPF patients with, for example,
advanced disease or those with the combined pulmonary fibrosis and emphysema syndrome, have been
poorly represented in recent trials.
Although cohorts are not, by design, the appropriate tool to demonstrate efficacy of treatment
interventions, they nevertheless provide the opportunity to monitor changes in disease course resulting
from novel therapies or general changes in management, thereby indirectly confirming (or not) evidence
from trials. One may hope, for example, that introducing antifibrotic drugs, which slow the rate of disease
progression in clinical trials, may eventually translate into improved duration of survival in cohorts, with
IPF becoming a truly chronic disease. This could not be addressed yet in the INSIGHTS-IPF cohort, but
may be a reasonable goal in years to come. In contrast to common belief, cohorts may be suboptimal for
epidemiology purposes, since registry data frequently suffer from bias due to incomplete registration,
precluding measurement of true incidence and prevalence. Cohorts further provide long-term data about
drug safety and tolerance, as well as invaluable information about the use of the healthcare system and
induced costs including non-elective hospitalisation. By providing information about the current
management, cohorts can help reducing the usage of drugs or of diagnostic procedures that are potentially
harmful, and provide guidance about which educational initiatives to prioritise. This is well illustrated by
BEHR et al. [18] who report that bronchoalveolar lavage and surgical lung biopsy are performed in a
surprisingly high proportion of patients (62% and 34%, respectively), whereas multidisciplinary discussion
was conducted in less than a quarter of cases.
What does the future hold? Prospective cohorts are the only way to conduct clinical research embracing
the complexity of chronic diseases and will surely develop further and be crucially important in IPF.
However, cohorts face many challenges and represent a major collective effort [21–25]. As there is
currently a momentum to create registries at the national level in multiple countries [26], stakeholders
should endeavour to share methodology with INSIGHTS-IPF so that data can be eventually combined,
aiming at expand on an international global registry [16, 17]. One further challenge will be to develop
multicentre repositories of biological samples that are linked to prospective clinical cohorts, as recently
emphasised [27, 28] and have already been initiated in the European IPF network initiative [16, 29]. This
further increases the difficulty of the task, as it has proven difficult in the past in other areas to ensure the

DOI: 10.1183/09031936.00036815 17
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INTERSTITIAL LUNG DISEASES | V. COTTIN AND W. WUYTS

quality and completeness of both the biorepository and of the linked clinical registry. Investigators who
have embarked on the INSIGHTS-IPF project may now consider combining the longitudinal clinical data
with biorepositories, thereby creating an invaluable tool to tackle IPF. This would undoubtedly encourage
further collaborative research between institutions and provide a resource for clinical and laboratory
research, as previously envisioned [16]. Meanwhile, one immediate value of real-life cohorts and registries
is to provide clinicians with a feedback of their management that is the starting point to improve daily
clinical practice and to identify the next clinical research questions and hypotheses.

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18 DOI: 10.1183/09031936.00036815
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