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Management of idiopathic pulmonary fibrosis: selected case reports

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In 2011, revised international guidelines were issued jointly by the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society and the Latin American Thoracic Association, which provide a valuable framework for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). However, due to the complexity of IPF, these guidelines may not comprehensively account for the management of individual IPF patients in clinical practice.

We describe three patient cases that were presented and discussed during the 2013 AIR: Advancing IPF Research meeting in Nice, France. These cases highlight the heterogeneity in the presentation, history and clinical course of IPF, together with expert insights regarding the diagnosis and management of IPF in the real-life setting.

• Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease in which progressive fibrosis and scarring of the lung parenchyma leads to symptoms such as dyspnoea on exertion, dry cough and, ultimately, respiratory failure [ 1 ]. IPF is a complex disease with several aspects that are not fully understood, including its pathogenesis and variable clinical course [ 1 – 4 ].

The 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) guidelines are a clear step forward in the diagnosis and treatment of IPF [ 5 ]. However, due to the complex course of this disease they do not comprehensively represent the management of all individual IPF patients. Moreover, in the 2011 ATS/ERS/JRS/ALAT guidelines, no pharmacological therapy received a positive recommendation. As new results from clinical trials have been published after these guidelines and with anticipated new insights into the treatment of IPF, an update of these recommendations is highly warranted in the near future. Currently, the only approved drug for the treatment of mild-to-moderate IPF within the European Union is pirfenidone, which is also approved for IPF in Canada, Japan, India and China [ 6 , 7 ].

The multifaceted clinical course of IPF in individuals and the lack of updated guidelines on pharmacological management can present a number of challenges to the clinician in the real-life setting. Herein, we report three case studies presented during the 2013 Advancing IPF Research (AIR) meeting in Nice, France, which provide insights into the complex management of IPF from a real-life perspective.

Complex diagnosis of IPF: a case-based discussion

The recommendations of the 2011 ATS/ERS/JRS/ALAT evidence-based guidelines apply to patients typically represented in clinical trial populations [ 5 ]. The presentation and course of IPF is, however, highly individual and the utility of these guidelines in the real-life setting is sometimes limited. Thus, to ensure effective treatment, patients with suspected interstitial lung diseases (ILDs) need multidisciplinary team (MDT) evaluation.

A 55-year-old female who was a current smoker presented in general practice with a 9-month history of respiratory symptoms, including dyspnoea on exertion, thoracic pain and dry cough, which were preceded by a pulmonary infection. Pulmonary function tests (PFTs) showed only mild impairment of vital capacity (VC) but a severely reduced diffusing capacity of the lung for carbon monoxide ( D LCO ). In accordance with the diagnostic algorithm for patients with suspected ILD [ 8 ], a chest multi-slice high-resolution computed tomography (HRCT) scan was performed ( fig. 1 and table 1 ). A number of findings were noted on the scan: 1) apical, paraseptal emphysema; 2) reticular abnormalities and honeycombing with traction bronchiectasis (predominantly in the subpleural and basal regions); and 3) extensive ground-glass opacities. According to the current guidelines, due to the ground-glass opacities a diagnosis of IPF could not be made [ 5 ].

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Chest high-resolution computed tomography scans. Multi-slice computed tomography demonstrates a) apical emphysema and b) honeycombing and reticulation with subpleural, basal predominance. Extensive ground-glass opacities can be seen in both panels. Image courtesy of Claus P. Heussel (Thoraxklinik, University of Heidelberg, Heidelberg, Germany).

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The patient was unable to undergo surgical lung biopsy (SLB) due to the severe functional impairments and, following a detailed MDT discussion, the patient was advised to stop smoking. A short-term follow-up of the patient was initiated. On examination 3 months later and after smoking cessation, the ground-glass opacities were significantly reduced on HRCT, while D LCO increased to 51%. To better define the diagnosis a further MDT meeting was held and it was decided to perform SLB. Histopathological evaluation of the biopsy demonstrated a typical usual interstitial pneumonia (UIP) pattern and emphysematous changes. In addition, there was diffuse pulmonary involvement of numerous macrophage accumulations within most of the distal airspaces, consistent with a desquamative interstitial pneumonia (DIP) pattern. Following a final interdisciplinary discussion, the patient was diagnosed with combined pulmonary fibrosis and emphysema in combination with another smoking-related disease, namely DIP ( fig. 2 ) [ 9 ].

a) Low magnification histopathological biopsy showing typical features of usual interstitial pneumonia pattern with a heterogeneous appearance and areas of fibrosis with scarring and honeycomb change. Areas with less affected parenchyma also show emphysematous changes. b) Higher magnification of the histopathological biopsy reveals diffuse pulmonary involvement of numerous macrophage accumulations within most of the distal airspaces, consistent with a desquamative interstitial pneumonia pattern. Image courtesy of Philipp A. Schnabel (Institute of Pathology, University of Heidelberg, Heidelberg, Germany).

The patient also had a number of comorbidities, including gastro-oesophageal reflux disease (GORD), a prior transient ischaemic attack and depression. A holistic management approach was discussed with the patient and then implemented. The plan involved initiation of pharmacological treatment with pirfenidone for mild-to-moderate IPF, a proton-pump inhibitor (PPI) for GORD and an antidepressant. The patient was also vaccinated for influenza and pneumococci and referred to an outpatient rehabilitation centre. In addition, information regarding patient support groups was provided as were supportive measures to help the patient maintain her smoking cessation.

Pirfenidone treatment resulted in a period of stabilisation; however, this was followed by a gradual decline and eventually a sharp decrease in the patient’s forced vital capacity (FVC). Subsequent investigations ruled out an acute exacerbation. The patient was further evaluated and it was then discovered that the patient had a neurological problem which led to back pain. The patient underwent surgery and following this there was a marked improvement in her FVC ( fig. 3 ).

Forced vital capacity (FVC) over the course of the disease, some disease stabilisation can be seen following initiation of pirfenidone therapy. However, there was a significant decline in FVC due to neurological disease. After treatment for this disease the patient’s FVC increased again.

This case illustrates the complexity faced by clinicians in the management of ILD patients in the real-life setting and raises a number of points outside of the clinical guidelines [ 10 ]. These include challenges in the diagnosis of IPF, such as the possibility of earlier diagnosis through auscultation for characteristic “velcro” crackles by general practitioners and issues in diagnosing IPF on HRCT [ 11 ]. The use of a MDT in such situations may overcome some of the problems related to ILD diagnosis. This case serves as an example of this as extensive ground-glass opacities should, in theory, have ruled out IPF according to the current guidelines. However, in this patient the ground-glass opacities corresponded to another smoking-related ILD. Extensive interdisciplinary discussion was key in exploring the potential differential diagnoses. Furthermore, the MDT meetings helped formulate and implement an effective management approach; for example, initiation of smoking cessation to manage the smoking-related ILD, namely DIP.

Selecting which treatments to prioritise for IPF may be challenging in the real-life setting. Treatments to consider include preventative care (such as vaccinations), symptom-based medications, and non-pharmacological approaches (such as patient support groups and sports). In addition, the physician may be faced with decisions relating to the treatment of comorbidities and the optimal time to initiate drug treatment. As patients are becoming increasingly well informed through sources such as the internet, they often want clinicians to explain which treatment has been selected for their condition and why.

In this case study there was an unexpected decline in lung function, which may have been caused by a number of conditions such as an acute exacerbation of IPF, lack of patient compliance with treatment or untreated comorbidities. In actual fact, the lung function was compromised through a neurological disease leading to back pain. In the real-life setting, the differentiation of stable disease from progressive fibrosis can also be complicated due to the variable course of IPF and associated conditions.

In summary, the 2011 ATS/ERS/JRS/ALAT guidelines provide an evidence-based approach to the diagnosis and management of IPF but cannot cover the full spectrum of challenges associated with managing IPF patients in the clinical practice. First and foremost, the physician should aim for the earliest possible diagnosis of IPF. Decisions relating to preventative treatments, management of comorbidities and treatment side-effects, drug initiation/termination, and, ultimately, palliative care should be tailored to the patient.

Managing an unusual case of IPF

IPF may be diagnosed in the context of various clinical backgrounds and the complex pathophysiology of this condition can sometimes present unusual or challenging situations in individual cases.

A 79-year-old male with a 45 pack-year smoking history first presented in February 2000 with chronic cough and rhinosinusitis. This was diagnosed clinically and histologically as cryptogenic organising pneumonia (COP). The patient was treated with a 6-month course of systemic steroids and the patient’s cough completely subsided. In addition, previous consolidation on computed tomography disappeared; however, mild septal thickening persisted.

The patient was next seen in May 2006 for pre-operative assessment (transurethral resection) during which physical examination and chest radiographs were unremarkable. PFTs were relatively normal and similar to those observed in 2000; however, a decline in D LCO from 100% in 2000 to 76% in 2006 was noted ( table 2 ).

By the third consultation in September 2011, the patient had developed symptoms of typical ILD and had cancelled his gym membership 2 months earlier (July 2011) due to slowly emerging dyspnoea on exertion. The patient had a productive cough (one tablespoon of sputum in 24 h) and a 6-min walk test distance of 300 m. Initial treatment included clarithromycin and ciprofloxacin but both were terminated early due to side-effects. Mild digit clubbing and dorsobasal velcro crackles were noted during physical examination. The patient was also found to have post-thrombotic syndrome (which had also been seen earlier in his history) along with lower limb pitting oedema. PFTs showed a further reduction in D LCO from 2006 and decreases in FVC, forced expiratory volume in 1 s (FEV 1 ) and VC; FEV 1 /VC was 65% ( table 2 ).

Bronchoalveolar lavage (BAL) was performed but was technically biased due to the patient’s cough. BAL findings included a predominance of macrophages (97%) without significant lymphocytosis (3%), ciliated epithelial cells and detritus. HRCT showed basal fibrosis and honeycombing. SLB was not performed since all the HRCT criteria for UIP pattern, as specified by the 2011 ATS/ERS/JRS/ALAT guidelines, were fulfilled [ 5 ]. The patient was diagnosed with IPF by the MDT and started treatment with full-dose pirfenidone (2403 mg·day −1 ) and a PPI due to reflux symptoms.

In January 2011, the patient was admitted with an infrarenal aortic aneurysm which was stented without complication. At follow-up, the patient’s cough had resolved and his dyspnoea on exertion had improved sufficiently for him to resume his gym membership. PFTs performed in October 2012 revealed stabilisation of D LCO (51.2%) and higher VC, FVC and FEV 1 values in comparison to October 2011 ( table 2 ). An improvement was also seen on the chest HRCT scan in 2012 compared to the scan performed in 2011 ( fig. 4 ). At the most recent consultation in 2013 no significant changes were observed in the PFTs compared to October 2012, except for a decreased D LCO . The patient was also noted to have more pronounced finger clubbing.

Chest high-resolution computed tomography scans performed on a) August 16, 2011 and b) September 4, 2012.

The patient’s age, smoking history, clinical presentation and radiology findings are consistent with the diagnosis of IPF [ 5 ], which was also concluded in a MDT discussion. However, this case has several unusual features. Both the initial presentation of COP in 2000 preceding IPF and its resolution upon cessation of corticosteroids was remarkable. Still, very limited reports on the progression of COP to fibrosis with honeycombing have been described [ 12 ] and it has to be kept in mind that in rare patients acute exacerbation of IPF may comprise organising pneumonia at lung biopsy [ 13 ]. However, the clinical course of this patient does not support the hypothesis of chronic COP as the underlying disease results in fibrotic lung disease or an initial acute exacerbation of an IPF with radiological features of COP. Moreover, the concurrent diagnosis of COP and IPF has been described previously [ 14 ]. In addition, a FVC/FEV 1 of 67%, although within the lower limit of normal, is uncharacteristically low for an IPF patient without emphysema, which was not present in this patient, and might account for some bronchiolar involvement [ 15 ]. The treatment of the infrarenal aortic aneurysm also presented a dilemma regarding whether it was better to treat the aneurysm with general anaesthesia and open surgery, which can further stress the patient, or to stent the aneurysm under local anaesthesia and risk an increased immune response.

Besides the unusual features of this case, the improvement in lung function with pirfenidone treatment was noticeable and has only rarely been reported to date. This is supported by the results of randomised controlled trials on pirfenidone reported to date [ 16 – 18 ]. In these trials some similar individual cases have been described. However, the underlying pathophysiology of this interesting observation is not fully understood and should be explored further.

Atypical accelerated UIP: a special challenge?

Some patients with IPF follow a relatively rapid decline but it is not known if this represents a distinct phenotype. Further characterisation of these patients could be important, particularly regarding earlier diagnosis and early treatment.

A 73-year-old retired, male executive had a cough which persisted for 3 months and was unresponsive to antibiotics. The patient was an ex-smoker with a 40 pack-year smoking history and his past medical history included coronary artery disease for which he underwent stenting procedures in 2005 and 2007. The patient did not, however, receive amiodarone for this condition. Investigations included a chest radiograph which was followed by a HRCT scan, both of which showed irregular results.

The patient was first referred to the respiratory clinic in 2010. On examination, the patient appeared relatively well with no shortness of breath or finger clubbing; however, minimal bi-basal, fine, end-respiratory crackles were present during auscultation. Serology testing (extractable nuclear antigens screen and anti-cyclic citrullinated peptides) was negative but initial PFTs revealed a number of low parameters including total lung capacity (72% predicted), VC (72% pred), FVC (69% pred) and D LCO (61% pred). Resting oxygen saturation was normal (96%) but low under exertion (91%) ( table 3 ). HRCT showed mild reticulation and sub-pleural honeycombing ( fig. 5 ).

Initial high-resolution computed tomography scans performed in November 2011 showing mild reticulation and sub-pleural honeycombing. Representative sections of the lungs from a) the upper to f) the lower zones.

The patient was diagnosed with IPF which was followed by a progressive decline in lung function with worsening PFTs and HRCT scans.

In December 2012, the patient started pirfenidone therapy and disease progression was reduced or stabilised according to PFTs ( fig. 6 ) and HRCT scans ( fig. 7 ) for a period of 6 months. However, he subsequently deteriorated and was placed on the lung transplantation list. Following this, in July 2013, he suffered an acute exacerbation of IPF for which he was admitted and treated but died shortly afterwards.

Progression in the patient’s pulmonary function tests from 2010 to 2013. a) Forced vital capacity (FVC); b) total lung capacity (TLC); c) diffusing capacity of the lung for carbon monoxide ( D LCO ); d) 6-min walking distance (6MWD); and e) oxygen saturation (arrow indicates patient was receiving supplemental oxygen). Start: oxygen saturation at the beginning of the 6MWD; end: oxygen saturation at the end of the 6MWD.

Patient computed tomography scans performed in a) 2010, b) 2012 and c) 2013. Representative sections of the lungs from the upper region to the lower region (left to right).

IPF is a disease with a highly variable course. Currently, there is no reliable marker to predict which patients may exhibit a more rapidly progressive course. Therefore, the only way to identify such patients is to follow their pulmonary function parameters (FVC, D LCO and 6-min walking distance) and, potentially, in some patients radiological examinations ( i.e. HRCT) over time. However, by the time the physician recognises that the decline represents an accelerated (and irreversible) progression of the disease, rather than biological variability or acute exacerbations, it may already be too late to intervene in the progressive fibrotic process. Still, one might argue that early identification of rapid progressors is mainly important for lung transplant listing and with regards to prognosis but not for pharmacological treatment because there were no adverse treatment implications of not “catching the disease early”.

Since the approval of pirfenidone and perhaps with other potential treatments on the horizon, this now raises the question as to whether it is critically important from a therapeutic perspective to make a more rapid diagnosis and start pharmacological treatment earlier. This is an attractive possibility, but at this point it is only a hypothesis with no supporting evidence. Analysing the available evidence from the CAPACITY trials does not suggest that pirfenidone is more effective in patients with mild, early disease or that it is effective in more severe disease [ 16 ]. The beneficial effect of pirfenidone, as demonstrated in randomised, double-blind, placebo-controlled trials, was not dependent on patients being randomised during a progressive period. Personal experience and currently unpublished data raise the possibility that pirfenidone may contribute to disease stabilisation in slightly more progressive phenotypes. In the absence of a defined “pirfenidone-responsive phenotype”, individual decisions on the optimal time to start treatment need to be made. While comparison of pre- and post-treatment trajectories of FVC decline may represent an attractive option to monitor disease progression, the highly variable and unpredictable nature of disease progression in IPF makes it difficult to assess treatment response in individual patients.

This was our intention in initiating treatment with pirfenidone in this case. It is interesting that examination of pulmonary function data, as well as clinical follow-up, suggests that initially there was a beneficial response to pirfenidone treatment. We noted a tendency for improvement in FVC, 6-min walking distance and oxygen saturations. However, despite receiving treatment with pirfenidone, the patient developed a fatal exacerbation of IPF. Whether earlier institution of pirfenidone would have stabilised (or improved) his pulmonary function is not yet supported by data and clinical trials with pirfenidone do not demonstrate prevention of acute exacerbations [ 16 ]. We await publication of further clinical data with pirfenidone, such as the ASCEND trial, which may further help to answer some of these questions, such as when it may be best to start treatment with pirfenidone, in which types of patients, the magnitude of benefit in terms of stabilising lung function, and evidence for future treatment modalities that may reduce the risk of exacerbations.

• Acknowledgments

The author contributions are as follows. Case 1: Michael Kreuter; Case 2: Peter Kardos; and Case 3: Victor Hoffstein.

This article is based on the proceedings of the 2013 Advancing IPF Research (AIR) meeting (Nice, France), which was sponsored by InterMune International AG (Muttenz, Switzerland). Medical writing support was provided by Michael Smith (IntraMed International, Milan, Italy), which was funded by InterMune International AG.

Provenance: Publication of this peer-reviewed article was sponsored by InterMune International AG, Muttenz, Switzerland (article sponsor, European Respiratory Review issue 132).

Conflict of interest: Disclosures can be found alongside the online version of this article at err.ersjournals.com

• Received March 10, 2014.
• Accepted March 14, 2014.

ERR articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0 .

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Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis

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• Peer review
• Gabrielle Y Liu , pulmonary and critical care fellow ,
• G R Scott Budinger , professor of medicine , chief of pulmonary and critical care in the Department of Medicine ,
• Jane E Dematte , professor of medicine
• Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA
• Correspondence to: J E Dematte j-dematte{at}northwestern.edu

Similarly to idiopathic pulmonary fibrosis (IPF), other interstitial lung diseases can develop progressive pulmonary fibrosis (PPF) characterized by declining lung function, a poor response to immunomodulatory therapies, and early mortality. The pathophysiology of disordered lung repair involves common downstream pathways that lead to pulmonary fibrosis in both IPF and PPF. The antifibrotic drugs, such as nintedanib, are indicated for the treatment of IPF and PPF, and new therapies are being evaluated in clinical trials. Clinical, radiographic, and molecular biomarkers are needed to identify patients with PPF and subgroups of patients likely to respond to specific therapies. This article reviews the evidence supporting the use of specific therapies in patients with IPF and PPF, discusses agents being considered in clinical trials, and considers potential biomarkers based on disease pathogenesis that might be used to provide a personalized approach to care.

Introduction

The term interstitial lung disease (ILD) encompasses a group of diffuse parenchymal lung diseases with varied clinical, radiographic, and pathologic manifestations reflecting their diverse underlying pathobiology. A subset of ILDs have a progressive fibrosing phenotype. Idiopathic pulmonary fibrosis (IPF) almost invariably has this phenotype. However, other ILDs may also develop this and are thereby termed progressive pulmonary fibrosis (PPF), previously known as progressive fibrosing interstitial lung disease (PF-ILD). 1 2 3 4 In this review, we will use PPF to refer specifically to non-IPF ILDs that have a progressive fibrosing phenotype. IPF and PPF share common downstream mechanistic pathways resulting in self-sustaining fibrosis that may be independent of the initial injury or trigger. However, PPF often begins with an inflammatory phase triggered by either an endogenous autoantigen or an exogenous antigen, such as an environmental trigger. 5 6 7 Therefore, making a distinction between the two is important, particularly when designing clinical trials and research studies for PPF. Connective tissue disease associated ILD (CTD-ILD), including rheumatoid arthritis associated ILD (RA-ILD), systemic sclerosis associated ILD (SSc-ILD), and myositis associated ILD, as well as chronic hypersensitivity pneumonitis (cHP), sarcoidosis, idiopathic nonspecific interstitial pneumonia (iNSIP), and unclassifiable ILD, are the ILDs most likely to develop a progressive fibrosing phenotype. However, the proportion of patients with these ILDs who develop this phenotype can vary significantly—from an estimated 13% of patients with fibrotic iNSIP to an estimated 87% of patients with cHP. 8 9

Beyond prognostication, identifying patients with PPF is clinically important because evidence from randomized placebo controlled clinical trials shows that nintedanib can slow decline in lung function in both patients with IPF and those with PPF. 10 11 12 This review summarizes the epidemiology and pathophysiology of IPF and PPF, their currently approved treatments, and promising therapies in the pipeline. It highlights the need for therapeutic trials based on specific biomarkers to develop a more personalized approach to therapy for patients with IPF and PPF in the future.

Sources and selection criteria

We searched PubMed and Ovid MEDLINE databases from 2000 to April 2021 using the following search terms: progressive fibrosing interstitial lung disease, idiopathic pulmonary fibrosis, pulmonary fibrosis, connective tissue disease associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, scleroderma interstitial lung disease, systemic sclerosis interstitial lung disease, sarcoidosis, myositis interstitial lung disease, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, unclassifiable interstitial lung disease, biomarkers interstitial lung disease, and biomarkers idiopathic pulmonary fibrosis. We reviewed published management guidelines from websites of professional societies and governmental bodies, including the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), Latin American Thoracic Association (ALAT), UK National Institute for Health and Care Excellence (NICE), Thoracic Society of Australia and New Zealand (TSANZ), and Lung Foundation of Australia (LFA). We also searched clinicaltrials.gov for all active phase 3 clinical trials for the treatment of idiopathic pulmonary fibrosis, as well as all active and completed phase 2 and 3 clinical trials of nintedanib and pirfenidone for the treatment of PF-ILDs/PPF. We included only full length, peer reviewed studies published in English. We prioritized phase 3 randomized controlled trials (RCTs), phase 2 RCTs, systematic reviews with meta-analyses, and observational cohort studies, in that order. Case reports were excluded. We also focused on high quality basic science manuscripts that contribute to the understanding of the pathobiology of pulmonary fibrosis and lung injury repair and the key mechanisms of action underlying the therapies reviewed. We reviewed basic science manuscripts with preclinical studies in mouse models of pulmonary fibrosis that provide insights into the pathobiology of lung fibrosis. We determined the quality of basic science papers by their selection for publication in high impact journals, their reproducibility across laboratories, their citations by other investigators, and qualitative assessment by the authors. The abstracts of more than 250 papers were reviewed by at least one of the authors, and more than 169 papers were reviewed in detail.

After the original search date in April 2021, the ATS/ERS/JRS/ALAT clinical practice guideline on IPF (an update) and PPF in adults was published in May 2022. 4 Therefore, this review was updated to use the term “PPF” rather than “PF-ILD,” as determined by this guideline. We updated the algorithm ( fig 1 ) to include the conditional recommendation that transbronchial lung cryobiopsy may be used as an alternative to surgical lung biopsy for making a histopathologic diagnosis in patients with ILD of undertermined type. We also updated the sections on “Conceptualizing and defining PPF,” “Currently approved therapy for IPF: Antacid therapy,” and “Guidelines” to reflect the updated clinical practice guideline.

Suggested algorithm for the evaluation and management of suspect fibrosing interstitial lung disease (ILD). *†American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines suggest bronchoalveolar lavage (BAL) cellular analysis and surgical lung biopsy or transbronchial lung cryobiopsy in the evaluation of patients in whom IPF is clinically suspected or who have an ILD of uncertain etiology and have a high resolution computed tomography (HRCT) pattern of probable usual interstitial pneumonia (UIP), indeterminate for UIP, or an alternative diagnosis. 13 BAL cellular fluid analysis, surgical lung biopsy, and transbronchial lung biopsy are not recommended in patients in whom idiopathic pulmonary fibrosis (IPF) is clinically suspected and who have an HRCT pattern of UIP. CTD-ILD=connective tissue disease associated interstitial lung disease; DLCO=diffusing capacity of the lung for carbon monoxide; FVC=forced vital capacity; GERD=gastresophageal reflux; iNSIP=idiopathic nonspecific interstitial pneumonia; IPAF=interstitial pneumonia with autoimmune features; LTOT=long term oxygen therapy; PFT=pulmonary function test; PPF=progressive pulmonary fibrosis

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Conceptualizing and defining PPF

The concept of grouping several non-IPF fibrosing ILDs together grew in part out of the recognition that an unmet need existed for treatment options for these lung diseases. Apart from SSc-ILD, robust RCT data to support the use of immunosuppression in fibrosing ILDs have been lacking. Additionally, many patients with fibrosing ILDs progressed despite conventional treatment. However, a challenge to the design of a robust randomized clinical trial to evaluate new therapies was the fact that the prevalence of each individual fibrosing ILD is relatively low. Thus, the term PF-ILD first came into use in 2017 with the design and development of the INBUILD trial (clinicaltrials.org; NCT02999178 ). INBUILD was a randomized, double blind, placebo controlled trial to study the efficacy and safety of nintedanib in patients with ILD diagnoses that were noted to behave similarly to IPF in that they were characterized by progressive pulmonary fibrosis, declining lung function, resistance to immunomodulatory therapies, and early mortality. 1

Before the publication of the ATS/ERS/JRS/ALAT clinical practice guideline on PPF in 2022, PF-ILD had been largely defined by selection criteria for clinical trials. Three randomized clinical trials—INBUILD, 12 RELIEF (German Clinical Trials Register; DRKS00009822), 14 and a phase 2 clinical trial evaluating the use of pirfenidone in patients with progressive fibrosing unclassifiable ILD ( NCT03099187 ) 15 —have proposed criteria for progressive fibrosis. The Erice ILD Working Group also proposed criteria for defining PPF. 16 These criteria shared several common elements. Firstly, the diagnosis must be an ILD other than IPF. This distinction is particularly important when considering the use of these criteria for the purpose of selecting populations for clinical trials. The ATS/ERS/JRS/ALAT clinical practice guideline underscores that PPF is not a diagnosis, but rather a manifestation of certain ILDs, and is agnostic to the underlying condition. 4 Secondly, evidence of fibrotic changes on high resolution computed tomography (HRCT) imaging must be present. These fibrotic features include coarse reticulation with traction bronchiectasis and honeycombing. INBUILD and the study of pirfenidone in unclassifiable ILD both required that participants have fibrotic changes on HRCT affecting at least 10% of lung volume at the time of enrollment. 12 15 Thirdly, evidence of progression of lung disease despite conventional treatment must exist. Each of these groups and trials had defined progression differently; however, with the 2022 ATS/ERS/JRS/ALAT clinical practice guideline, a consensus definition of PPF was determined and is shown in box 1 .

Identifying progressive pulmonary fibrosis 4

Interstitial lung disease diagnosis other than idiopathic pulmonary fibrosis

Radiologic evidence of pulmonary fibrosis

Evidence of progression, defined as meeting at least two of three criteria within the previous year with no alternative explanation:

Worsening respiratory symptoms

Absolute decline in FVC >5% predicted or absolute decline in DLCOc ≥10% predicted within one year of follow-up

Radiologic evidence of progression, including:

Increased extent or severity of traction bronchiectasis or bronchiolectasis

New ground glass opacity with traction bronchiectasis

New fine reticulation

Increased extent or coarseness of reticulations

New or increased honeycombing

Increased lobar volume loss

DLCOc=diffusing capacity of the lung for carbon monoxide corrected for hemoglobin; FVC=forced vital capacity

Progression of fibrosis may be more relevant than just its presence. A study that followed patients from the Scleroderma Lung Studies I and II for a median of eight years found that decline in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) over two years was a better predictor of mortality than baseline FVC and DLCO. 17 However, progression can be determined only by serial testing, which may delay lung preserving therapy. Figure 1 shows a suggested algorithm for the evaluation and management of patients with suspected fibrosing ILD.

Epidemiology

Idiopathic pulmonary fibrosis.

IPF is the first or second most commonly encountered ILD in pulmonary practice and is estimated to account for 17-37% of all ILD diagnoses. 18 19 The incidence of IPF in the US and Europe is estimated to be 3-17 per 100 000 person years. 18 19 20 The lowest incidence rate of IPF globally is in Asia, with rates ranging from 1.2 to 4.6 per 100 000 per year. 21 In a study using Medicare data limited to people in the US aged 65 years and older, the incidence of IPF was as high as 93.7 per 100 000 person years and the prevalence was 494.5 cases per 100 000, reflecting age as the major risk factor for IPF. 22

Most common ILDs manifesting PPF

Rheumatoid arthritis is the most common autoimmune disease worldwide and is estimated to have a prevalence of 400-1000 cases per 100 000. 21 Clinically significant ILD occurs in 8-20% of patients with rheumatoid arthritis and is more common in men and those with greater overall disease severity. 21 23 The proportion of patients with RA-ILD who have progressive decline in lung function is estimated at 40%, on the basis of a study that found that 40% of patients with RA-ILD had a DLCO <40% predicted by five years after diagnosis of ILD. 24 The detection of a usual interstitial pneumonia (UIP) pattern on HRCT scan is associated with increased risk of both progressive lung disease and death, compared with a nonspecific interstitial pneumonia (NSIP) or organizing pneumonia pattern. 24 25

The prevalence of systemic sclerosis is estimated to be 7.2-33.9 cases per 100 000 in Europe and 13.5-44.3 cases per 100 000 in North America. 26 The proportion of people with systemic sclerosis who have SSc-ILD is as high as 90% on the basis of HRCT scanning. 27 Of patients with SSc-ILD, 18-25% have progressive worsening of lung function or HRCT findings. 10 28 29 30 Clinical features that predict progressive ILD include Black/African-American race, older age at disease onset, diffuse cutaneous skin disease, detection of antitopoisomerase antibodies, and lower baseline FVC and DLCO. 31 32 Histologic patterns of NSIP or UIP are not significantly associated with overall mortality in SSc-ILD. 33

Myositis related ILD

Idiopathic inflammatory myopathies are a group of rare systemic autoimmune disorders characterized by inflammation of skeletal muscle and sometimes skin, with a reported incidence of 0.2-0.9 cases per 100 000 person years. 34 The subtypes most commonly associated with ILD are dermatomyositis, polymyositis, and antisynthetase syndrome. 35 The reported prevalence of ILD in myositis ranges widely from 19.9% to 86%. 35 In a single center retrospective study, 31% of patients diagnosed as having myositis had ILD. 36 Of the patients with ILD, 33% had complete resolution of their lung disease with treatment and 16% had deterioration of their ILD after a median 34 months of follow-up. 36 An organizing pneumonia pattern on HRCT often responds to immunosuppressive therapy leading to clinical resolution of disease, whereas a UIP pattern is associated more often with progressive disease and clinical deterioration. 36 37 38 39

Chronic hypersensitivity pneumonitis

In a study using US administrative claims based data, the prevalence of hypersensitivity pneumonitis was estimated to be only 1.67-2.71 cases per 100 000, of which approximately 25% met criteria for fibrotic or chronic hypersensitivity pneumonitis. 40 However, in studies from cohorts of patients with ILD of new onset, a clinical diagnosis of hypersensitivity pneumonitis is made in 18-47% of patients. 41 42 43 Most patients with hypersensitivity pneumonitis who have fibrotic disease at baseline will have progressive disease. 8 44 45 Salisbury and colleagues found that compared with patients with IPF, those with cHP and honeycombing on HRCT had a greater decline in FVC and similar median survival. 8

Idiopathic NSIP

The estimated prevalence of iNSIP is 1-9 cases per 100 000. 46 In a retrospective cohort study of patients with fibrotic iNSIP, 13% had progression of radiologic findings on HRCT, 36% had radiologic improvement, and 23% had stable findings. 9 The prognosis of fibrotic iNSIP is generally better than that of IPF, with a five year survival rate ranging from 45% to 90%. 47 48 49

Sarcoidosis

In the US, the prevalence of sarcoidosis is 141.4 per 100 000 in people identifying as Black or African-American, 49.8 in those identifying as white, 21.7 in those identifying as Hispanic, and 18.9 in those identifying as Asian. 50 Fibrotic (stage IV) lung disease is estimated to occur in less than 20% of people with pulmonary sarcoidosis. 51 52 In a retrospective cohort study of patients with stage IV sarcoid, 24.8% had worse lung function after a mean 6.2 years of follow-up, whereas lung function was improved in 39.3% and stable in 35.9%. 53

Unclassifiable ILD

The proportion of patients with new onset ILD who are deemed to have unclassifiable ILD after multidisciplinary discussion was 10% in one single center retrospective study. 54 In this study, 52% of patients had significant progressive decline in lung function or death. Additionally, patients with unclassifiable ILD had longer survival rates compared with IPF and similar survival compared with other ILDs with progressive fibrosis. 54

Pathophysiology

Pulmonary fibrosis is increasingly recognized to begin with damage to the epithelium, possibly induced by environmental insults including cigarette smoke, viruses, environmental dusts (for example, silica or asbestos), or, perhaps, autoimmune injury ( fig 2 ). 55 56 In support of this hypothesis, some genetic mutations associated with pulmonary fibrosis involve genes that are exclusively expressed in the lung epithelium. These include a mutation in the promoter region of MUC5B that enhances its expression and mutations in SFTPC that lead to production of a misfolded protein. 57 58 59 Furthermore, genetic studies in mice localize the fibrotic effects of mutations in genes associated with pulmonary fibrosis that are expressed in all cells to the lung epithelium. Important examples include deficiency in genes that maintain telomere length and genes associated with the Hermansky-Pudlak syndrome. 60 61 62

Mechanisms and signals involved in the development of pulmonary fibrosis and therapeutic targets. During normal repair after lung injury, tissue resident alveolar macrophages interact with other cells in the alveolar epithelium to clear apoptotic cells, particulates, and pathogens without disrupting the normal gas exchanging functions of the alveolus. Alveolar type 2 (AT2) cells differentiate into alveolar type 1 (AT1) cells, passing through a transitional state characterized by expression of keratin-17, thereby restoring the normal alveolar epithelium. During disordered repair, recurring injuries to alveolar epithelium, by either environmental insults or antigen stimulation, cause AT1 cell death as well as aberrant activation of AT2 cells. The process of AT2 cells differentiating into AT1 cells is impaired in regions of lung fibrosis. Partially differentiated keratin-17 positive (KRT17+) epithelial cells accumulate, where they are associated with fibrosis. These KRT17+ cells produce large amounts of connective tissue growth factor (CTGF) and express αvβ6 integrin, which has been shown to activate latent transforming growth factor β (TGF-β), both of which promote differentiation of fibroblasts into myofibroblasts. The abnormally activated alveolar epithelial cells also contribute to fibroblast and myofibroblast proliferation through the production of platelet derived growth factor (PDGF), TGF-β, and CTGF. In response to this failed attempt at epithelial repair, circulating monocytes are recruited into the alveolar space and differentiate into profibrotic alveolar macrophages. These monocyte derived alveolar macrophages (Mo-AM) secrete PDGF and other growth factors that promote the activation and proliferation of fibroblasts as well as their differentiation into myofibroblasts. In a reciprocal positive feed-forward loop, fibroblasts secrete macrophage colony stimulating factor (M-CSF), which maintains alveolar macrophages at the site of injury. Myofibroblasts secrete excessive extracellular matrix (ECM) proteins, leading to stiffening of lung tissue. Myofibroblasts over time produce TGF-β in an autocrine manner and lose their need for macrophages in order to proliferate. The stiff matrix inhibits fibroblast apoptosis in another positive feed-forward loop that contributes to self-sustaining fibrosis. Recombinant human pentraxin (rhPTX)-2 has been proposed to inhibit the recruitment of alveolar macrophages to areas of fibrosis, which in turn inhibits myofibroblast activation. Nintedanib (NTB) likely inhibits fibroblasts by blocking PDGF signaling, among other profibrotic signaling pathways. The exact mechanisms by which pirfenidone (PFD) slows the progression of interstitial pulmonary fibrosis remain incompletely understood. Pamrevlumab (Pmab) is an anti-CTGF antibody that also likely inhibits fibroblasts

The advent of single cell RNA sequencing and its application to animal models of lung fibrosis and clinical samples from patients with pulmonary fibrosis have brought the multicellular nature of pulmonary fibrosis into focus. 63 64 65 66 67 68 Repair of the injured alveolar epithelium requires the asymmetric division followed by differentiation of alveolar type 2 cells into alveolar type 1 cells. 69 70 During the process of alveolar type 2 to type 1 cell differentiation, a transitional cell population characterized by expression of keratin-8 in mice and keratin-17 in humans forms. 68 71 72 73 These keratin-8 or keratin-17 positive epithelial cells are found at low concentrations in the normal mouse or human lung, but they increase during pulmonary fibrosis and are specifically localized to fibrotic lung regions in mice and humans. 64 65 68 71 72 74 These results suggest that normal epithelial repair is disrupted in regions of lung fibrosis. In response to this failed repair, circulating monocytes are recruited to the alveolar space where they rapidly differentiate into profibrotic monocyte derived alveolar macrophages. 62 75 76 77 These alveolar macrophages form reciprocal circuits with matrix fibroblasts in which fibroblasts secrete macrophage colony stimulating factor (M-CSF) to maintain alveolar macrophages at the site of injury and alveolar macrophages secrete platelet derived growth factor (PDGF) and other growth factors that drive the differentiation of fibroblasts into myofibroblasts, which excrete excessive matrix proteins. 66 78 In addition, alveolar epithelial injury induces the activation of latent transforming growth factor β (TGF-β) in the matrix. 79 TGF-β is a cytokine that modulates cellular differentiation, proliferation, and apoptosis, as well as extracellular matrix production. 80 It also maintains alveolar macrophages and activates myofibroblasts. 81 82 Over time, myofibroblasts lose their requirement for alveolar macrophages for proliferation and matrix secretion, in part through autocrine production and activation of TGF-β, 83 84 resulting in spatially restricted regions of progressive fibrosis. 78 This model of pulmonary fibrosis suggests a multimodal strategy for treatment. Such a strategy might include therapies to accelerate the differentiation of alveolar type 2 into alveolar type 1 cells through inhibition of the integrated stress response, 68 85 therapies that reduce the recruitment or prevent the maintenance of profibrotic monocyte derived alveolar macrophages in the alveolar space, 86 and therapies that target signaling through TGF-β, PDGF, and other growth factors in myofibroblasts (for example, nintedanib). 11

Management of IPF

Currently approved treatment.

The most recent ATS/ERS/JRS/ALAT clinical practice guideline on the treatment of IPF recommends only two drugs for the treatment of IPF—pirfenidone and nintedanib. 4 The 2015 ATS/ERS/JRS/ALAT guideline also included a conditional recommendation for antacid therapy, and therefore its evidence is also discussed here. 87 Table 1 lists the major clinical trials that examined the use of pirfenidone and nintedanib in the treatment of IPF and PPF.

Major randomized clinical trials evaluating the use of antifibrotic medications in the treatment of IPF and progressive pulmonary fibrosis (PPF)

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Pirfenidone

The US Food and Drug Administration (FDA) approved pirfenidone for the treatment of IPF in October 2014. The approval was based on data from three phase 3 clinical trials—CAPACITY I, CAPACITY II, and ASCEND. With pooled data from the CAPACITY I and II trials, primary endpoint analysis found that pirfenidone reduced the mean decline in FVC per cent predicted over 72 weeks compared with placebo (−8.5% v −11.0%; P=0.005). 88 The ASCEND trial found that pirfenidone led to a 47.9% reduction in the proportion of particpants who had an absolute decline of 10% or more in the FVC per cent predicted or who died after 52 weeks (16.5% v 31.8%; P<0.001). 89 Prespecified secondary analyses that pooled data with the two CAPACITY trials found that treatment with pirfenidone was associated with decreased all cause mortality (3.5% v 6.7%; P=0.01) and IPF specific mortality (1.1% v 3.5%; P=0.006), compared with placebo. 89 Separate post hoc analysis of pooled data from the CAPACITY and ASCEND trials also found that participants receiving pirfenidone had a lower risk of respiratory related hospital admissions (7% v 12%; P=0.001). 91 The exact mechanisms by which pirfenidone slows the progression of IPF are not known, although several have been proposed. 92

The US FDA also approved nintedanib for the treatment of IPF in October 2014. This was based on two INPULSIS phase 2 clinical trials, which both found that nintedanib reduced the annual rate of decline in FVC at week 52 compared with placebo. 11 In INPULSIS 1, the difference in annual rate of decline in FVC was 125.3 (95% confidence interval 77.7 to 172.8) mL/year (P<0.001); in INPULSIS 2, the difference was 93.7 (44.8 to 142.7) mL/year (P<0.001). In prespecified pooled analyses, no significant difference was seen between nintedanib and placebo groups in the time to first investigator reported acute exacerbation, death from any cause, or death from a respiratory cause. Nintedanib is a tyrosine kinase inhibitor that was originally developed as an anti-angiogenic cancer drug designed to bind and block platelet derived growth factor receptor (PDGFR), fibroblast growth factor receptor 1 (FGFR-1), and vascular endothelial growth factor receptor 2. 93 94 PDGF is made by alveolar macrophages in response to injury and inflammation and contributes to the proliferation, survival, and migration of myofibroblasts, which deposit extracellular matrix proteins in the interstitial space. 94 95 FGF/FGFR signaling also contributes to lung fibrosis, specifically through FGF-2 which induces fibroblast proliferation and collagen synthesis in lung fibroblasts and myofibroblasts. 96 97 Through its inhibition of growth factor signaling, nintedanib is thought to reduce the proliferation and migration of lung fibroblasts, the transdifferentiation of fibroblasts to myofibroblasts, and the deposition of extracellular matrix. 94

Antacid therapy

Abnormal gastroesophageal reflux is common in patients with IPF and is a known risk factor for aspiration and microaspiration. 98 Regular use of antiacid therapy, either with proton pump inhibitors or histamine-2 blockers, is believed to decrease the lung injury induced by microaspiration of acidic gastric juices. 99 Although the 2015 ATS/ERS/JRS/ALAT IPF treatment guidelines give a conditional recommendation for the use of antacid therapy, even in patients without symptoms of gastroesophageal reflux, the 2022 updated guideline makes a conditional recommendation against its use for the purpose of improving respiratory outcomes. 4 The TSANZ/LFA guidelines state that antacid therapy has unclear benefit and do not make a recommendation for or against its use. 101 When examining IPF patients in the placebo arms of RCTs, one study that used the IPFnet trials found that antacid use at baseline was associated with reduced decline in FVC 102 ; however, a more recent study using the CAPACITY and ASCEND trials found that antacid therapy did not improve outcomes and was associated with an increased risk of infection in patients with advanced lung disease. 103 Similarly, the WRAP-IPF trial, a phase II randomized, unblinded, controlled trial, found that laparoscopic antireflux surgery in patients with IPF and abnormal gastroesophageal reflux did not significantly reduce the decline in FVC over 48 weeks. 104 However, in a pilot randomized, placebo controlled trial of participants with IPF and a history of cough, omeprazole use was associated with a reduction in cough frequency of 39.1% (−66.0% to 9.3%), although it was not statistically significant owing to small sample size. 105

Non-drug management

The most recent guidelines from leading international societies of pulmonary medicine recommend long term oxygen therapy for IPF patients with resting hypoxemia, as well as referrals for pulmonary rehabilitation and lung transplant evaluation in appropriate patients. 101 106 107 The current recommendation for supplemental oxygen therapy in IPF is largely based on indirect evidence from two landmark RCTs in obstructive lung disease that showed a survival benefit with long term oxygen therapy in patients with resting hypoxemia (PaO 2 55-65 mm Hg). 108 109 Evidence to directly support the use of supplemental oxygen in people with IPF and resting or exertional hypoxemia is limited. A 2016 Cochrane review that included three RCTs found no evidence to support or refute the use of ambulatory or short burst oxygen in patients with ILD and exertional hypoxemia owing to the limited data 110 ; however, a subsequent systematic review that included studies examining the use of oxygen during exercise or exercise training found that ambulatory oxygen was associated with a consistent increase in exercise capacity. 111

Pulmonary rehabilitation is a comprehensive intervention that includes exercise training, education, and behavior change. 112 A Cochrane review that included five randomized or quasi-randomized controlled trials found that among people with ILD, and IPF specifically, significant improvements in exercise capacity, dyspnea, and quality of life were seen immediately after pulmonary rehabilitation, with the quality of evidence rated as low to moderate. 113 A subsequent meta-analysis of four RCTs found that, in patients with IPF, pulmonary rehabilitation had no detectable benefit at long term follow-up. 114 The current ATS/ERS/JRS/ALAT guidelines recommend that most patients with IPF be treated with pulmonary rehabilitation (weak recommendation, low quality of evidence). 106

Given the progressive natural history of IPF, with a median survival time of 3.8 years after diagnosis, 22 guidelines recommend that appropriate patients undergo lung transplantation and that discussion of transplantation should occur at the time of diagnosis or soon after. 101 106 107 In North America, the percentage of lung transplants performed in patients with IPF has been increasing over the past three decades, and from 2010 to 2018 IPF was the most common indication for lung transplantation. 115 Although post-transplant survival is worse for patients with IPF than for those with COPD and other matched non-IPF patients, 115 116 lung transplantation is associated with a 75% reduction in risk of death. 117 From 1992 to 2017 median survival time for patients with IPF was 5.2 years post-transplant, which increased to 7.3 years among those who survived at least one year post-transplant. 118

Therapies in the pipeline for treatment of IPF

Several drugs for the treatment of IPF—recombinant human pentraxin 2, pamrevlumab, treprostinil, and N-acetylcysteine—have recent phase 3 clinical trials. Table 2 lists these trials along with the data from the phase 2 and 3 trials that support the potential role of these drugs as treatment for IPF.

Recent active phase 3 clinical trials of treatments for idiopathic pulmonary fibrosis and phase 2/3 trials supporting their study

Recombinant human pentraxin 2 (rhPTX-2; PRM-151)

PRM-151 is a recombinant human pentraxin 2 protein (rhPTX-2). Pentraxin 2, also known as serum amyloid P, inhibits the recruitment of profibrotic monocyte derived alveolar macrophages to areas of fibrosis. 123 This is predicted to limit signaling by macrophages that drive matrix remodeling and myofibroblast activation. 63 75

The effect of rhPTX-2 was studied in a phase 2 double blind, randomized, placebo controlled trial of patients with mild to moderate IPF. 86 Concurrent therapy with pirfenidone or nintedanib was permitted. For the primary efficacy endpoint, the least squares mean change in FVC per cent predicted at week 28 in participants treated with rhPTX-2 was −2.5, compared with −4.8 in those given placebo (difference of 2.3, 90% confidence interval 1.1 to 3.5; P=0.001). An open label extension study found a persistent treatment effect in participants who continued taking rhPTX-2, with a decline in the FVC per cent predicted of −3.6% per year. 119 In participants who started taking rhPTX-2, FVC decline improved from −8.7 per cent predicted per year in weeks 0-28 (while taking placebo) to −0.9 per cent predicted per year in weeks 28-52. Thirteen (12%) of 111 participants had adverse events that led to discontinuation of rhPTX-2. Four participants had events that were considered by investigators to be related to rhPTX-2, including IPF exacerbation, tendinitis, dysgeusia, and cardiomyopathy. A phase 3 randomized, double blind, placebo controlled trial to study the efficacy and safety of rhPTX-2 began recruitment in March 2021, with an estimated study completion date in March 2023 ( NCT04552899 ).

Pamrevlumab

Pamrevlumab is an anti-connective tissue growth factor (CTGF) antibody under investigation for the treatment of IPF. CTGF is a mediator of tissue remodeling, acting downstream of TGF-β on connective tissue cells and functioning to stimulate fibroblast proliferation and the production of extracellular matrix. 124 125 CTGF is produced at high concentrations by airway and epithelial cells, as well as by activated fibroblasts in the lung tissue of patients with IPF. 64

The effect of pamrevlumab in patients with IPF was investigated in the phase 2 randomized, double blind, placebo controlled PRAISE trial. 120 Patients included had mild to moderate IPF and were not permitted to be on treatment with pirfenidone or nintedanib. Patients treated with pamrevlumab had a decline in FVC of 2.9 per cent predicted per year compared with 7.2 per cent predicted per year with placebo (difference of 4.3 (0.4 to 8.3) per cent predicted per year; P=0.033). The proportion of patients with disease progression, as defined by decline from baseline FVC per cent predicted ≥10% or death at week 48, was also reduced in the pamrevlumab group compared with the placebo group (10.0% v 31.4%; P=0.013). The frequency of adverse events was similar in the pamrevlumab and placebo groups, and the events were generally mild or moderate in severity and typical of participants’ underlying medical conditions. ZEPHYRUS 1 and 2 are ongoing phase 3 randomized, placebo controlled trials to further evaluate the use of pamrevlumab in patients with IPF and are estimated to complete in 2023 ( NCT03955146; NCT04419558 ).

Inhaled treprostinil

Treprostinil is a prostacyclin analog that is approved by the US FDA as an inhaled solution (Tyvaso) for treatment of pulmonary arterial hypertension and pulmonary hypertension associated with ILD. Inhaled treprostinil causes vasodilation of pulmonary and systemic arterial vascular beds and inhibits platelet aggregation. 126 It has also been shown to reduce collagen deposition in a bleomycin induced mouse model of pulmonary fibrosis, in part by inhibiting TGF-β1 induced expression of collagen mRNA and protein. 127

INCREASE was a randomized, double blind trial that examined the use of inhaled treprostinil in the treatment of pulmonary hypertension in people with ILD. 121 The trial met its primary efficacy endpoint in finding that the least squares mean difference between the inhaled treprostinil group and placebo group in the change from baseline six minute walk distance was 31.12 (16.85 to 45.39) m; P<0.001). Serious adverse events were similar in the inhaled treprostinil and placebo groups. Post hoc analysis found a difference in change in FVC per cent predicted of 1.8% (0.2% to 3.4%; P=0.028), favoring inhaled treprostinil over placebo, by week 16. 128 Notably, this study also found that the largest treatment effect occurred in patients with IPF. Based on these data, a phase 3 randomized, double blind, placebo controlled study began in April 2021 to evaluate the safety and efficacy of inhaled treprostinil in people with IPF, with change in FVC as the primary outcome measure ( NCT04708782).

N-acetylcysteine

N-acetylcysteine is a tripeptide precursor of glutathione that has antioxidant effects in the lung. 129 130 Three randomized, placebo controlled trials have examined the use of N-acetylcysteine monotherapy in the treatment of IPF. 131 132 133 The primary outcome in each of these studies was change in FVC, and none found a significant difference between N-acetylcysteine and placebo groups. Similarly, after the results of these three RCTs were pooled, no significant benefit on mortality, change in FVC, quality of life, or adverse outcomes was seen. 87 Two randomized, placebo controlled studies, including the PANORAMA study, then examined N-acetylcysteine in combination with pirfenidone in patients with IPF. 134 135 Although neither found a significant difference in the incidence of adverse events, both studies found a greater decline in FVC in patients receiving N-acetylcysteine; however, both were limited by small sample size.

However, a post hoc analysis of the PANTHER-IPF trial, which randomized participants with IPF to receive N-acetylcysteine monotherapy, combined prednisone, azathioprine, and N-acetylcysteine, or placebo, identified a subgroup of patients with the TOLLIP TT genotype in which N-acetylcysteine monotherapy was associated with a significant decrease in the composite endpoint of lung disease progression, hospital admission, transplantation, or death (hazard ratio 0.14, 95% confidence interval 0.02 to 0.83; P=0.03). 136 The TOLLIP CC genotype was associated with a non-significant increase in risk of the composite endpoint (hazard ratio 3.23, 0.79 to 13.16; P=0.10), which was significant in replication cohorts. Based on these data, the PRECISIONS trial is a phase 3 clinical trial comparing the effect of N-acetylcysteine plus standard care in patients with IPF who have the TOLLIP TT genotype ( NCT04300920 ).

Treatment of inflammatory ILDs

The currently accepted treatment for inflammatory ILDs, including CTD-ILD, cHP, iNSIP, and unclassifiable ILD, is immunosuppression. However, the only RCT data supporting this approach come from studies in patients with SSc-ILD. 137 138 139 Additionally, the only immunosuppressive drug that is approved by the FDA for the treatment of SSc-ILD is tocilizumab. FaSScinate, a phase 2/3 RCT, and focuSSced, a phase 3 RCT, were the basis for the FDA approval of tocilizumab for the treatment of SSc-ILD. 139 140 The focuSSced trial randomly assigned 210 people with diffuse cutaneous systemic sclerosis to receive tocilizumab or placebo. 139 People with severe ILD were excluded, and the cohort had a mean baseline FVC per cent predicted of 82% and evidence of SSc-ILD on HRCT in 65% of cases. Although the primary endpoint of change in the modified Rodman skin score was not met, on analysis of secondary outcomes participants who received tocilizumab had less decline in FVC per cent predicted than did those who received placebo (absolute difference in least square mean of 4.2%, 2.0% to 6.4%; P=0.0002).

Although cyclophosphamide and mycophenolate mofetil are not approved by the FDA for the treatment of SSc-ILD, their use is supported by the Scleroderma Lung Studies I and II. In the Scleroderma Lung Study I, which randomized 158 patients with SSc-ILD to receive cyclophosphamide or placebo, the mean absolute difference in adjusted FVC per cent predicted at 12 months was 2.53% (0.28% to 4.79%; P<0.03), favoring cyclophosphamide. 138 The Scleroderma Lung Study II subsequently randomized 126 patients with SSc-ILD to receive either cyclophosphamide or mycophenolate mofetil. 137 No significant difference was seen in the primary outcome of FVC per cent predicted at 24 months, but mycophenolate mofetil was associated with fewer toxicities and was better tolerated.

The evidence to support the use of immunotherapies such as steroids, mycophenolate mofetil, azathioprine, cyclophosphamide, tacrolimus, and rituximab for the treatment of other inflammatory ILDs is limited to observational studies and case series. Despite this, immunosuppression remains the standard of care for CTD-ILD and cHP and should be considered as first line therapy. The RECITAL trial is ongoing and has randomized patients with severe and/or progressive CTD-ILD to receive either cyclophosphamide (as standard of care) or rituximab as first line therapy and may further clarify the role of rituximab in CTD-ILD. 141

Despite the use of immunosuppressive treatment, high morbidity and mortality associated with these ILDs remain. Thus, a clear mandate exists for better treatment strategies that may be informed by understanding the progressive fibrosing phenotype and the role of antifibrotics in its treatment.

Treatment of PPF

Although the non-uniformity of the interstitial lung diseases that manifest PPF poses a challenge to designing and conducting clinical trials, several studies have established a role for antifibrotic therapy in PPF ( table 1 ). 10 12 15 90

Strong evidence supports the use of nintedanib for PPF. The SENSCIS trial was a phase 3 RCT that investigated the efficacy of nintedanib versus placebo in 576 people with SSc-ILD. 10 Enrollment did not require evidence of disease progression but included only people who had fibrosis affecting at least 10% of the lungs on baseline HRCT. The primary endpoint, annual rate of decline in FVC over 52 weeks, was lower in the nintedanib arm (difference 41.0 (2.9 to 69.0) mL/year). INBUILD, another phase 3 RCT of nintedanib versus placebo, expanded inclusion criteria to any non-IPF progressive fibrosing ILD. 12 Enrollment required meeting the study criteria for progressive fibrosis, based on FVC decline, or a combination of worsening FVC, symptoms, or imaging findings. The primary endpoint of annual rate of decline in FVC over 52 weeks was again lower in the nintedanib arm (difference 107 (65.4 to 148.5) mL/year). The difference was greater for the nearly two thirds of participants with a radiographic pattern of UIP (difference 128.2 (70.8 to 185.6) mL); however, a definitive treatment effect could not be inferred for other radiographic patterns of fibrosis.

Nearly half of the participants in the SENSCIS trial (48.5%) were concurrently taking mycophenolate mofetil, and subgroup analysis found no heterogeneity in nintedanib’s treatment effect according to baseline mycophenolate mofetil use. 10 142 Although the absolute reduction in FVC decline associated with nintedanib use was less in participants taking mycophenolate mofetil, the relative reduction in FVC decline was similar in those taking and those not taking mycophenolate mofetil (40% v 46%). Notably, participants receiving mycophenolate mofetil and placebo had a similar adjusted mean annual rate of FVC decline to those receiving nintedanib alone (−66.5 v −63.9 mL/year); however, the authors note that this comparison was out of the scope of the trial. The INBUILD trial excluded people who were receiving concomitant immunosuppression for ILD.

The data supporting pirfenidone in PPF are less robust. Pirfenidone was studied in two completed phase 2/2b RCTs. The first enrolled 253 people with unclassifiable ILD, including those with interstitial pneumonia with autoimmune features, and evidence of progressive loss of lung function. 15 The primary endpoint used home spirometry and provided unreliable results that could not be analyzed. The secondary outcome, using on-site spirometry, compared the mean decline in FVC over 24 weeks and showed a treatment difference favoring pirfenidone over placebo (difference 95.3 (35.9 to 154) mL; P=0.002). The RELIEF study enrolled only 127 of the planned 374 people with PPF, including those with CTD-ILD, cHP, iNSIP, and asbestos induced lung fibrosis. 90 The trial was terminated early owing to slow enrollment and for futility. The result was that 47% of participants, in both arms, had imputed data. Despite being underpowered by early termination, when imputed data were included, the primary endpoint of absolute change in FVC per cent predicted from baseline to 48 weeks was lower in participants taking pirfenidone (P=0.049). The median difference in change in FVC per cent predicted per year ranged from 1.69% to 3.53%, depending on the test used. The finding remained significant on multiple sensitivity analyses. Although the analysis of the primary outcome performed without imputation was not statistically significant, these findings may be clinically relevant. Clinical trials of both pirfenidone and nintedanib that are ongoing in a variety of PPF subsets are noted in table 3 .

Ongoing randomized clinical trials of antifibrotic drugs for treatment of idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung disease

Gaps in knowledge in management of PPF

Identifying and treating ppf.

Recognition of a progressive fibrosing phenotype of ILD is important to both treatment strategies and prognosis. However, before May 2022, the diagnosis of PPF had been hampered by the lack of established clinical criteria and biomarkers. Additionally, the proposed criteria do not account for time from disease onset and may identify early inflammatory disease without a progressive fibrosing phenotype. Early decline in FVC in inflammatory ILDs may be remediated with immunosuppressive treatment, and a progressive fibrosing phenotype may never occur despite the proposed criteria being met early in the course of disease. Nevertheless, this needs to be balanced with the consideration that earlier treatment directed toward fibrosis may help to preserve lung function in patients who ultimately develop a progressive phenotype.

When immunosuppressive treatment is efficacious in inflammatory ILDs, it is continued. When an inflammatory ILD has progressive fibrosis despite immunosuppression, the question is whether to escalate immunosuppressive therapy or to start treatment with an antifibrotic drug such as nintedanib. Treatment decisions should consider the time from disease onset, as immunosuppressive therapies may be more likely to be effective early in the disease course. The prospective trials of immunosuppressive treatments for SSc-ILD recruited people early in the disease course and showed stabilization of lung function with cyclophosphamide, mycophenolate, or tociluzimab. 137 138 139 Acute and subacute cases of hypersensitivity pneumonitis may resolve with antigen avoidance with or without a short course of corticosteroids. However, once cHP develops and fibrotic features are present on imaging, five year mortality is similar to that of IPF at 50%. 8 In this setting, immunosuppressive therapy is unlikely to be beneficial and treatment with antifibrotics should be offered. Similarly, in CTD-ILD, antifibrotics should be strongly considered once progressive fibrosis has been established. Whether immunosuppression should continue when antifibrotic therapy is introduced also remains unclear. Although it is associated with worse outcomes in IPF, data in SSc-ILD from the SENSCIS trial suggest that treatment with combined immunosuppression and antifibrotic therapy may be advantageous. 10

Given the complex and multicellular pathobiology of pulmonary fibrosis, defining disease endotypes that can be identified by patterns of clinical characteristics, radiologic features, and biomarkers is important. These endotypes can then be used to guide initial therapy and to modify treatment over time. The recognition of PPF creates a further need to develop biomarkers of progressive disease. A comprehensive review of diagnostic and prognostic biomarkers was recently published. 143 Of the many studies examining biomarkers, most are observational and retrospective in design and few have been validated in separate prospective cohorts. For these reasons, biomarkers are infrequently used in clinical practice. 143 Single cell RNA sequencing and spatial transcriptomic studies conducted on explanted lungs obtained at the time of transplant when fibrosis is well established suggest relatively little heterogeneity between pulmonary fibrosis with differing initiating factors. 63 64 144 These findings suggest the need to obtain samples from patients with early disease to guide the selection of initial therapy and monitor the response to therapy over time.

The first large prospective study to evaluate biomarkers in IPF examined serum specimens from the PROFILE cohort, a longitudinal cohort of treatment-naive patients with IPF. 145 After measuring 123 serum proteins, the investigators focused on surfactant protein D (SFTPD), matrix metalloproteinase-7 (MMP7), CA19-9 (ST6GALNAC6), and CA-125 (MUC16). Including the discovery and validation phases of the trial, the study included 312 participants with IPF (145 with stable disease and 155 with progressive disease at follow-up) and 50 healthy controls. Although MMP7 was higher in patients with IPF compared with controls, it did not predict disease progression or mortality. SFTPD had higher discriminatory power for distinguishing IPF from healthy controls and identifying patients at high risk of progression. Although neither CA19-9 nor CA-125 could distinguish disease from controls, CA19-9 was most highly predictive of progressive fibrosis, and increasing concentrations of CA-125 predicted both disease progression and overall survival. As CA19-9 and CA-125 are relatively new markers in IPF, immunohistochemical localization of these markers was done in control and fibrotic lung tissue to ensure relevance to lung disease. CA19-9 and CA-125 were present in the apical bronchial epithelium in normal lungs, whereas in the fibrotic lung these markers were seen throughout the metaplastic epithelium in fibrotic lesions.

The largest study to examine biomarkers in non-IPF ILD is a retrospective study in 148 people with CTD-ILD, 98 with cHP, and 159 with unclassifiable ILD. 146 Six biomarkers of interest were evaluated with the primary endpoint of progression-free survival defined as survival without lung transplant or ≥10% decline in FVC over two years. The investigators found that increased serum concentrations of CXCL13 were associated with decreased survival in all three disease subgroups, but the optimal threshold concentration varied substantially between subgroups. CXCL13 is a chemokine that is chemotactic for B lymphocyte migration, and increased concentrations have been associated with ectopic germinal centers in autoimmune disease. 147 The authors speculate that the CXCL13 threshold variability may reflect different underlying biology, with inflammatory phenotypes of ILD having a higher baseline concentration overall, and therefore may indicate that CXCL13 could be useful in identifying a population of patients responsive to immunosuppression.

Genetic biomarkers may identify patients at increased risk for pulmonary fibrosis and predict disease progression. Patients with heterozygous mutations of either the TERT gene or the TERC gene, which are part of the telomerase complex genes, are at increased risk of IPF, as are those with shortened telomeres. 148 Although the use of telomere length testing in patients with suspected familial forms of idiopathic ILD varies in clinical practice, no formal recommendations on its use exist. A single nucleotide polymorphism (SNP) in the promotor region of the MUC5B gene (rs35705950) that increases the expression of the gene is associated with the development of IPF but has unclear effects on disease severity and survival. 149 150 Three SNPs in the TOLLIP gene have also been associated with IPF. 151 TOLLIP encodes toll interacting proteins that are linked to the lung’s immune responses, including modulation of TGF-β signaling. 152 Post hoc genotyping of TOLLIP and MUC5B was performed on previously collected samples from people enrolled in the PANTHER trial, 132 and identified polymorphisms within these genes were suggested to modify the effect of treatment with N-acetylcysteine or immunosuppression. 136 The results of this analysis were used to support further investigation of N-acetylcysteine in IPF patients with the TOLLIP rs3750920 TT genotype through the PRECISION trial ( NCT04300920 ).

Emerging therapies and diagnostics

Advanced diagnostics.

Newer methods that exploit advances in transcriptomics and proteomics may not only advance our understanding of the pathobiology of fibrosing lung diseases but may also serve to improve the utility of biomarkers. They offer a personalized approach to the management of PPF by eliciting the specific biologic pathways that are active at a given point in time and thereby might facilitate targeted therapy. Machine learning tools offer promise to iteratively improve the predictive power of these information-rich multi-omics data by incorporating detailed clinical and imaging metadata, including the response to therapy.

Currently available for clinical use, the Envisia Genomic Classifier (EGC) was developed using machine learning methods applied to exome enriched RNA sequencing data from whole lung biopsies (bulk RNA) in combination with histologically confirmed diagnoses. The product of this is an algorithm that differentiates UIP from non-UIP histologic patterns by recognizing the transcriptomic signature of UIP. This classifier was validated using an independent dataset in the BRAVE studies. 153 In these studies, samples were obtained from 84 people with suspected ILD undergoing planned, clinically indicated lung biopsy procedures. The transcriptome analysis showed that biopsy samples histologically classified as UIP were enriched for gene expression pathways associated with cellular metabolism, adhesion, and developmental processes. However, samples histologically classified as non-UIP showed gene expression pathways associated with immune activities, lipid metabolism, stress response, and cell death. Using the developed algorithm and a single transbronchial lung biopsy sample to distinguish UIP from non-UIP histologic patterns, the EGC had a sensitivity of 63% (95% confidence interval 51% to 74%) and a specificity of 86% (71% to 95%). If three to five samples were used, the sensitivity improved to 74% (51% to 90%) and specificity improved to 93% (68% to 100%). The EGC has now been validated in an additional study using the BRAVE cohort, which found that it had a negative predictive value of 60.3% (46.6% to 73.0%) and a positive predictive value of 92.1% (78.6% to 98.3%) for histology proven UIP. 154

The EGC identifies a transcriptomic pattern associated with histologic UIP in patients with indeterminant radiographic patterns. This does not equate to a diagnosis of IPF. Rather, the results from EGC are an additional piece of data that can be incorporated into a multidisciplinary discussion to achieve a consensus diagnosis. The ECG has also not yet been studied in PPF. However, future studies to evaluate the use of transcriptomic tools to identify or predict progressive fibrosis and predict response to antifibrotics in this patient population may be instrumental in developing precise therapeutic targets.

Bulk RNA sequencing like that used in the EGC provides an average measure of gene expression across the heterogenous cell populations that make up the lung. This creates a problem of averaging in which a change in cellular composition (for example, an increased number of inflammatory cells) can drive changes in average gene expression and biologically important signals in cell populations or subpopulations can be missed. Single cell RNA sequencing avoids these problems by measuring gene expression within each individual cell, allowing one to compare cell populations—for example, alveolar type 2 cells—in health and disease. In addition to identifying biomarkers, single cell RNA sequencing allows one to generate hypotheses about which cellular interactions drive fibrosis and can be targeted pharmacologically. Although still too costly and time consuming for clinical practice, single cell RNA sequencing has become an invaluable discovery tool, particularly when applied to small samples from patients with early disease, including those obtained by bronchoscopic lavage or biopsy.

Along with improved tools for exploring the pathobiology of IPF and PPF, several national and international ILD registries are enrolling people. Registries differ from clinical trials in that they are large, they allow for prolonged follow-up time, and enrollment is inclusive and thus more reflective of the general population of patients with a given disease. Participants should be well characterized as to important clinical features of their disease. Insights derived from registries complement clinical trials and may answer questions about the long term effectiveness of treatments. Current registries will need to be expanded to accommodate digitized images and genomic data that will facilitate the training of multimodal machine learning classifiers to predict disease endotypes and responsiveness to therapy.

Resolution of fibrosis

IPF and PPF are characterized by self-sustaining fibrosis and progressive decline in lung function. The therapies approved and undergoing phase 3 clinical trials for the treatment of IPF and PPF have been shown only to slow decline in lung function, and none has shown resolution of fibrosis. However, growing evidence suggests that fibrosis may be reversible, particularly with removal of the underlying cause of injury. 155 A recent review covered the biology of self-sustaining fibrosis and emphasized three processes necessary for resolution of fibrosis—elimination of matrix producing cells, clearance of excess matrix, and regeneration of normal tissue constituents. 5

Metformin has been found to ameliorate pulmonary fibrosis in bleomycin induced mouse models of lung fibrosis. 156 157 Metformin inhibits mitochondrial complex I to activate adenosine monophosphate activated protein kinase (AMPK), which subsequently inhibits TGF-β. 157 158 159 160 Metformin is able to normalize myofibroblast sensitivity to apoptosis and stimulate turnover of collagen via AMPK dependent activation of autophagy. 156 By eliminating matrix producing myofibroblasts and promoting the clearance of excess matrix, metformin, or other AMPK activators, may be able to reverse established fibrosis. Notably, however, when patients who were randomized to placebo in the CAPACITY and ASCEND trials of pirfenidone were stratified by baseline metformin use, no significant difference in disease progression associated with metformin use was seen. 161 One potential reason for the discrepancy between these findings and experimental studies may be the high doses (65-300 mg/kg) of metformin and intraperitoneal route used in the mouse models. 156 157

The resolution of fibrosis requires not only breaking the positive feed-forward loops that sustain and amplify fibrosis but also regenerating normal tissue to occupy the area of former fibrosis. Alveolar type 2 cells are a partially committed stem cell population in the adult lung that undergo asymmetric division and differentiation to replace damaged alveolar type 1 cells 69 74 162 ; however, when alveolar type 2 cells are isolated from IPF lung tissue they have impaired regenerative ability compared with healthy tissue. 163 In single cell RNA sequencing data from lung explants from patients with pulmonary fibrosis, investigators have noted the emergence of a population of epithelial cells characterized by expression of low concentrations of keratin-5 and increased levels of keratin-17. 64 65 These cells also express high levels of genes associated with senescence, including p16 ( CDKN2A ), p21 ( CDKN1A ), and plasminogen activator inhibitor 1 ( SERPINE1 ), among others. A transcriptionally similar population of cells has been observed in murine models of pulmonary fibrosis and in a murine model of alveolar regeneration after pneumonectomy. 68 71 72 73 In all of these studies, these cells are characterized by increased expression of keratin-8, along with similar senescence associated genes. All three initial reports of these cells showed them to be a transitional cell population that forms during the differentiation of alveolar type 2 to type 1 cells. 68 71 72 Strunz and colleagues showed that, during bleomycin induced fibrosis, these cells develop a transcriptomic signature suggestive of activation of the integrated stress response during their differentiation. 68 This is of interest because inhibitors of the integrated stress response have been shown to reduce fibrosis in animal models. 164 Watanabe and colleagues followed up on these results, showing that a small molecule inhibitor of the integrated stress response, ISRIB, accelerated the differentiation of alveolar type 2 cells into alveolar type 1 cells during fibrosis, reducing the number of keratin-8 positive cells. 85 This suggests that a decline in the function of the proteostasis network, as occurs during aging in model organisms, might impair the differentiation of alveolar type 2 cells, predisposing to the development of fibrosis. 165 Future studies are needed to determine whether the emergence of keratin-17 cells explains some of the increase in senescence markers observed in lung fibrosis. 166

Table 4 summarizes the most recent guidelines from the leading international societies on the management of idiopathic pulmonary fibrosis and highlights some of the key commonalities and differences between the recommendations. The ATS/ERS/JRS/ALAT clinical practice guidelines published in 2011 were updated in 2015 and 2022. 4 87 106 The JRS published a separate clinical practice guideline in 2018, which provided additional recommendations not previously included in the 2015 joint guidelines. 167 Specifically, for patients experiencing an acute exacerbation of IPF, they recommend against the use of polymyxin B (weak recommendation, low quality of evidence), neutrophil elastase inhibitors (weak recommendation, very low quality of evidence), and recombinant thrombomodulin (weak recommendation, low quality of evidence) and recommend the use of immunosuppressant drug therapy (weak recommendation, low quality of evidence).

Comparison of guideline recommendations from ATS/ERS/JRS/ALAT, JRS, NICE, and TSANZ/LFA for treatment of idiopathic pulmonary fibrosis

NICE guidelines on the diagnosis and management of IPF were published in 2013 and last updated in 2017. 107 168 169 As seen in table 4 , NICE guidelines have minor differences from the ATS/ERS/JRS/ALAT guidelines, which may reflect the fact the NICE Guideline Development Group is required to make decisions based on the best available evidence of both clinical effectiveness and cost effectiveness. 170 The TSANZ and the LFA published a position statement on the treatment of IPF in 2017, which differs from the ATS/ERS/JRS/ALAT guidelines in its recommendation to use disease severity to guide decisions on antifibrotic therapy and its neutral stance on antacid therapy. 101

The first international gudelines on the treatment of PPF came in May 2022 with the ATS/ERS/JRS/ALAT clinical practice guideline. 4 This guideline suggested nintedanib for the treatment of PPF in patients who have not responded to standard management for non-IPF fibrotic ILD (conditional recommendation, low quality evidence). The committee made no recommendation for or against the use of pirfenidone for the treatment of PPF and recommended further research into the use of pirfenidone in non-IPF ILDs.

Tremendous advances have been made in elucidating the biologic processes that promote and sustain pulmonary fibrosis. The recognition that ILDs other than IPF may also have a progressive fibrosing phenotype has also been instrumental in moving forward the treatment options for patients with PPF and conceptualizing how to best manage these patients in the future. Importantly, nintedanib has been shown to slow progression of disease in patients with PPF, and several ongoing clinical trials are examining whether pirfenidone may also be beneficial. Several promising therapies are in the pipeline that may offer novel ways of treating IPF that could potentially be used instead of or in addition to the currently available antifibrotics. However, significant gaps in knowledge surrounding the treatment of IPF and PPF remain. Notably, we lack biomarkers and other diagnostic tests that can be used early in the disease course (before functional decline is present) to determine when patients with PPF may benefit from antifibrotics. Additionally, more studies are necessary to examine whether antifibrotics should be used in lieu of or in addition to immunosuppression when no extrapulmonary indications for immunosuppressive therapy are present. The essential question of whether and how established fibrotic disease can actually be reversed and normal lung tissue and function restored also remains. Future research must consider these questions to continue advancing the care for patients with these devasting diseases.

Glossary of abbreviations

ALAT—Latin American Thoracic Association

AMPK—adenosine monophosphate activated protein kinase

ATS—American Thoracic Society

cHP—chronic hypersensitivity pneumonitis

CTD-ILD—connective tissue disease associated ILD

CTGF—connective tissue growth factor

DLCO—diffusing capacity for carbon monoxide

EGC—Envisia Genomic Classifier

ERS—European Respiratory Society

FDA—Food and Drug Administration

FGFR-1—fibroblast growth factor receptor 1

FVC—forced vital capacity

HRCT—high resolution computed tomography

ILD—interstitial lung disease

iNSIP—idiopathic nonspecific interstitial pneumonia

IPF—idiopathic pulmonary fibrosis

JRS—Japanese Respiratory Society

LFA—Lung Foundation of Australia

M-CSF—macrophage colony stimulating factor

MMP7—matrix metalloproteinase-7

NICE—National Institute for Health and Care Excellence

NSIP—nonspecific interstitial pneumonia

PDGF—platelet derived growth factor

PDGFR—platelet derived growth factor receptor

PF-ILD—progressive fibrosing interstitial lung disease

PPF—progressive pulmonary fibrosis

RA-ILD—rheumatoid arthritis associated ILD

RCTs—randomized controlled trials

rhPTX-2—recombinant human pentraxin 2

SFTPD—surfactant protein D

SNP—single nucleotide polymorphism

SSc-ILD—systemic sclerosis associated ILD

TGF-β—transforming growth factor β

TSANZ—Thoracic Society of Australia and New Zealand

UIP—usual interstitial pneumonia

Research questions

What drives progressive pulmonary fibrosis in patients with interstitial lung disease (ILD)?

Do biomarkers exist that can predict which patients with ILD will develop progressive pulmonary fibrosis before they have lung function decline?

What is the optimal timing for starting antifibrotics in patients with non-idiopathic pulmonary fibrosis fibrotic? Should antifibrotics be started only after patients have shown progression on immunosuppression?

Should immunosuppression be continued in patients with progressive pulmonary fibrosis who start treatment with antifibrotics?

Do therapies exist that can reverse or resolve pulmonary fibrosis?

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: All authors contributed to the intellectual content, did the literature search, and participated in the preparation, editing, and critical review of the manuscript.

Funding: GYL is supported by NIH grant F32-HL162318 and North Western University’s Lung Sciences Training Program 5T32HL076139-17. GRSB is supported by supported by NIH grants ES013995, HL071643, and AG049665 and the Veterans Administration grant BX000201.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare: none.

Patient involvement: No patients or members of the public were involved in the design, conduct, reporting, or dissemination plans of this manuscript.

Provenance and peer review: Commissioned; externally peer reviewed.

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Article Contents

Introduction, case report.

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Reversal of lung fibrosis: an unexpected finding in survivor of acute respiratory distress syndrome

• Article contents
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• Supplementary Data

C -H Chang, Y -H Juan, H -C Hu, K -C Kao, C -S Lee, Reversal of lung fibrosis: an unexpected finding in survivor of acute respiratory distress syndrome, QJM: An International Journal of Medicine , Volume 111, Issue 1, January 2018, Pages 47–48, https://doi.org/10.1093/qjmed/hcx190

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Learning point for clinicians

• Radiologic signs of delayed pulmonary fibrosis from acute respiratory distress syndrome, such as reticular opacities and traction bronchiectasis, can potentially be reversed.

• Whether corticosteroid has benefit to lung fibrosis remains controversial.

Acute respiratory distress syndrome (ARDS) has high mortality rates. The survivors after ARDS may also have pulmonary or non-pulmonary sequelae, such as cognitive impairment, pulmonary function impairment and decreased health-related quality of life. We would present a case, a survivor of ARDS with reversal of lung fibrosis 7 months after treatment.

A 67-year-old man was transferred to our hospital due to acute respiratory failure requiring mechanical ventilation. The patient never smoked and had hypertension under medical treatment. He had progressive dyspnea 2 weeks earlier before admission, and he was treated with intravenous antibiotics for suspected pneumonia at the local hospital. However, the symptoms aggravated with development of acute respiratory failure. The arterial blood gas analysis under mechanical ventilation on 60% of FiO 2 showed PO 2 116 mmHg, PCO 2 35.7 mmHg, pH 7.366, SaO 2 98% and bicarbonate 20 meq/L. The positive end-expiratory pressure was 12 cm H 2 O. The diagnosis of ARDS was made. Chest computed tomography (CT) examination showed bilateral lung infiltration and lung fibrosis with bronchiectasis changes ( Figure 1A ). Because of ARDS with unknown etiology, bronchoalveolar lavage was done, but the microbiology and cytology results were all negative. Surgical lung biopsy was done, and the pathological results showed diffuse alveolar damage. After supportive treatment in intensive care unit, mechanical ventilation was gradually weaned off on the 33rd day, and the patient was extubated. He was discharged after 56 days of hospitalization.

Serial axial CT images demonstrating the development and gradual reversal of pulmonary fibrosis from ARDS. ( A ) Axial CT images showing marked evidences of pulmonary fibrosis, including reticular thickenings and traction bronchiectasis and predominantly in the non-dependent lung predominantly as a sequelae of ARDS. ( B ) Axial CT images showing evidences of gradual reversal of pulmonary fibrosis during sequential imaging follow-up.

Two months later after discharge from the hospital, he was re-hospitalized because of pneumonia associated with cough and fever. Repeated chest CT at the emergent department showed persistent of lung fibrosis and new onset of ground glass opacity (GGO), compatible with new onset of infection. After antibiotics treatment, the patient was discharged and was followed up at our outpatient clinic. He has received short course of corticosteroid treatment prednisolone 10 mg daily for 3 months.

After 7 months of illness, the chest CT showed resolution of the GGO and a significant improvement in lung fibrosis ( Figure 1B ). One year after the illness, his pulmonary function was normal: the forced vital capacity 80%, forced expiratory volume in 1 s 86%, diffusing capacity for carbon monoxide 61% and diffusing capacity divided by the alveolar volume 80%. He returned to his normal daily activities.

The common CT findings in ARDS are GGOs, consolidations, interstitial thickening, traction bronchiectasis and honeycombings. 1 , 2 The typical pathological findings of ARDS is diffuse alveolar damage. Increased lung area involvement and increased bronchiectasis is also associated with high mortality rate in patients with pathology confirmed ARDS. 1 , 2 Fibrosis can be a result of various types of injuries, such as skin scar, liver cirrhosis or lung fibrosis. A recent review article indicated that the process of fibrosis and dysregulated extracellular matrix remodeling are not all irreversible. 3

The anti-fibrotic targeted therapy regulated important proinflammatory and profibrotic cytokine cascades, and it reduced collagen synthesis and fibroblast proliferation. Both nintedanib and pirfenidone could reduce the rate of lung function decline in idiopathic pulmonary fibrosis, but its effect on the reversal of pulmonary fibrosis remained uncertain. 4 , 5 As for our presented case, the fibrosis resolved after 3-month low dose of corticosteroid treatment. Whether corticosteroid treatment has benefit in ARDS remains controversial. 6 The potential side effect of corticosteroid will influence clinical physicians whether use of steroid in ARDS.

This study was approved by the institutional review boards at Chang Gung medical foundation (IRB Number: 201700566B0).

Conflict of interest : None declared.

Chung JH , Kradin RL , Greene RE , Shepard JA , Digumarthy SR. CT predictors of mortality in pathology confirmed ARDS . Eur Radiol 2011 ; 21 : 730 – 7 .

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Rockey DC , Bell PD , Hill JA. Fibrosis–a common pathway to organ injury and failure . N Engl J Med 2015 ; 372 : 1138 – 49 .

Richeldi L , du Bois RM , Raghu G , Azuma A , Brown KK , Costabel U , et al.  Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis . N Engl J Med 2014 ; 370 : 2071 – 82 .

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• pulmonary fibrosis
• respiratory distress syndrome, adult

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• Patient Care & Health Information
• Diseases & Conditions
• Pulmonary fibrosis

Pulmonary fibrosis is scarred and thickened tissue around and between the air sacs called alveoli in the lungs, as shown on the right. A healthy lung with healthy alveoli is shown on the left.

Pulmonary fibrosis is a lung disease that occurs when lung tissue becomes damaged and scarred. This thickened, stiff tissue makes it harder for the lungs to work properly. Pulmonary fibrosis worsens over time. Some people can stay stable for a long time, but the condition gets worse faster in others. As it gets worse, people become more and more short of breath.

The scarring that happens in pulmonary fibrosis can be caused by many things. Often, doctors and other healthcare professionals cannot pinpoint what's causing the problem. When a cause cannot be found, the condition is called idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis usually occurs in middle-aged and older adults. Sometimes pulmonary fibrosis is diagnosed in children and infants, but this is not common.

The lung damage caused by pulmonary fibrosis cannot be repaired. Medicines and therapies can sometimes help slow down the rate of fibrosis, ease symptoms and improve quality of life. For some people, a lung transplant might be an option.

Pulmonary fibrosis care at Mayo Clinic

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Symptoms of pulmonary fibrosis may include:

• Shortness of breath.
• Extreme tiredness.
• Weight loss that's not intended.
• Aching muscles and joints.
• Widening and rounding of the tips of the fingers or toes, called clubbing.

How fast pulmonary fibrosis worsens over time and how severe the symptoms are can vary greatly from person to person. Some people become ill very quickly with severe disease. Others have moderate symptoms that worsen more slowly, over months or years.

When symptoms suddenly get worse

In people with pulmonary fibrosis, especially idiopathic pulmonary fibrosis, shortness of breath can suddenly get worse over a few weeks or days. This is called an acute exacerbation. It can be life-threatening. The cause of an acute exacerbation may be another condition or an illness, such as a lung infection. But usually the cause is not known.

When to see a doctor

If you have symptoms of pulmonary fibrosis, contact your doctor or other healthcare professional as soon as possible. If your symptoms get worse, especially if they get worse fast, contact your healthcare team right away.

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Pulmonary fibrosis is scarring and thickening of the tissue around and between the air sacs called alveoli in the lungs. These changes make it harder for oxygen to pass into the bloodstream.

Damage to the lungs that results in pulmonary fibrosis may be caused by many different things. Examples include long-term exposure to certain toxins, radiation therapy, some medicines and certain medical conditions. In some cases, the cause of pulmonary fibrosis is not known.

Your work and surroundings

The type of work you do and where you work or live could be the cause or part of the cause for pulmonary fibrosis. Having continuous or repeated contact with toxins or pollutants — substances that harm the quality of water, air or land — can damage your lungs, especially if you do not wear protective gear. Examples include:

• Silica dust.
• Asbestos fibers.
• Hard metal dusts.
• Wood, coal and grain dusts.
• Bird and animal droppings.

Radiation treatments

Some people who receive radiation therapy to the chest, such as for lung or breast cancer, show signs of lung damage months or sometimes years after treatment. How severe the damage is may depend on:

• How much of the lung was exposed to radiation.
• The total amount of radiation given.
• Whether chemotherapy also was used.
• Whether there is underlying lung disease.

Many medicines can damage the lungs. Some examples include:

• Chemotherapy. Medicines designed to kill cancer cells, such as methotrexate (Trexall, Otrexup, others), bleomycin and cyclophosphamide (Cytoxan), can damage lung tissue.
• Heart medicines. Some medicines used to treat irregular heartbeats, such as amiodarone (Nexterone, Pacerone), may harm lung tissue.
• Some antibiotics. Antibiotics such as nitrofurantoin (Macrobid, Macrodantin) or ethambutol (Myambutol) can cause lung damage.
• Anti-inflammatory medicines. Certain anti-inflammatory medicines such as rituximab (Rituxan) or sulfasalazine (Azulfidine) can cause lung damage.

Medical conditions

Lung damage can also result from a number of conditions, including:

• Dermatomyositis, an inflammatory disease marked by muscle weakness and a skin rash.
• Lupus, a disease that occurs when the body's immune system attacks its own tissues and organs.
• Mixed connective tissue disease, which has a mix of symptoms of different disorders, such as lupus, scleroderma and polymyositis.
• Pneumonia, an infection that inflames the air sacs in one or both lungs.
• Polymyositis, an inflammatory disease that causes muscle weakness on both sides of the body.
• Rheumatoid arthritis, an inflammatory disease that affects joints and other body systems.
• Sarcoidosis, an inflammatory disease that most often affects the lungs and lymph nodes.
• Scleroderma, a group of rare diseases that involve hardening and tightening of the skin as well as problems inside the body.

Idiopathic pulmonary fibrosis

Many substances and conditions can lead to pulmonary fibrosis. Even so, in many people, the cause is never found. But risk factors such as smoking or exposure to air pollution could be related to the condition, even if the cause cannot be confirmed. Pulmonary fibrosis with no known cause is called idiopathic pulmonary fibrosis.

Many people with idiopathic pulmonary fibrosis also may have gastroesophageal reflux disease, also called GERD. This condition occurs when acid from the stomach flows back into the esophagus. GERD may be a risk factor for idiopathic pulmonary fibrosis or cause the condition to worsen faster. But more studies are needed.

Risk factors

Pulmonary fibrosis has been found in children and infants, but this is not common. Idiopathic pulmonary fibrosis is much more likely to affect middle-aged and older adults. Other types of pulmonary fibrosis, such as that caused by connective tissue disease, can occur in younger people.

Factors that can raise your risk of pulmonary fibrosis include:

• Smoking. If you smoke now or used to smoke, you're at a higher risk of pulmonary fibrosis than people who never smoked. People with emphysema are at higher risk, too.
• Certain types of work. You have a higher risk of developing pulmonary fibrosis if you work in mining, farming or construction. The risk also is higher if you have continuous or repeated contact with pollutants known to damage the lungs.
• Cancer treatments. Having radiation treatments to your chest or using certain chemotherapy medicines can raise your risk of pulmonary fibrosis.
• Genetics. Some types of pulmonary fibrosis run in families, so genes may play a role.

Complications

Complications of pulmonary fibrosis may include:

• High blood pressure in the lungs. Called pulmonary hypertension, this type of high blood pressure affects the arteries in the lungs. These are the pulmonary arteries. Stiff and thick arteries may slow down or block blood flow through the lungs. This raises the pressure inside the pulmonary arteries and the lower right heart chamber, called the right ventricle.
• Right-sided heart failure. This serious condition occurs when your heart's right chamber has to pump harder than usual to move blood through partly blocked pulmonary arteries.
• Respiratory failure. This is often the last stage of long-term lung disease. It occurs when blood oxygen levels fall dangerously low.
• Lung cancer. Long-standing pulmonary fibrosis increases your risk of developing lung cancer.
• Other lung problems. As pulmonary fibrosis gets worse over time, it may lead to serious problems such as blood clots in the lungs, a collapsed lung or lung infections.
• Raghu G, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: An official ATS/ERS/JRS/ALAT clinical practice guideline. American Journal of Respiratory and Critical Care Medicine. 2022; doi:10.1164/rccm.202202-0399stt.
• Broaddus VC, et al., eds. Idiopathic pulmonary fibrosis. In: Murray and Nadel's Textbook of Respiratory Medicine. 7th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed April 5, 2023.
• Broaddus VC, et al., eds. Pleural fibrosis and unexpandable lung. In: Murray and Nadel's Textbook of Respiratory Medicine. 7th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed April 5, 2023.
• Idiopathic pulmonary fibrosis. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health/idiopathic-pulmonary-fibrosis. Accessed April 5, 2023.
• Baqir M, et al. Idiopathic pulmonary fibrosis and gastroesophageal reflux disease: A population-based, case-control study. Respiratory Medicine. 2021; doi:10.1016/j.rmed.2021.106309.
• Strykowski R, et al. Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Immunology and Allergy Clinics of North America. 2023; doi:10.1016/j.iac.2023.01.010.
• Ahmad K, et al. Lung disease-related pulmonary hypertension. Cardiology Clinics. 2022; doi:10.1016/j.ccl.2021.08.005.
• Collins BF, et al. Diagnosis and management of fibrotic interstitial lung diseases. Clinics in Chest Medicine. 2021; doi:10.1016/j.ccm.2021.03.008.
• Lee JYT, et al. Self-management for pulmonary fibrosis: Insights from people living with the disease and healthcare professionals. Patient Education and Counseling. 2022; doi:10.1016/j.pec.2021.07.005.
• Wuyts WA, et al. Idiopathic pulmonary fibrosis: Best practice in monitoring and managing a relentless fibrotic disease. Respiration. 2020; doi:10.1159/000504763.
• Glass DS, et al. Idiopathic pulmonary fibrosis: Current and future treatment. Clinical Respiratory Journal. 2022; doi:10.1111/crj.13466.
• Dempsey TM, et al. Pulmonary function tests for the generalist: A brief review. Mayo Clinic Proceedings. 2018; doi:10.1016/j.mayocp.2018.04.009.
• Pulmonary rehabilitation. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health/pulmonary-rehabilitation. Accessed April 5, 2023.
• Park Y, et al. Occupational and environmental risk factors of idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Scientific Reports. 2021; doi:10.1038/s41598-021-81591-z.
• Jarzebska N, et al. Scarred lung. An update on radiation-induced pulmonary fibrosis. Frontiers in Medicine. 2021; doi:10.3389/frmed.2020.585756.
• Broaddus VC, et al., eds. Drug-induced pulmonary disease. In: Murray and Nadel's Textbook of Respiratory Medicine. 7th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed April 11, 2023.
• Table: Substances with toxic pulmonary effects. Merck Manual Professional Version. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/drug-induced-pulmonary-disease. Accessed April 11, 2023.
• Baqir M (expert opinion). Mayo Clinic. June 16, 2023.
• Allscripts EPSi. Mayo Clinic.

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• Published: 02 March 2021

Occupational and environmental risk factors of idiopathic pulmonary fibrosis: a systematic review and meta-analyses

• Yeonkyung Park 1   na1 ,
• Chiwon Ahn 2   na1 &
• Tae-Hyung Kim 3  

Scientific Reports volume  11 , Article number:  4318 ( 2021 ) Cite this article

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• Environmental sciences
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• Health occupations

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease of unknown cause. It has a high risk of rapid progression and mortality. We conducted a systematic review and meta-analysis to evaluate the risk factor of IPF. We searched Medline, Embase, and the Cochrane library from the earliest record to March, 2020. Case–control studies on occupational and environmental risk factors or on jobs with a risk of IPF were searched for. From 2490 relevant records, 12 studies were included. Any occupational or environmental exposure to metal dust (OR 1.83, 95% CI 1.15–2.91, I 2  = 54%), wood dust (OR 1.62 5% CI 1.04–2.53, I 2  = 5%) and pesticide (OR 2.07, 95% CI 1.24–3.45, I 2  = 0%) were associated with an increased risk of IPF. Farming or agricultural work (OR 1.88, 95% CI 1.17–3.04, I 2  = 67%) was also associated with an increased risk of IPF. Moreover, smoking increased IPF risk with an odds ratio of 1.39 (95% CI 1.01–1.91, I 2  = 29%). In conclusion, metal dust, wood dust, pesticide, occupational history of farming or agriculture and ever smoking increased the risk of IPF.

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Introduction.

Interstitial lung disease (ILD) causes abnormal collagen deposition by proliferation of interstitial compartments and infiltration of various inflammatory cells, and fibrotic changes. Idiopathic pulmonary fibrosis (IPF) is a special form of chronic ILD of unknown cause that occurs mainly in the lungs with increasing age and is associated with histopathological or radiological form of usual interstitial pneumonia (UIP). To diagnose IPF, other types of ILD should be ruled out, including drug-induced ILD, ILD through environmental exposure, or systemic disease-related ILD 1 . It has been reported that increasing age, genetic predisposing factors, smoking, or continuous exposure to various environmental and occupational factors can cause physical irritation and damage to the lungs 2 . IPF prevalence is higher in men and increases with age. According to a national survey in Korea, 72.4% of IPF patients are men and the average age at diagnosis is 69 years 3 .

Several studies conducted in various countries have investigated the association between occupational and environmental exposure factors, and IPF over the past decades. According to the 2015 Korean National Health and Nutrition Survey, those exposed to occupational and environmental dust were diagnosed with IPF at a younger age and had a longer period of symptomatic symptoms at the time of diagnosis. Moreover, it has been reported to be related to increase the mortality rate of IPF patients in exposed group 4 .

Case–control studies have investigated the association of IPF incidence with each of the exposure factors that can cause IPF in various countries like the UK 5 , 6 , 7 , 8 , the USA 9 , 10 , Sweden 11 , Mexico 12 , Egypt 13 , South Korea 14 , 15 , and Southern Europe 16 . Exposure to metal dust 5 , 6 , 7 , 9 , 15 , 16 , 17 , wood dust 6 , 7 , 11 , 13 , stone or sand dust 9 , 14 , and raising of birds or livestock and working in agriculture 6 , 9 , 13 , 16 are associated with IPF incidence. Although smoking has not been established as a causative agent, it has been shown to increase the risk of IPF 18 . In 2006, Taskar and Coultas et al. reported a significant increase in risk of IPF on stone/sand/soil exposure in a meta-analysis of four papers 18 . Additionally, a survey of occupational burdens in benign respiratory diseases, jointly conducted by the American Respiratory Society and the European Respiratory Society in 2019, revealed that exposure to silica, wood dust, metal dust, agricultural dust, and vapors, gas, dust, or fumes increased the risk of IPF 19 .

Workers in agriculture 9 , 13 , 16 , livestock industry 9 , chemical, petrochemical industry 13 , woodworking industry 13 , and steel industry 16 had higher risk of IPF. On the other hand, a study on the occupational burden in benign respiratory diseases conducted by the American Respiratory Society and the European Respiratory Society showed no significant association between IPF incidence with these specific occupational groups 19 .

IPF is ILD due to unknown causes. Case–control studies have been conducted on the relationship between various occupational and environmental risk factors and IPF. However, the results of such studies are inconsistent. Therefore, in this study, through systematic literature review, the effects of occupational and environmental exposure factors on IPF incidence and the influence of the individual’s past or present occupation and IPF incidence were investigated. The relationship between smoking history and the incidence of IPF was also investigated.

Search result

In total, 2852 studies were included: Medline (n = 1413); Embase (n = 1423); the Cochrane Library (n = 15); additionally identified in the literature review process (n = 1). By reviewing the title and the abstract, a total of 73 papers were analyzed, excluding documents that did not meet the purpose of this study. In total, 8 case–control studies were included. Fifty-nine articles with unclear data or not with a case–control study design were excluded. Two abstracts, one of which was later published as an article, were excluded; another abstract sharing the same case–control cohort was excluded. Three case–control studies diagnosed IPF based on chest X-ray and physical exam were excluded. In total, 8 case–control studies were included (Fig.  1 ).

PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow diagram.

Characteristics of studies and participants included

Table 1 summarizes the characteristics of the eight studies and participants included. The studies were conducted in various countries, such as the United States, Japan, Sweden, Southern Europe, Mexico, Egypt, and South Korea. In four of the eight studies, the non-IPF control group included healthy adults from the community or hospital patients without lung disease including IPF. However, in their non-IPF control group Miyake et al. included patients who visited the hospital with acute bacterial pneumonia or cold; Garcia-Sancho et al., with asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and otorhinolaryngology problems; Awadalla et al., with chest infection, bronchial asthma, COPD, bronchiectasis, pulmonary embolism, and bronchogenic carcinoma; Koo et al., with pulmonary tuberculosis and community acquired pneumonia. In two studies, the survey was conducted using organized questions through a self-reporting questionnaire or a phone call or mail. All studies analyzed occupational and environmental exposure risk factors and five studies analyzed occupation types. In the included studies, the mean age of the subjects ranged between 50 and 75 years, and in four of the eight studies, the age-sex distribution between the IPF patient group and the non-IPF control group was matched without statistically significant differences. Four studies did not provide data or did not match the age and sex proportions between the two groups. High rates of smoking were observed in the IPF patient group, except for the study by Awadalla et al. which matched smoking history in advance.

Quality assessment of studies

Among the eight studies included, five studies score less than 1 with high quality, one study in moderate quality, and two studies in low quality. In the measurement of intervention category, two studies were evaluated as “high” because the questionnaire was self-reported by postal questionnaire or telephone interview. In the confounding variables category, two studies showing differences in age or sex composition between the IPF and non-IPF groups were evaluated as “high”. In the selective outcome-reporting category, one study was evaluated as “high” because only statistically significant exposure risk factor results were mentioned (Supplementary Fig. S1 ).

Occupational and environmental exposure factors and risk of IPF

Seven studies (2845 subjects) investigated metal dust exposure. Three papers 9 , 15 , 16 had increased the risk of IPF and four studies had no relationship 11 , 13 , 14 , 17 . Awadalla et al., Gustafon et al., Kim et al. and Paolocci et al. investigated the metal dust and metal fumes as one category. Baumgartner et al. with metal dust excluding aluminum, beryllium, and cobalt and Koo et al. investigated metal dust and fumes separately. With seven studies on analysis, metal dust increased the risk of IPF with an odds ratio of 1.83 (95% CI 1.15–2.91, p = 0.01, I 2  = 54%) (Fig.  2 A, Supplementary Table S2 ).

Risk of IPF in exposure to occupational and environmental risk factors compared with non-IPF subjects. ( A ) metal dust, ( B ) wood dust, ( C ) stone and sand dust, ( D ) textile dust, and ( E ) pesticide.

Four studies (1599 subjects) investigated wood dust exposure. Among them, Awadalla et al. investigated exposure to wood dust and to wood preservatives as one exposure factor and Gustafon et al. investigated exposure to wood dust, hardwood dust and birch into different risk factor. Exposure to wood dust statistically significantly increased the risk of IPF with an odds ratio of 1.62 (95% CI 1.04–2.53, p = 0.03, I 2  = 5%) (Fig.  2 B, Supplementary Table S2 ).

Four studies (1446 subjects) investigated stone/sand dust exposure. Miyake et al. and Baumgather et al. investigated stone and sand dust exposure; Awadalla et al., stone, glass, and concrete dust exposure. Kim et al. surveyed exposure to stone and sand dust containing silica. On combining all their results, the risk of IPF was not increased with an odds ratio of 2.27 (95% CI 0.92–5.60, p = 0.06, I 2  = 56%) when exposed to stone/sand dust (Fig.  2 C, Supplementary Table S2 ).

Four studies (2182 subjects) investigated textile dust exposure. The risk of IPF did not increase on exposure to textile dust with an odds ratio of 1.26 (95% CI 0.85–1.86, p = 0.25, I 2  = 0%) (Fig.  2 D, Supplementary Table S2 ).

Four studies (1446 subjects) investigated pesticide exposure, which on meta-analysis was found to increase IPF risk with an odds ratio of 2.07 (95% CI 1.24–3.45, p = 0.005, I 2  = 0%) (Fig.  2 E, Supplementary Table S2 ).

Job and risk of IPF

Five studies (1792 subjects) investigated exposure through working in the construction industry, including working at building construction and sites. IPF risk on such exposure increased with an odds ratio of 1.39 (95% CI 0.89–2.18, p = 0.15, I 2  = 20%), but it was not statistically significant (Fig.  3 A, Supplementary Table S3 ).

Risk of IPF in occupation compared to non-IPF controls. ( A ) building construction and demolition workers, ( B ) farming or agriculture workers, ( C ) carpentry and wood workers, and ( D ) textile making workers.

Four studies (1631 subjects) investigated exposure through working in the agriculture sector. Paolocci et al. classified agriculture, veterinarians, and gardeners into one occupation group. Miyake et al. unified agriculture and fisheries into one occupational category. While, Awadalla et al., separated agriculture and fisheries into different occupational categories. Therefore, the study by Miyake et al. was excluded from the analysis. On meta-analysis, exposure as agricultural workers increased IPF risk statistically significantly (OR 1.88, 95% CI 1.17–3.04, p = 0.009, I 2  = 67%) (Fig.  3 B, Supplementary Table S3 ). Heterogeneity was high in this analysis. When the sensitivity analysis was performed excluding Paolocci et al., the heterogeneity decreased to I 2  = 0 (OR 1.43, 95% CI 1.08–1.90, p = 0.01) and it was as statistically significant as the previous results. This was confirmed because Paolocci et al. included veterinarians and gardeners into the same occupation group as agricultural workers, unlike the other 3 studies.

Four studies (1631 subjects) analyzed exposure through working in the wood working industry. This factor tends to increase IPF risk with an odds ratio of 1.56 (95% CI 0.87–2.82, p = 0.14, I 2  = 38%), which was below statistically significant level (Fig.  3 C, Supplementary Table S3 ).

Four studies (1631 subjects) investigated exposure through working in the textile industry. This included work involving manufacturing or repairing of textiles. This factor did not increase IPF risk significantly with an odds ratio of 1.08 (95% CI 0.64–1.82, p = 0.76, I 2  = 0%) (Fig.  3 D, Supplementary Table S3 ).

Smoking and the risk of IPF

Among the studies, Awadalla et al. was excluded because it was a smoking-matched case–control study. Meta-analysis showed that smoking increased IPF risk with an odds ratio of 1.38 (95% CI 1.09–1.74, p = 0.008, I 2  = 10%), which was statistically significant (Fig.  4 , Supplementary Table S4 ).

Risk of IPF in ever smoker compared with never smoker.

From previous case-controls studies, we found that metal dust 6 , 7 , 9 , 15 , 16 , 17 increased the risk of IPF and wood dust 6 , 7 , 11 , 13 increased IPF risk with statistical significance. Additionally, the exposure to livestock like cattle and birds, livestock feed, pesticides, mold, soil dust, stone dust, stone polishes, and smoke increases IPF prevalence.

On our analysis metal dust, wood dust and pesticide increased the risk of IPF. From the previous case control studies with metal dust and IPF some studies had significant relationship with disease but some other studies did not 11 , 12 , 14 . A cohort study of United Kingdom engineering company, increased proportional mortality increased in relation to the duration of metal-working 5 . Metal dust and metal related fumes can deposit in the lung by inhalation or ingestion of the particles and interfere with the pulmonary immune system but specific pathogenesis is not known 20 .

Although a recent, informal meta-analysis, conducted by the international pulmonology conference, meaningful results were found about IPF risk on exposure to the wood dust, metal dust, silica dust, agriculture dust and vapors, gas, dust or fumes 19 . In our study, agricultural dust was not included because only occupational and environmental exposure factors that were included in more than four studies were considered, and silica was excluded because silica was already widely known with silica related lung disease.

Unlike previous studies, our meta-analysis showed statistically significant increase in IPF risk on pesticide exposure (Fig.  2 E). Earlier, a case control study about pesticides from Egypt had shown increased risk of IPF 13 . Pesticide exposure can directly and indirectly increase the risk of COPD and asthma 21 . The chemicals can persist in soil for decades. The specific pathogenesis related to ILD is unknown.

A longer occupational exposure period is known to increase IPF risk 16 . Exposure through working in agriculture, livestock, beauty, chemical/petrochemical, woodworking, and steel industries was reported to increase IPF risk previously 9 , 13 , 14 , 16 , 17 . On meta-analysis, we found statistically significantly increased IPF risk in only agricultural workers. Additionally, the risk of IPF increased through working in building, woodworking, and textile industries, but did not reach statistically significant level.

Only two of the seven included studies showed that individuals’ smoking history statistically significantly increased the risk of developing IPF, but when meta-analysis was conducted, we found that smoking increased IPF risk with an odds ratio of 1.38 (Fig.  4 , Supplementary Table S4 ).

Smoking has been found to increase the risk of IPF in several studies 9 , 14 , 16 , 22 . Studies to date suggest that the increased oxidative stress caused by smoking affects IPF progression in former and current smokers compared to non-smokers 23 . In a study conducted using a population-based registry in Sweden, the risk of IPF increased with an odds ratio of 2.10 (95% CI 1.20–3.68) when subjects smoked for 10–19 pack years and with an odds ratio of 2.25 (95% CI 1.26–4.02) when subjects smoked more for than 20 pack years. Dose-dependent increase was reported for smoking as a risk factor for IPF 23 . Our study also confirmed that the risk of IPF increased in smoker compared to never smoker from meta-analysis on case–control studies.

There were several limitations in this study. First, recall bias may be a limitation of this study. Because the subject’s occupational and environmental risk factors were collected retrospectively, the quality of information may deteriorate because they rely on recall. In four studies, the questionnaire was minimized by direct questionnaire by specialized researchers like occupational environment experts. But remain studies were conducted by the patient himself or herself. Second, a quantitative analysis considering the degree and frequency of exposure would be more informative when investigating risk factors, rather than a simple exposure analysis. However, such an analysis could not be conducted in this study. In terms of occupation type exposure, the actual amount, duration, and frequency of risk factor exposure during the period of exposure in a particular job type was neither conducted nor comparatively analyzed. Third, although studies from various countries are included, they did not have national representation because each study covers a specific region of the country. Also, mainly in the studies in the United States, some European countries, and Asia (where only Japan and Korea are included), racial differences may not be reflected. Fourth, as the diagnostic definition of IPF has been changing for decades. Heterogeneity among the included cases may exist due to the development of imaging technology which may have affected the diagnosis. The first international guidelines 24 , based on expert opinions on the diagnosis and treatment of IPF, were published in 2000 and evidence-based revised new treatment guidelines have been published in 2011, integrating the patient’s clinical symptoms, pathogenesis, and natural course 25 . Later, as new drugs for IPF treatment were developed focusing on early treatment and diagnosis, the new IPF diagnostic criteria, complemented with high-resolution computed tomography imaging and related pathological findings, were presented in 2018 26 , 27 . This study includes about 30 years of research from 1990 to recent studies. To minimize of misdiagnosis and overdiagnosis of IPF, case control studies that had diagnosed IPF mainly based on chest X-ray were removed 6 , 7 , 10 . Finally, in some studies, the control group was not a healthy adult control group. Inclusion of patients with respiratory diseases, such as acute bacterial pneumonia, chronic obstructive pulmonary disease, lung cancer, and pulmonary tuberculosis other than IPF may have affected the interpretation of the results. The effect of smoking as a multiplicative risk for the development of IPF cannot be omitted.

In conclusion, meta-analysis of patient-control studies revealed that exposure to pesticides, metal dust, and wood dust increases the risk of IPF. Additionally, the risk of IPF was more in agricultural workers. Lastly, smoking also increased the risk of IPF.

Searching strategy

The Patient populations, Intervention, Comparison, Outcomes (PICO) of this study are as follows:

Adult, IPF cases.

Environmental and occupational exposure, occupation.

Non-IPF controls.

Risk of IPF depending on exposure to each factor.

This study was conducted according to the systematic literature review reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 28 . Medline, Embase, and the Cochrane Library were searched for papers published by March 2020 using the Ovid interface. The search terms were “Idiopathic Pulmonary Fibrosis” [ALL] OR “Idiopathic Pulmonary Fibroses” [ALL] OR “Cryptogenic Fibrosing Alveolitis” [ALL] OR “Cryptogenic Alveolitides” [ALL] OR “Idiopathic Fibrosing Alveolitis” [ALL] OR “Idiopathic Fibrosing Alveolitides” [ALL] OR “Usual Interstitial Pneumonitis” [ALL] OR “Usual Interstitial Pneumonitides” [ALL] OR “Usual Interstitial Pneumonia” [ALL] OR “Usual Interstitial Pneumonias” [ALL]. The studies not recorded in the databases but existing in previous meta-analysis studies were directly searched and added. Additional details are listed in Supplementary Table 1 .

Inclusion and exclusion criteria

Two investigators independently selected the studies after confirming the title and abstract according to the inclusion and exclusion criteria of this study. Duplicate papers were excluded.

The inclusion criteria were: (1) study on adult population over 18 years of age; (2) IPF diagnosis criteria based on the clinician’s judgment of the patient’s symptoms, clinical findings, and imaging findings (histological diagnosis may not have been necessarily included in the diagnosis); (3) categorization of the surveyed jobs or occupational and environmental exposure factors that could lead to risk of IPF. The survey methods for occupational and environmental exposure factors included any method that is systematic and planned, ranging from self-reporting by mail or telephone to face-to-face surveys with experts. Additionally, the effect of cigarettes was analyzed by studying individuals who had smoked in the past or who are currently smoking.

Reviews, letters, editorials, case reports, studies on animals or children, theoretical studies on the medical system itself, revisions after the medical system were introduced, papers or papers not related to the research purpose, papers written in languages other than English were excluded. Additionally, studies that only focused on known risk factors, such as asbestosis, coal worker’s pneumoconiosis, and silicosis, were excluded.

Evaluation of paper quality

Quality evaluation was conducted for papers that met the inclusion criteria, which was quantitatively evaluated using Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) 29 . This tool includes 6 items, including selection of participants, confounding variables, exposure measurement, outcome assessment blinding, incomplete outcome data, and selective reporting. Each item was rated as “high”, “low”, and “uncertain”; 0 for “low”, + 1 for “uncertain”, and + 2 for “high”. On summation, a score of 1 or less meant the paper was of high quality; 2–3, of moderate quality; 4 or more, low in quality.

Extraction of data

Authors, publication year, location of study, multi-center study, research method, number of experimental and control groups, age, sex, and smoking status were extracted and summarized for the finally included papers.

The number of exposure factors examined in each study was varied. Among them, if more than four studies investigated a common exposure factor, that exposure factor was analyzed. Finally, our analysis was conducted on five exposure factors.

We analyzed four occupations types which were included in four or more studies. Five of the 12 studies included occupational classification in the case–control group 9 , 13 , 14 , 16 , 17 . Among them, researchers such as Kim and Miyake conducted research according to the Korean Standard Classification of Occupations and Japanese Standard Occupational Classification standards, respectively. The analyzed occupations were classified in each study according to the classification criteria set by the researchers.

The individual's smoking history was classified into two groups, the smoking group including both past and present smoking, and the non-smoking group who had never smoked.

Statistical analysis

We used Review Manager Version 5.3 (The Cochrane library, Oxford, UK) was used. To minimize the influence of other variables as much as possible, the unadjusted odds ratio value was used. When raw data were presented in the paper, the unadjusted odds ratio was calculated using the presented values. If multiple adjusted odds ratios were presented, the odds ratio values corresponding to the same criteria were used after consultation between authors. Statistical meta-analysis was then performed using the extracted ratio values.

In the main analysis, the occupational and environmental exposure factors included were five types of metal dust, wood dust, stone/sand dust, textile dust, and pesticides. The occupation types included were construction, agriculture, woodworking, and textile. Additionally, the relationship between the individual's smoking history and disease was investigated.

To evaluate statistical heterogeneity in each study, I 2 test of Higgins was calculated with a 95% confidence interval (CI). Statistical heterogeneity was considered low if I 2 value was less than 25%, moderate if it was between 25 and 50%, high if it was between 50 and 75%, and very high if it was more than 75%.

After obtaining the odds ratios of each factor, the pooled effect size was estimated using the inverse variance weighted method 30 . The 95% confidence interval and weight are presented as a forest plot.

Sensitivity analysis was conducted to exclude studies of low quality or which included specific conditions or characteristics. If more than 10 studies included in the analysis, a statistical analysis of the asymmetry was performed using Egger’s test to confirm the publication error, and a visual analysis of the asymmetry was performed using a funnel plot.

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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These authors contributed equally: Yeonkyung Park and Chiwon Ahn.

Authors and Affiliations

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, South Korea

Yeonkyung Park

Department of Emergency Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Hanyang University Guri Hospital, 153, Gyeongchun-ro, Guri-si, Gyeonggi-do, 11923, South Korea

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All authors conceived the study and designed the review. Y.P. and C.A. performed the searches and screened studies for eligibility. All authors assessed the quality of the papers and Y.P. and C.A. performed the statistical analysis. Y.P. and C.A. drafted the manuscript, and all authors contributed substantially to its revision. T.-H.K. takes responsibility for the paper as a whole.

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Park, Y., Ahn, C. & Kim, TH. Occupational and environmental risk factors of idiopathic pulmonary fibrosis: a systematic review and meta-analyses. Sci Rep 11 , 4318 (2021). https://doi.org/10.1038/s41598-021-81591-z

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Volume 6 Supplement 1

IPF in 2011 - Key updates on guidelines and therapeutics. Case studies

• Case Report
• Open access
• Published: 16 April 2013

Clinical case: Differential diagnosis of idiopathic pulmonary fibrosis

• Carlos Robalo Cordeiro 1 , 2 ,
• Tiago M Alfaro 1 , 2 &
• Sara Freitas 1 , 2  

BMC Research Notes volume  6 , Article number:  S1 ( 2013 ) Cite this article

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The diagnosis of idiopathic pulmonary fibrosis can be quite challenging, even after careful clinical evaluation, imaging and pathological tests. This case report intends to demonstrate and discuss these difficulties, especially those concerning the differential diagnosis with chronic hypersensitivity pneumonitis.

Case presentation

A 58-year-old white male presented with shortness of breath, dry cough, fatigue and weight loss for two months. He was a former smoker and had regular exposure to a parakeet and poultry. Physical examination revealed bilateral basal crackles and chest imaging showed subpleural cystic lesions and traction bronchiectasis with a right side and upper level predominance. Auto-antibodies and IgG immunoglobulins to parakeet and fungal proteins were negative. Lung function tests displayed moderate restriction, low diffusion capacity and resting hypoxaemia. Bronchoalveolar lavage showed increased lymphocytes (28%) and neutrophils (12%) and surgical lung biopsy was compatible with a pattern of usual interstitial pneumonia. According to the possibility of either idiopathic pulmonary fibrosis or chronic hypersensitivity pneumonitis, treatment included prednisolone, azathioprine, acetylcysteine and avoidance of contact with the parakeet, but there was an unfavorable response and the patient was subsequently referred for lung transplant.

Chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis can present with the same clinical and radiological manifestations In this case, despite careful evaluation, no definite diagnosis could be achieved.

Brief introduction

This case demonstrates the difficulties that can occur during the diagnosis of patients with Idiopathic Pulmonary Fibrosis (IPF), and the importance of careful clinical evaluation followed by the appropriate tests.

Patient history

A 58-year old male was referred to our outpatient consultation centre with complaints of shortness of breath, dry cough and fatigue over the previous two months. He also reported anorexia and involuntary weight loss for the same period of time. His primary care physician had treated him with antibiotics, but no response or improvement in symptoms were noted. The patient’s past medical history included an episode of pesticide poisoning 35 years ago for which no information was available and occasional gout that responded to anti-inflammatory medication. The patient was an ex-smoker of 80-pack years and a moderate drinker. No known allergies were reported. His occupational history included working as a stacker in a warehouse for 20 years, with moderate dust exposure, and following this, as an administrative worker for 20 years. He was regularly exposed to a parakeet (Melopsittacus undulatus), chickens, and cats. The patient was unaware of any exposure to tuberculosis patients, recent trips abroad or family history of respiratory disease.

Physical examination

On physical examination, he was in good general condition, but crackles were heard in both lung bases. No other changes were noted.

Diagnostic tests

The patient’s chest X-ray showed bilateral diffuse interstitial infiltrates with a predominant reticular pattern and no spared areas (Figure 1 ). This was followed by a high resolution computed tomography (HRCT) scan of the chest that showed several areas of subpleural cystic lesions and traction bronchiectasis affecting all lobes, but having an upper and middle level predominance and being much more extensive in the right lung. There were also multiple mediastinal enlarged lymph nodes and an enlargement of the pulmonary artery (3.2 cm diameter) and right cardiac cavities (Figure 2 ). Cardiac tests were performed, including an electrocardiogram and echocardiogram, and no other signs of cardiac disease were found. Blood tests, including those for auto-antibodies and IgG immunoglobulins (to parakeet and fungal proteins) were negative. Lung function tests suggested moderate restriction (percentage predicted forced vital capacity [FVC], 57.5%), low diffusion capacity ([DLco] 36% of the predicted value) and resting hypoxaemia (PaO2, 69.7 mmHg). The decision was made to perform bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. Upon examination, the bronchial mucosa showed moderate signs of inflammation, but no other morphological changes. Bronchoalveolar lavage showed an increase in the total cell count (300 cells/µL), and increased percentage of lymphocytes (28%) and neutrophils (12%). The CD4/CD8 ratio was 0.2. Transbronchial biopsy showed no specific findings. A transthoracic biopsy was then performed, but the results were also inconclusive. The patient was referred for surgical lung biopsy. The pathology of the surgical specimen was compatible with a pattern of usual interstitial pneumonia (Figure 3 ).

Chest X-ray showing bilateral diffuse interstitial infiltrates with a predominantly reticular pattern and no spared areas.

HRCT scans showing honeycombing and traction bronchiectasis affecting all lobes of the lungs, enlarged mediastinal lymph nodes and enlargement of the pulmonary artery (3.2 cm in diameter) and the right cardiac cavities.

Surgical lung biopsy showing aspects compatible with a pattern of usual interstitial pneumonia.

Treatment and patient management

At this time no definite diagnosis could be made, as the clinical, radiological and pathological findings were compatible with both chronic hypersensitivity pneumonitis and IPF. Nevertheless, treatment with prednisolone, azathioprine and acetylcysteine commenced. The patient was also instructed to avoid any contact with the parakeet. Despite the treatment, the patient got progressively worse, and has been referred for lung transplantation.

Chronic hypersensitivity pneumonitis and IPF can present with the same clinical and radiological manifestations [ 1 ]. A careful clinical evaluation is therefore fundamental, and the surgical pulmonary biopsy is usually helpful in performing the differential diagnosis [ 2 ], but not in this case. A UIP pattern can be seen on biopsy (and/or CT) in both IPF and chronic HP. The addition of BAL can give a decisive contribution to the diagnostic procedures [ 3 ]. A cut-off level of 30% for lymphocytes in BAL demonstrated a favorable discriminative power for the diagnosis of IPF [ 4 ]. In this case, despite careful evaluation, no definite diagnosis could be achieved.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, 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. 10.1164/rccm.2009-040GL.

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Ohshimo S, Bonella F, Cui A, Beume M, Kohno N, Guzman J, Costabel U: Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009, 179 (11): 1043-1047. 10.1164/rccm.200808-1313OC.

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Acknowledgements

The author thanks C. Trenam, I. Mandic and M. Smith of IntraMed Communications for editorial assistance in the preparation of the manuscript. Development of this article was supported by InterMune AG.

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This article has been published as part of BMC Research Notes Volume 6 Supplement 1, 2013:IPF in 2011 – Key updates on guidelines and therapeutics. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcresnotes/supplements/6/S1 . This supplement originates from presentations given at the symposium “AIR: Advancing IPF Research. Working together to translate IPF research into practice” held in Berlin in November 2011. The publication was supported by InterMed Communications with funding from InterMune, AG. The content was proposed by InterMed Communications and developed with the journal. All articles in the supplement have undergone the journal’s standard peer review process.

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Carlos Robalo Cordeiro, Tiago M Alfaro & Sara Freitas

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CRC was a speaker at the AIR meeting, receiving fees. SF and TMA reported no competing interests.

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TMA and SF performed the data collection and drafted the manuscript. CRC conceived and supervised the whole study and made the final revision to the manuscript. All authors read and approved the final manuscript.

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Cordeiro, C.R., Alfaro, T.M. & Freitas, S. Clinical case: Differential diagnosis of idiopathic pulmonary fibrosis. BMC Res Notes 6 (Suppl 1), S1 (2013). https://doi.org/10.1186/1756-0500-6-S1-S1

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• Idiopathic Pulmonary Fibrosis
• High Resolution Compute Tomography
• Acetylcysteine
• Lung Function Test
• Usual Interstitial Pneumonia

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• Research article
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• Published: 22 May 2017

Mechanical ventilation in idiopathic pulmonary fibrosis: a nationwide analysis of ventilator use, outcomes, and resource burden

• Joshua J. Mooney 1 ,
• Karina Raimundo 2 ,
• Eunice Chang 3 &
• Michael S. Broder 3  

BMC Pulmonary Medicine volume  17 , Article number:  84 ( 2017 ) Cite this article

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Idiopathic pulmonary fibrosis (IPF) is associated with increased risk of respiratory-related hospitalizations. Studies suggest mechanical ventilation (MV) use in IPF does not improve outcomes and guidelines recommend against its general use. Our objective was to investigate MV use and association with cost and mortality in IPF.

This retrospective study, using a nationwide sample, included claims with IPF (ICD-9-CM: 516.3) in 2009–2011 and principal respiratory disease diagnosis (ICD-9-CM: 460–519); excluding lung transplant. Regression models were used to determine predictors of MV and association with cost, LOS, and mortality. Domain analysis was used to account for use of subpopulation. Costs were adjusted to 2011. Data on patient severity not available.

Twenty two thousand three hundred fifty non-transplant IPF patients were admitted with principal respiratory disease diagnosis: Mean age 70.0 (SD 13.9), 49.1% female, mean LOS 7.4 (SD 8.2). MV was used in 11.4% of patients with a non-significant decline over time. In regression models, MV was associated with an increased stay of 9.78 days (95% CI 8.38–11.18) and increased cost of $36,583 (95% CI $32,021–41,147). MV users had significantly increased mortality (OR 15.55, 95% CI 12.13–19.95) versus nonusers.

Conclusions

Mechanical ventilation use has not significantly changed over time and is mostly used in younger patients and those admitted for non-IPF respiratory conditions. MV was associated with a 4-fold admission cost increase ($49,924 versus $11,742) and a 7-fold mortality increase (56% versus 7.5%), although patients who receive MV may differ from those who do not. Advances in treatment and decision aids are needed to improve outcomes in IPF.

Peer Review reports

Idiopathic pulmonary fibrosis (IPF), a form of interstitial pneumonia, affects 0.5% of US adults over age 65 [ 1 ]. The disease is characterized by progressive lung fibrosis [ 2 ] and unpredictable episodes of disease worsening, which may lead to hospitalization and frequently death [ 3 , 4 , 5 ]. The median survival from diagnosis is 3–5 years [ 6 ]. Although two pharmacologic treatments that slow physiologic decline are now available [ 7 , 8 ], limited options remain for IPF patients hospitalized with respiratory-related symptoms or failure.

Management of respiratory failure in IPF is challenging as patients can develop acute disease episodes that necessitate ventilator support. In select IPF patients, ventilator support can be used as a bridge to lung transplant [ 9 , 10 ] or could allow for treatment of reversible non-IPF causes of respiratory failure. However, overall outcomes of IPF patients who require non-invasive ventilation or mechanical ventilation (MV) are poor [ 11 , 12 , 13 , 14 , 15 , 16 ]. A systematic review [ 17 ] summarizing 9 single-center studies reported an 87% in-hospital mortality rate for IPF patients who received MV. Given this evidence, IPF treatment guidelines recommend the majority of IPF patients with respiratory failure not receive MV, and when used should occur after assessing patient-specific goals of care or lung transplant candidacy [ 10 ].

While studies have repeatedly demonstrated high mortality with MV, the nationwide pattern of its use in IPF patients has not been well characterized. In this study, we investigated US trends in the use of non-invasive ventilation and MV for IPF, predictors of use, and association with hospital cost, length of stay (LOS), and mortality. We also examined whether MV had a direct effect on mortality, or whether the effect was entirely mediated by the patients’ underlying disease and comorbid conditions.

Design and data sources

We conducted a retrospective cohort study using the Nationwide Inpatient Sample (NIS), the largest publicly available US inpatient database that includes individuals covered by Medicare, Medicaid, or private insurance, as well as the uninsured. Data elements include diagnoses, procedures, demographics, hospital characteristics, payment source, charges, discharge status, LOS, and severity measures [ 18 ]. The study used de-identified data and was exempt from institutional review board review.

Patient Population

We included all hospitalizations from 2009–2011 with claims for IPF (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 516.3) and a principal diagnosis of respiratory disease (ICD-9-CM: 460–519). Hospital discharge records may contain multiple diagnoses, with the primary cause for admission listed as “principal.” A hospitalization for a patient with IPF admitted with pneumonia as the principal diagnosis would have been included in our study, as pneumonia is a respiratory disease, as would a hospitalization with a principal diagnosis of IPF (also a respiratory disease). An admission with a principal diagnosis of hip fracture would not be included, even if IPF was listed as a secondary diagnosis. Included patients had ≥ 1 inpatient claim with IPF as a discharge diagnosis between 2009–2011. We excluded lung transplant admissions (ICD-9-CM: 33.5×, 33.6).

Outcome variables of interest were non-invasive (ICD-9-CM: 93.90) and MV (ICD-9-CM: 96.7×) use, hospital LOS, total inpatient costs, and in-hospital mortality. Other study variables include demographics, primary payer type, hospital characteristics, and all patient refined diagnosis-related group (APR-DRG) severity of illness. APR-DRG assigns patients to severity and mortality subclasses using co-morbidities, age, procedures, and principal diagnosis [ 19 ]. We looked for evidence of concomitant acute and chronic pulmonary conditions, including chronic obstructive pulmonary disease (COPD), bacterial pneumonia, and lung cancer. Cardiovascular conditions were identified, including ischemic heart disease, myocardial infarction (MI), congestive heart failure, and pulmonary hypertension. The number of chronic conditions for each patient, calculated using the Chronic Condition Indicator, was reported. This indicator uses 5 digit ICD-9-CM codes to categorize conditions as chronic or not chronic [ 20 ]. Admissions were characterized as elective, emergency, urgent, or other non-elective. Discharge disposition was reported as routine, transfer to short-term hospital, transfer to other facilities, home health care, died in hospital, or unknown.

Statistical analysis

Variables were weighted to represent national estimates and rounded to the nearest integer. NIS reports only charges, so cost-to-charge ratios were used to estimate costs. These ratios are constructed using costs and charge information from hospital reports to CMS. Hospital-specific ratios were used if available; otherwise a weighted group average was used. Costs were adjusted to 2011 US$ using the medical care component of the consumer price index [ 21 ]. For categorical variables, Rao-Scott chi-square goodness-of-fit tests adjusting for sampling design were used, relevant p-values reported. We calculated variance using domain analysis to account for subpopulations. Linear regression models were used for LOS and cost, logistic regression models for MV and mortality. Models were adjusted for age, gender, race, principal diagnosis of IPF, lung cancer, selected cardiovascular conditions, hospital region, hospital teaching status, and MV use, as appropriate. Adjusted mean LOS and hospital cost, and adjusted inpatient mortality rate (and 95% confidence intervals) were reported for MV users and nonusers.

Patients with certain characteristics may have a higher risk of inpatient mortality and MV use. To investigate whether MV use was a mediator between clinical characteristics and mortality (rather than directly related), we followed the approach described by Baron and Kenny [ 22 ]. We conducted additional regression models to examine the association of clinical conditions/characteristics (the causal variables) on both the MV use (the mediator) and mortality (the outcome variable). Model results were compared to determine whether mediation effects were identifiable. Data transformations and statistical analyses were performed using SAS® version 9.4.

From 2009–2011 42,924 IPF patients were admitted to US short-stay hospitals; 23,739 admissions had a principal diagnosis of respiratory disease. The remainder of admissions for these IPF patients were for non-respiratory conditions. After excluding 1,379 lung transplant admissions and 10 with missing age, final sample size was 22,350: 7,346 in 2009, 6,643 in 2010, and 8,362 in 2011. MV was used in 11.4% (2,546) of admissions: 12.1% (887) in 2009, 11.5% (764) in 2010, and 10.7% (894) in 2011 ( p  = 0.578). Non-invasive ventilation was used in 8.9% (1,995) of admissions: 7.9% (583) in 2009, 8.3% (550) in 2010, and 10.3% (862) in 2011 ( p  = 0.112) (Fig.  1 ).

Trend in Ventilation Use in IPF Hospitalizations. The proportion of IPF hospitalizations where mechanical ventilation was used declined each year, going from 12.1% (887) in 2009, to 11.5% (764) in 2010, and 10.7% (894) in 2011 ( p  = 0.578). The use of non-invasive ventilation increased over the same period: 7.9% (583) in 2009, 8.3% (550) in 2010, and 10.3% (862) in 2011 ( p  = 0.112)

Unadjusted analysis

Mean age was 65.9 (+/−0.62) for MV users and 70.5 (+/−0.34) for nonusers ( p  < 0.001). Overall, 49.1% (10,976) of patients were female: 40.2% (1,024) of MV users and 50.3% (9,953) of nonusers ( p  < 0.001). The majority (64.4%, n  = 14,404) of patients were White, 9.4% Hispanic, 7.6% Black, with no significant difference by MV use. The primary payer was Medicare for 58.9% of admissions at which MV was used, compared to 69.7% where it was not ( p  < 0.001). A principal diagnosis of IPF was present in 31.5% of admissions at which MV was used vs. 44.6% where it was not ( p  < 0.001) (Table  1 ).

ICD-9-CM diagnoses of pneumonia (49.2% vs. 37.1%, p <0.001) and MI (10.5% vs. 5.4%, p <0.001) were more common in patients requiring MV, while COPD (28.9% vs. 39.4%, p  < 0.001) was less common. As is the case for all diagnoses in this study, these conditions were not confirmed clinically. MV users had significantly fewer chronic conditions (4.2 vs. 4.3, p <0.001) (Table  2 ). Patients who used MV had longer hospital stays (16.5 days [+/−0.73] vs. 6.2 [+/−0.10], p  < 0.001), were more likely to have died in the hospital (55.3% vs. 8.8%) and less likely to have a routine home discharge (9.3% vs. 51.2%) ( p  < 0.001). Costs ($49,924 vs. $11,742, p  < 0.001) were higher in MV users compared to nonusers (Table  3 ).

Adjusted analysis

MV was associated with an adjusted LOS of 16.1 days (95% CI: 15; 17.5) versus 6.3 days (95% CI: 6; 6.5) for nonusers. The adjusted cost associated with MV was $48,772 (95% CI: 43,979; 53,565) versus $11,861 (95% CI: 11,292; 12,431) for nonusers. The adjusted in-hospital death rate for MV users and nonusers was 55.7% (95% CI: 50.3; 61.0) and 7.5% (95% CI: 6.6; 8.4) (Table  4 ). Each year of increased age was associated with shorter LOS (−0.03; 95% CI: −0.06; −0.01) and lower cost ($-143; 95% CI: −208; −78) but greater in-hospital death (OR 1.02; 95% CI: 1.01; 1.03). The use of non-invasive ventilation was associated with increased LOS (2.03 days; 95% CI: 0.93; 3.14), cost ($5,119; 95% CI: 2,000; 8,238) and death (OR 4.77; 95% CI: 3.48; 6.55) (Fig.  2 ). A principal diagnosis of IPF was associated with increased cost ($1,731; 95%CI: 636; 2,827) and death (OR 1.78; 95% CI: 1.42; 2.24) but no change in LOS (Fig.  2 ).

Linear Regression Model for LOS and Costs. Age, bacterial pneumonia, and use of mechanical ventilation were statistically significantly ( p  < 0.001) associated with cost and LOS. Admission with a principal diagnosis of IPF was significantly associated with cost but not LOS. Use of mechanical ventilation had the largest effect on LOS and cost, with an increase of 9.78 days [95% CI: 8.38 - 11.18] and $36,583 [32,021 – 41,147] respectively. Non-invasive ventilation was associated with an increase of 2.03 days [0.93 – 3.14] in LOS and $5,119 [2,000 – 8,238] in cost. Point estimates and 95% CI for LOS and cost are adjusted for all listed variables. CI Confidence interval; a Ischemic heart disease, myocardial infarction, and congestive heart failure

To investigate the association among clinical conditions/characteristics, MV use, and inpatient mortality, we conducted two additional logistic regression models. In the model for risk of MV, we controlled for patient and hospital characteristics. In this model, decreasing age (OR 0.97, 95% CI: 0.97; 0.98), female gender (OR 0.68, 95% CI: 0.55; 0.85), Hispanic ethnicity (OR 0.66, 95% CI: 0.45; 0.97) and principal diagnosis of IPF (OR 0.60, 95% CI: 0.48; 0.76) were associated with a lower risk of MV. Cardiovascular conditions (OR 1.34, 95% CI: 1.08; 1.65; p  = 0.007), bacterial pneumonia (OR 1.55, 95% CI: 1.27; 1.90; p <0.001), and teaching hospital admission (OR 1.58, 95% CI 1.26; 1.98; p  < 0.001) were associated with higher risk of MV. In the model for in-hospital death that excluded MV as a predictor, female gender was associated with a lower risk of death (OR 0.62, 95% CI: 0.52; 0.74; p  < 0.001), whereas principal diagnosis of IPF (OR 1.26, 95% CI: 1.03; 1.55; p  = 0.026), teaching hospital admission (OR 1.37, 95% CI 1.11; 1.69; p  = 0.003), cardiovascular conditions (OR 1.26, 95% CI: 1.04; 1.51; p  = 0.017), and bacterial pneumonia (OR 1.42. 95% CI: 1.18; 1.71; p  < 0.001) were associated with increased risk (Table  5 ).

Our study of IPF patients admitted to a nationwide sample of acute care hospitals found 11-12% of IPF patients admitted with a respiratory condition used MV, with no significant change from 2009–2011. Younger, male patients with fewer comorbidities and/or with a non-IPF principal diagnosis (e.g., pneumonia) were more likely to use MV. MV was associated with nearly 10-day longer hospital stays, $37,000 higher cost, and a more than 7-fold increase in mortality (56% versus 7.5%). Less than 10% of patients who used MV were discharged home routinely, compared to more than half of nonusers. Non-invasive ventilation was associated with increased LOS and cost, although to a lesser extent than MV.

The unchanging nationwide use of MV over time, despite IPF treatment guidelines conditionally recommending against MV use, reflects the limited options available to clinicians treating acute worsening of IPF and the difficulty of advance care planning in IPF. As acute worsening leading to respiratory failure can occur quickly and unexpectedly, MV can provide time to evaluate for possible treatable conditions, to assess patient preferences and/or to support gas-exchange while awaiting lung transplant. Lung transplantation remains the only curative and life-prolonging option for select patients with advanced IPF and respiratory failure. Notably, IPF patients who received MV were younger with fewer chronic medical conditions, more often admitted at a teaching hospital, and more frequently coded with a non-IPF principal respiratory diagnosis (e.g., pneumonia). This suggests a nationwide preference for MV use in younger, somewhat healthier, IPF patients or in those with a clinical suspicion of a reversible condition. Possible explanations for this finding are that younger patients with less chronic comorbidity may be potential lung transplant candidates or clinicians may feel compelled to offer them a trial of ventilator support. We cannot ascertain from the data if patients were awaiting transplant or later transferred for transplant evaluation.

The overall economic and health care burden of IPF is well-recognized [ 23 , 24 , 25 , 26 , 27 ]. This study uniquely highlights the burden associated with MV use in IPF, while reinforcing with nationwide data the poor outcomes reported in prior smaller studies. Hospital cost was more than 4-fold greater and mortality 7-fold greater in IPF patients hospitalized with a respiratory problem requiring MV. While in-hospital mortality (55.3%) was lower than previously reported, this underestimates mortality as a significant number of patients were transferred to short-term hospitals (6.9%) or other facilities (20.8%) where their final vital status is unknown. Only 16.4% of MV users were discharged home. The high mortality and economic burden associated with MV in IPF stresses the need to improve the quality of medical care for IPF patients, including advances in prevention, treatment, and patient-clinician shared decision-making. While recently approved pharmacologic therapies slow disease progression and may reduce acute exacerbations [ 7 , 8 , 28 ], the course of IPF remains unpredictable. Therefore, early patient-centered discussions on treatment expectations, appropriate referrals for transplant and/or palliative care, and coordination of care across providers, remain integral to honoring patients’ values while ensuring high value care. IPF-specific decision aids are needed to help guide patients.

Some conditions that lead to MV may themselves be associated with greater mortality, confounding the interpretation of our findings. We used a method similar to that of Baron and Kenny [ 22 ] to test whether MV simply mediated the mortality effects of other variables. Our results suggest that this was not true of a principal IPF diagnosis, as it remains associated with mortality in the models both with and without MV use. Both cardiovascular conditions and bacterial pneumonia had statistically significant effects in the model that did not include MV, and smaller, not statistically significant, effects in the model that included it. This suggests the association between these characteristics and in-hospital death results, at least in part, from their association with MV, which independently increases the risk of death. However, some residual confounding by indication likely still exists.

This study has limitations. First, there is debate on how to identify IPF patients using claims data. The ICD-9-CM code we used has been used before in several publications [ 1 , 6 , 23 , 24 ], however a recent validation study (not in the NIS) found it had a positive predictive value of 30-60% [ 29 ]. While less than desirable, this positive predictive value is within the range reported in study of ICD-9-CM codes for 32 conditions (median 80.7%, mean 77%, range 23-100%) [ 30 ]. Similarly, none of the conditions we identified (e.g., COPD) were confirmed clinically. Identification relied on ICD-9-CM codes, which are designed and used primarily for billing. Our study was further limited in that the NIS does not allow patients to be followed through subsequent outpatient care, repeat hospitalizations, or transfer to other facilities. We could not determine whether a subject died, received a transplant, or was discharged home after being transferred. The study relied on secondary data collected at discharge for administrative purposes, so no clinical information, including disease severity, was available. We could not determine whether medical conditions were present on admission or developed during hospitalization, nor could we determine the order in which diagnoses were made or treatments were given. Further, less severe comorbid conditions common to patients with IPF (e.g., obesity and gastroesophageal reflux) may be undercoded. Finally, as in prior studies [ 23 , 24 ] we excluded transplant-related expenditures. This exclusion allows for a close look at direct costs of IPF-related care, but underestimates the complete cost of IPF.

A strength of the study is the use of the Nationwide Inpatient Sample, which was designed to inform policy decisions regarding health and health care at national and regional levels. Previous evaluations of IPF MV use and cost have been limited to specific centers or populations (e.g., Medicare and select private insurers) and their findings may be less generalizable. The NIS includes patients with Medicare, Medicaid, and private insurance, as well as the uninsured, making this dataset the best way to produce estimates valid for the overall US population.

In a nationwide sample of IPF patients, MV was used in 11-12% of those hospitalized due to a respiratory diagnosis with no significant change in its use over time. Mechanical ventilation was more frequent in younger male IPF patients, those admitted at teaching hospitals, and those with fewer chronic medical conditions or a non-IPF respiratory diagnosis. Its use was associated with a 4-fold increase in admission cost ($49,924 compared to $11,742) and a 7-fold increase in admission mortality (56% compared to 7.5%). Further advances in IPF treatment and development of IPF-specific decision aids are needed to improve the resource burden, outcomes, and use of MV in IPF.

Abbreviations

All patient refined diagnosis-related group

Confidence interval

Chronic obstructive pulmonary disease

Current procedural terminology

Emergency department

International classification of diseases, 9th revision, clinical modification

• Idiopathic pulmonary fibrosis

Length of stay

Myocardial infarction

• Mechanical ventilation

Nationwide inpatient sample

Clinical modification

Standard deviation

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Acknowledgments

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This study was funded by Genentech, Inc. The sponsor was involved in the study design, interpretation, and manuscript writing. K. Raimundo is an employee of Genentech, Inc. E. Chang and M. Broder are employees of Partnership for Health Analytic Research, LLC, a health services research company paid by Genentech to conduct this research.

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The Nationwide Inpatient Sample (NIS) inpatient data that support the findings of this study are available for purchase from the Healthcare Cost and Utilization Project (HCUP).

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All authors meet the ICMJE criteria for authorship. All authors were equally involved in the design of the study. EC conducted the statistical analyses and all authors contributed equally in the interpretation of results and writing of the manuscript. All authors read and approved the final manuscript.

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K. Raimundo is an employee of Genentech, Inc. E. Chang and M. Broder are employees of Partnership for Health Analytic Research, LLC, a health services research company paid by Genentech to conduct this research.

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Mooney, J.J., Raimundo, K., Chang, E. et al. Mechanical ventilation in idiopathic pulmonary fibrosis: a nationwide analysis of ventilator use, outcomes, and resource burden. BMC Pulm Med 17 , 84 (2017). https://doi.org/10.1186/s12890-017-0426-2

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A case of idiopathic pulmonary fibrosis

Chest imaging

Clinical Cases

A. Strutynskaya 1 , M. Karnaushkina 2

1     Federal state autonomous institution “National Medical Research Center for Children's Health” of the Russian Federation Ministry of Health. Lomonosov Avenue, 2, building 1. Moscow, Russia 2     I.M. Sechenov First Moscow State Medical University. Bolschaya Pirogovskaya street, 2 building 4. Moscow, Russia Corresponding author – A. Strutynskaya. Email: [email protected]

64 years, female

A 64-year-old female patient complaining of cough with scarce yellowish sputum, severe exertional dyspnoea and weakness in the last 3 weeks and treating with aminopenicillins and ipratropium bromide+fenoterol for 7 days with minimal effect. Her lung function had progressively deteriorated during last 2 years. She had stopped smoking 6 years ago. Clinical examination revealed dyspnoea and tachypnoea with multiple predominantly bibasal crackles, O2 saturation was 85%, restrictive changes were identified at spirometry.

Inspiratory chest CT showed inhomogeneous decrease of pneumatisation, multiple foci of irregularly spaced reticulation, honeycombing pattern (clustered cystic air spaces of variable diameters, occasionally up to 15 mm, with thick, dense walls) and traction bronchiectasis. The latter is defined as irregular bronchial dilatation surrounding retractile pulmonary fibrosis. It is important that all the reticular abnormalities are predominantly in subpleural zones and there is craniocaudal gradient of the lesions, seen on coronal images. Also sliding hiatal hernia (no contrast enema was given) is observed. Described features are consistent with usual interstitial pneumonia (UIP) pattern. Considering the appropriate anamnesis and clinical findings, idiopathic pulmonary fibrosis (IPF) was diagnosed.

Background IPF is a chronic, progressive, fibrotic interstitial lung disease of unknown cause [1]. Repeated alveolar micro-injury superimposed on pro-fibrotic epigenetic reprogramming, impaired mechanisms of alveolar epithelium repair and dysfunction of surfactant leads to development of fibrosis [3-5]. IPF requires differentiation with alternative causes of pulmonary fibrosis, preferentially with connective tissue disorders (e.g. rheumathoid arthritis, antisynthetase and Sjogren's syndromes), chronic hypersensitivity pneumonitis, occupational lung diseases and drug toxicity [1,2].

Clinical Perspective A diagnosis of IPF requires multidisciplinary discussion among clinician, radiologist, pathologist and other specialists if it’s needed (e.g. in cases of connective tissue disorders suspected). Especially when clinical history or radiological patterns are not definite. A diagnostic search begins with clinician’s work, who has to establish a probability of interstitial lung diseases (ILD) presence and exclude their known causes like occupational exposure, connective tissue disorders, drug addiction. The probability of the diagnosis is increased in male patients, smokers, over 60 y/o with a family history of ILD and/or comorbid lung pathology [1,2,6]. Physical examination can reveal unexplained exertional dyspnoea, progressing with time, chronic dry cough, fine high-pitched bibasilar inspir¬atory crackles (so called velcro-like sounds). Spirometry typically detects restrictive changes and plethysmography - a reduction in diffusing capacity of the lung for carbon monoxide [1,2,5]. In our case, a diagnosis of IPF was proposed at the stage of clinical examination due to the anamnesis and clinical findings. Although in a differential list, there was also pneumonia, chronic bronchitis and COPD. After revising CT results according to ATS/ERS guidelines, serological testing was provided, and connective tissue diseases were excluded.

Imaging perspective

High-resolution CT protocols are required with the thinnest collimation and should include both inspiratory and expiratory images. All consequences of pathophysiologic processes can be clearly seen on chest CT. Fibrotic changes implicate interstitium inside the secondary pulmonary lobule, which appears on CT as intralobular reticular pattern with irregular thickening of the interstitium. Because of aberrant alveolar repair and continuous micro-injuries, acinar structure is completely destroyed and alveoli become deformed. They evolve into cysts of different sizes and shapes, surrounded by walls of variable thickness. In total all these changes are named as honeycombing pattern. Patchy, basal subpleural predominant distribution of honeycombing, fit by presence of reticular abnormalities, traction bronchiectasis or bronchioloectasis represents UIP pattern. In some cases, these lesions may be associated with ground glass opacity (GGO). If all features of UIP except for honeycombing are presented, such pulmonary lesion is regarded as probable UIP pattern. In both cases definite diagnosis of IPF can be made, considering appropriate anamnesis (patients over 60 years, smokers, with progressive deterioration of lung function, absence of other potential causes of ILD) and clinical data (worsening of dyspnoea, cough with sputum, restrictive changes at spirometry). When there is no strong evidence of UIP pattern – only subtle reticulation with basal subpleural predominant distribution and probable mild GGO is presented, intermediate for UIP pattern should be assigned. In such cases, and when an alternative diagnosis is suggested, a biopsy is required [1,2,4,5]. Although according to ATS/ERS guidelines even in cases of probable UIP pattern with inappropriate anamnesis and clinical data biopsy is recommended [6]. In the described case there are quite extensive areas of GGO, which match up with honeycombing distribution and aren’t as pronounced as reticulation abnormalities. Such changes may be regarded as demonstration of fibrotic changes and as sign of infection. The letter is more probable in our case in the background of clinical examination.

Treatment As first-line therapy, Nintedanib e.g. pirfenidone, having a number of anti-inflammatory and antifibrotic effects, are recommended [1 3-5]. Several options for non-pharmacologic treatment are available: smoking cessation, supplemental oxygen therapy, administration, special complex of pulmonary rehabilitation exercises, and age-appropriate vaccines [1,4,5].

Take home massages: 1.    At least brief knowledge of IPF pathogenesis is crucial for understanding the nature of pathologic findings from the CT image. 2.    Since IPF has no single pathognomonic feature, it should be diagnosed based on complex assessment of anamnesis, symptoms, chest CT data and pathologic findings. 3.    In cases of typical or probable UIP patterns, considering exact IPF anamnesis and clinics, no biopsy is required for diagnosis.

Written informed patient consent for publication has been obtained.

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The Impact of Autoantibodies on Outcomes in Patients with Idiopathic Pulmonary Fibrosis: Post-Hoc Analyses of the Phase III ASCEND Trial

• Original Research
• Open access
• Published: 29 July 2024

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• Tejaswini Kulkarni   ORCID: orcid.org/0000-0002-4251-4988 1 ,
• Chad A. Newton   ORCID: orcid.org/0000-0001-5256-9029 2 ,
• Sachin Gupta   ORCID: orcid.org/0000-0003-2912-5619 3 ,
• Katerina Samara   ORCID: orcid.org/0000-0001-5710-1943 4 &
• Elana J. Bernstein   ORCID: orcid.org/0000-0001-5560-6390 5  

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Introduction

Clinical practice guidelines recommend autoimmune serological testing in patients newly diagnosed with interstitial lung disease of apparently unknown cause who may have idiopathic pulmonary fibrosis (IPF), in order to exclude connective tissue disease (CTD). Autoantibody positivity has been associated with unique patient profiles and prognosis in patients with IPF who otherwise lack a CTD diagnosis.

This post-hoc analysis of patients with IPF from the Phase III ASCEND trial (NCT01366209) evaluated the association of antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) status with baseline disease characteristics, disease progression [percent predicted forced vital capacity (%FVC), forced vital capacity (FVC) volume and progression-free survival (PFS)], and treatment outcomes with pirfenidone and placebo (%FVC, FVC and PFS).

Of 555 participants, 244/514 (47.5%) were ANA positive (ANA+), 83/514 (16.1%) had high ANA+ (ANA titre ≥ 1:160 or positive nucleolar- or centromere-staining patterns), 60/555 (10.8%) were RF positive (RF+) and/or anti-CCP positive (anti-CCP+) and 270/514 (52.5%) were autoantibody negative (AAb−). Baseline demographics and characteristics were generally comparable between autoantibody subgroups. Although not statistically significant, more placebo-treated participants with ANA+ or high ANA+ had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb− group (%FVC or death: 42.0%; FVC volume or death: 42.0%). The RF+ and/or anti-CCP+ group was similar to AAb−. No differences were observed in PFS. A treatment benefit for pirfenidone versus placebo was observed regardless of autoantibody status [PFS: ANA+ HR (95% CI): 0.56 (0.37 to 0.86), P  = 0.007; AAb− HR (95% CI): 0.50 (0.32 to 0.78), P  = 0.002].

IPF disease course did not differ by autoantibody status in ASCEND. Pirfenidone had a treatment benefit regardless of the presence of ANA.

Trial Registration

ClinicalTrials.gov identifier, NCT01366209.

Plain Language Summary

People with idiopathic pulmonary fibrosis sometimes have abnormal antibodies, called autoantibodies, in their blood. Uncommonly, autoantibodies may mistakenly target the person’s own tissues, including the lungs. It is unknown whether these autoantibodies cause idiopathic pulmonary fibrosis or make it worse. This analysis looked at data from the ASCEND clinical trial in people with idiopathic pulmonary fibrosis, who were split randomly into two groups to receive tablets of either a medicine called pirfenidone or a placebo for 52 weeks. One goal was to see whether people with certain autoantibodies called antinuclear antibodies (‘ANA’ for short), rheumatoid factor (‘RF’) and anti-cyclic citrullinated peptide (‘anti-CCP’) had different traits from people without autoantibodies, such as age, race or smoking history. Other goals were to see if autoantibodies affected (1) how well people’s lungs worked during the trial, (2) how quickly people’s idiopathic pulmonary fibrosis got worse or they died and (3) how well pirfenidone worked. The analysis showed that most traits were similar in people with and without autoantibodies. In people who received placebo, the change in lung function during the trial was not different for people with ANA, RF or anti-CCP compared with people with no autoantibodies. People who received pirfenidone were less likely to have worsening lung function, or die, than people who received placebo, regardless of whether or not they had autoantibodies. Doctors evaluating patients with idiopathic pulmonary fibrosis should consider the impact of autoantibodies and feel confident that pirfenidone is effective regardless of whether or not autoantibodies are present.

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Interstitial lung disease (ILD) is a large and heterogeneous group of pulmonary disorders; some are associated with an underlying autoimmune aetiology and some are linked to environmental exposures, whereas others have unknown causes [ 1 , 2 ]. It can be challenging to differentiate between different types of ILD due to overlapping clinical, radiological and pathological presentations [ 1 ]. Diagnostic guidelines recommend that patients with suspected idiopathic pulmonary fibrosis (IPF), the most common and severe form of ILD, undergo autoantibody testing as part of the initial evaluation to assess for autoimmune-mediated diseases [ 3 , 4 , 5 ]. In previous studies, autoantibodies such as antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) have been reported in 22–33% of patients with IPF in the absence of connective tissue disease (CTD) on initial evaluation, with one study reporting that up to 10% of patients with IPF progressed to CTD [ 6 , 7 , 8 ]. However, the link between markers of autoimmunity and disease characteristics is not fully understood and may be an important factor to consider in the initial diagnosis and management of patients with IPF [ 1 , 3 ] who do not otherwise manifest clinically with CTD.

Previous studies have suggested that differences in autoantibody status may be associated with unique patient profiles and differences in prognosis in patients with IPF, and that the presence of autoantibodies in IPF may represent a novel subgroup of patients, but this evidence is based on limited patient numbers, short follow-up duration and a lack of robust clinical data [ 6 , 7 , 9 , 10 ]. Here, in this post-hoc analysis, we aimed to determine the association between autoantibody status and baseline disease characteristics, disease progression and treatment outcomes in patients with IPF who were randomised to receive pirfenidone or placebo in ASCEND, a large, well-characterised Phase III clinical trial.

The trial design of ASCEND (NCT01366209) has been previously reported [ 11 ]. In brief, ASCEND was a randomised, double-blind, placebo-controlled Phase III trial in which 555 patients with IPF were randomised to receive either oral pirfenidone (2403 mg/day; n  = 278) or placebo ( n  = 277) for 52 weeks.

Eligible participants were aged 40–80 years and had a centrally confirmed diagnosis of IPF with findings on high-resolution computed tomography (HRCT) of the chest indicating either definite or possible usual interstitial pneumonia (UIP), with a surgical lung biopsy to confirm the presence of definite or probable UIP in the latter group. Patients with diagnosis of any CTD, including scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus (SLE) or rheumatoid arthritis, or any known explanation for ILD, including sarcoidosis and hypersensitivity pneumonitis, were excluded [ 11 ]. In addition, participants were recruited if they had 50–90% of percent predicted forced vital capacity (%FVC), 30–90% of percent predicted carbon monoxide diffusing capacity (%DLco), forced expiratory volume in 1 s/forced vital capacity (FVC) ratio of ≥ 0.80 and a 6-min walk distance (6MWD) of ≥ 150 m. All participants randomised to pirfenidone or placebo in the ASCEND trial with any autoantibody result at screening were included in this post-hoc analysis.

The ASCEND trial was conducted in compliance with Good Clinical Practice as described in FDA regulations and the 1996 International Council for Harmonisation document, in consistence with the principles stated in the Declaration of Helsinki. The protocol for the ASCEND trial was approved by the institutional review board or ethics committee at each participating centre and all patients provided written informed consent for participation in the trial. No prospective data were collected during this post-hoc analysis; therefore, ethical approval was not required.

Post-Hoc Analysis

Peripheral blood samples collected at screening were used to determine the presence of the following autoantibodies: ANA, RF and anti-CCP. Autoantibody status was defined by the following titres and staining patterns:

ANA-positive (ANA+) participants had ANA titre ≥ 1:40 or nucleolar-staining pattern or centromere-staining pattern as defined by previous studies, regardless of RF or anti-CCP positivity [ 2 , 12 ].

Participants with high ANA+ levels (H-ANA+) had ANA titre ≥ 1:160 or a positive nucleolar-staining pattern or centromere-staining pattern (regardless of titre level), both of which were independent of RF or anti-CCP positivity; a previous study suggests the ≥ 1:160 cutoff would be likely to exclude 95% of individuals without systemic sclerosis, SLE or Sjogren’s syndrome [ 12 ].

Participants with low ANA+ levels had ANA titre ≥ 1:40 to < 1:160 and absence of both nucleolar-staining pattern and centromere-staining pattern, regardless of RF or anti-CCP positivity; a previous study suggests that an ANA cutoff level of 1:40 could have diagnostic value, and a survey of laboratories participating in the College of American Pathologists’ Proficiency Testing Programme suggests that a majority of US laboratories use this traditional cutoff for reporting ANA positivity [ 12 , 13 ].

RF-positive (RF+) participants had RF titre ≥ 20 IU/mL.

Anti-CCP–positive (anti-CCP+) participants had anti-CCP titre ≥ 20 IU/mL.

Autoantibody-negative (AAb−, triple negative) participants had ANA titre < 1:40, “negative” titre with an absence of nucleolar-staining pattern or centromere-staining pattern, and negative RF (< 20 IU/mL) and negative anti-CCP (< 20 IU/mL) titres.

The endpoints of the current analysis focused on participants who were classified as ANA+, H-ANA+, RF+ and/or anti-CCP+ and AAb−. The endpoints included:

Summaries of the demographic and baseline characteristics organised by autoantibody subgroup and/or treatment arm.

Changes in %FVC from baseline to Week 52, determined using a fixed effect rank analysis of covariance, where the outcome variable was standardised ranked change from baseline, and fixed effect was either the participant ANA status, treatment arm or RF/anti-CCP status. The ranked baseline %FVC was included as a covariate (deaths were ranked worst according to time until death).

Changes in FVC volume (litres) from baseline to Week 52, determined using the same approach as for the %FVC and by ranking the relative change in volume defined as (Week 52 FVC volume − baseline FVC volume)/baseline FVC volume.

Estimation of progression-free survival (PFS), defined as first occurrence of death, confirmed ≥ 10% decline from baseline in %FVC or confirmed ≥ 50 m decline from baseline in 6MWD. The decline in either %FVC or 6MWD was confirmed at two consecutive assessments at least 6 weeks apart. PFS was analysed using the product limit method log-rank test and a proportional hazards model with treatment as a covariate. ANA status or RF/anti-CCP status was used to estimate the hazard ratio (HR) and Kaplan–Meier estimates were used to summarise PFS time.

Data from participants receiving placebo were analysed to determine the effect of autoantibody status (ANA+, H-ANA+, RF+ and/or anti-CCP+, or AAb−) on the course of disease, whereas data from participants receiving pirfenidone versus those receiving placebo were analysed to assess the impact of autoantibody status (ANA+ or AAb−) on response to treatment. P values for autoantibody-positive groups versus the AAb− group were calculated using Pearson’s chi-squared test. Comparisons of some subgroups of placebo- or pirfenidone-treated participants (e.g., those who were H-ANA+ and RF+ and/or anti-CCP+) were not included in the analysis due to their small sample size.

Autoantibody Analysis

All 555 enrolled participants from the ASCEND trial had autoantibody data available for analysis (Table  1 ). In total, 514 participants were tested for the presence of ANA, of whom 47.5% (244/514) were classed as ANA+ and 16.1% (83/514) of participants were further categorised as H-ANA+. Additionally, 10.8% (60/555) participants were classed as RF+ and/or anti-CCP+. Overall, 52.5% (270/514) of participants were classed as AAb−, i.e., had a confirmed negative status for all the tested autoantibodies.

Baseline demographics and characteristics by autoantibody status (ANA+, H-ANA+, RF+ and/or anti-CCP+ and AAb−) for all participants are presented in Table  2 and for participants receiving pirfenidone or placebo are presented in Table  3 . Key baseline demographics and characteristics were broadly similar between participants who were ANA+ and those who were AAb− (Table  2 ). However, there was a higher proportion of American Indian or Alaska Native participants in the ANA+ (8.6%) and RF+ and/or anti-CCP+ (8.3%) groups versus the AAb− (3.3%) group. There was also a greater proportion of women in the H-ANA+ (27.7%) and RF+ and/or anti-CCP+ (31.7%) groups versus the AAb− (20.0%) group (Table  2 ). Additionally, when compared with the AAb− group, the H-ANA+ group had a lower proportion of current smokers (51.8% vs. 64.1%), a lower proportion of patients requiring supplemental oxygen (19.4% vs. 30.4%) and a lower 6MWD (400.0 m vs. 424.0 m) (Table  2 ).

Disease Course in Placebo-Treated Participants

Overall, the disease course in placebo-treated participants was similar regardless of autoantibody status. Numerically, a greater proportion of participants in the ANA+ and H-ANA+ groups had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb− group (%FVC or death: 42.0%; FVC volume or death: 42.0%) (Fig.  1 ). However, there were no statistically significant differences in decline in %FVC or death or in FVC volume or death between the AAb− group and the ANA+ and H-ANA+ groups (Fig.  1 ). The proportions of patients with decline in %FVC or death or in FVC volume or death, in the RF+ and/or anti-CCP+ group were similar to those in the AAb− groups, again with no statistically significant difference (Fig.  1 ). There was no difference in PFS between the ANA+ group versus the AAb− group [HR (95% confidence interval [CI]): 1.14 (0.78 to 1.66); P  = 0.5] (Fig.  2 A) or between the H-ANA+ group versus the AAb− group [HR (95% CI): 1.22 (0.69 to 2.17); P  = 0.5] (Fig.  2 B). Due to small sample sizes, analysis of PFS for the H-ANA+ and RF+ and/or anti-CCP+ groups was not performed.

Placebo-treated participants with decline from baseline to Week 52 of ≥ 10% in %FVC or in FVC volume, or death, stratified by ANA+, H-ANA+, RF+ and/or anti-CCP+ and AAb− status. P values were calculated using Pearson’s chi-squared test. %FVC percent predicted forced vital capacity, AAb autoantibody, ANA antinuclear antibody, anti-CCP anti-cyclic citrullinated peptide, FVC forced vital capacity, H-ANA+ high antinuclear antibody titre, RF rheumatoid factor

PFS in placebo-treated participants, stratified by A ANA+ versus AAb− and B H-ANA+ versus AAb− status. AAb autoantibody, ANA antinuclear antibody, CI confidence interval, H-ANA+ high antinuclear antibody titre, HR hazard ratio, PFS progression-free survival

Response to Pirfenidone Treatment

Clinically relevant trends towards a treatment effect for pirfenidone over placebo were observed for patients who were ANA+. Numerically lower proportions of participants with ANA+ who received pirfenidone than who received placebo had decline in %FVC or death, or decline in FVC volume or death, although this difference did not reach statistical significance for either endpoint (%FVC or death: pirfenidone 37.2% vs. placebo 48.7%, P  = 0.093; FVC volume or death: pirfenidone 35.7% vs. placebo 48.7%, P  = 0.053) (Fig.  3 ). In the AAb− group, there was a statistically significant benefit of pirfenidone over placebo for both decline in %FVC or death and decline in FVC volume or death (both endpoints: pirfenidone 29.1% vs. placebo 42.0%, P  = 0.039) (Fig.  3 ). PFS was statistically significantly higher for participants receiving pirfenidone compared with those receiving placebo in both the ANA+ group [HR (95% CI): 0.56 (0.37 to 0.86); P  = 0.007; Fig.  4 A] and the AAb− group [HR (95% CI): 0.50 (0.32 to 0.78); P  = 0.002; Fig.  4 B]. Due to small sample sizes, analysis of PFS for the H-ANA+ group and the RF+ and/or anti-CCP+ group was not performed.

Proportion of participants treated with pirfenidone or placebo with decline from baseline to Week 52 of ≥ 10% in A %FVC or death or B FVC volume or death stratified by ANA+ and AAb−. P values were calculated using Pearson’s chi-squared test. %FVC , percent predicted forced vital capacity, AAb autoantibody, ANA antinuclear antibody, d day, FVC forced vital capacity

PFS for A pirfenidone versus placebo in participants with ANA+ and B pirfenidone versus placebo in participants with AAb−. AAb autoantibody, ANA antinuclear antibody, CI confidence interval, d day, HR hazard ratio, PFS progression-free survival

In this post-hoc analysis of data from the ASCEND trial, we report the impact of autoantibody status on disease progression and treatment responses in patients with IPF. We did not identify any prominent pulmonary physiologic differences in baseline characteristics of participants with IPF who were classed as positive for commonly tested autoantibodies versus AAb−. Some differences were observed between the subgroups of participants with high ANA levels versus AAb−, such as a higher proportion of women and American Indians or Alaska Natives, and a lower proportion of ever smokers and supplemental oxygen users; however, other baseline clinical characteristics (%FVC, %DLco) were comparable between groups. Our findings support those of previous studies of patients with IPF that found broadly similar results in baseline demographics, pulmonary function tests and definite UIP pattern on HRCT based on the presence of autoantibodies [ 6 , 14 , 15 , 16 ].

Among placebo-treated participants, there was no difference in PFS between the AAb− group and the ANA+ or H-ANA+ groups, despite participants who were ANA+ or H-ANA+ being more likely to exhibit a non-statistically significant decline of ≥ 10% in %FVC or FVC volume compared with those who were AAb−. Several studies have previously examined the associations between autoantibody status and outcomes in patients with IPF [ 6 , 9 , 14 , 16 , 17 ]; however, ours is the largest analysis reporting post-hoc prospective data from a randomised controlled trial. Although data on other autoantibodies were not available for this analysis, an analysis of patients with IPF who were part of the Pulmonary Fibrosis Foundation Patient Registry suggested that baseline characteristics and clinical outcomes were generally similar among patients regardless of baseline seropositivity status across a wide range of autoantibodies, including ANA, RF, anti-CCP, anti-Smith and anti-myositis antibodies [ 18 ].

Our analysis, based on a large, well-characterised clinical trial population, indicates that participants responded to pirfenidone treatment regardless of their ANA status, with a treatment effect of pirfenidone over placebo for PFS in both the ANA+ and the AAb− groups. A significant treatment effect was also observed for ≥ 10% percent predicted FVC decline or death and ≥ 10% FVC volume decline or death from baseline to Week 52 in the AAb− group, although this clinically relevant trend in the ANA+ group did not reach statistical significance. These findings mirror those shown in a smaller, 6-month follow-up, retrospective observational study that also reported a pirfenidone treatment effect irrespective of autoantibody status [ 15 ].

Diagnostic guidelines recommend that patients with suspected IPF undergo autoantibody testing as part of the initial evaluation, but no consensus was reached about which autoantibodies should be included in screening panels [ 3 ]. Initial screening for a broad range of autoantibodies is not deemed mandatory for all patients with suspected IPF, although it could be useful in cases where other potential causes of ILD are clinically suspected [ 3 ]. The prognostic value of autoantibodies in patients diagnosed with IPF is not yet fully understood [ 1 ], and, as such, it will be important to consider further which autoantibodies should be included in the initial diagnostic screen [ 3 ].

Apart from its possible link with autoimmune diseases, ANA positivity has also been described as a factor of ageing, as its prevalence generally increases with age and it also correlates with shorter telomere length, a marker of biological age [ 19 , 20 ]. Cellular senescence associated with ageing has been described in the pathogenesis of IPF, a disease of the aged population; whether the high prevalence of ANA positivity is merely an association or has pathological implication is unclear [ 21 ]. Nevertheless, therapeutic response to pirfenidone remains unaffected by autoantibody positivity in this study.

There are several limitations of this analysis. Firstly, it was a post-hoc exploratory analysis with only 52 weeks of follow-up available. Secondly, data on autoantibodies other than ANA, RF and anti-CCP, change in positivity or titre, and whether participants went on to develop systemic autoimmune rheumatic diseases, were not collected. Thirdly, the small number of participants in certain groups (e.g., H-ANA+, and RF+ and/or anti-CCP+) may limit the interpretation of the data and impact the observed outcomes; therefore, these results should be interpreted with caution. Fourthly, we present here available data for the three commonly evaluated autoantibodies that were included during screening for ASCEND. Diagnostic guidelines suggest screening for the presence of these antibodies in patients with suspected IPF, with evaluation using a full antibody panel reserved for cases where other autoimmune diseases are clinically suspected [ 3 ]. We recommend that screening for other disease-related autoantibodies be included in future studies in order to broaden potential analyses. Finally, although we used the placebo arm of the ASCEND trial as a proxy for the natural disease progression in IPF in this analysis, we cannot rule out the presence of a placebo effect in these patients, which could have influenced disease outcomes.

This post-hoc analysis of data from the ASCEND trial in patients with IPF indicates that disease course did not differ by ANA, RF or anti-CCP autoantibody status, although patients in the H-ANA subgroup have differences in certain baseline demographics compared with antibody-negative patients. Importantly, we observed a treatment benefit for pirfenidone regardless of ANA status, particularly in relation to PFS. This analysis underscores that, while some patients with IPF may have autoantibody positivity, in the absence of other clinical features of systemic autoimmune rheumatic disease, clinical outcomes and management remain unchanged.

Data Availability

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Acknowledgments

Medical Writing, Editorial, and Other Assistance.  Statistical analyses were performed by Jinnie Ko and Yiling Chen of Genentech, Inc. Medical writing support, under the direction of the authors, was provided by Nikoleta Tzioutziou, PhD, formerly of CMC AFFINITY, a division of IPG Health Medical Communications, funded by F. Hoffmann-La Roche, Ltd. in accordance with Good Publication Practice (GPP 2022) guidelines.

The data and analyses reported in this manuscript are directly derived from research sponsored by F. Hoffmann-La Roche, Ltd./Genetech, Inc. The funder also approved the final version of the manuscript and covered the cost of the journal’s rapid service fee.

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Tejaswini Kulkarni

University of Texas Southwestern, Medical Center, Dallas, TX, USA

Chad A. Newton

Genentech, Inc., South San Francisco, CA, USA

Sachin Gupta

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Katerina Samara

Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

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Contributions

Substantial contributions to the conception or design of the work: Tejaswini Kulkarni, Chad A. Newton, Sachin Gupta, Katerina Samara, Elana J. Bernstein. Data acquisition: Sachin Gupta. Data interpretation: Tejaswini Kulkarni, Chad A. Newton, Sachin Gupta, Katerina Samara, Elana J. Bernstein. All authors were involved in the drafting or critical review of the manuscript for important intellectual content and approved the final version for submission.

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Tejaswini Kulkarni reports consultancy and speaker fees from Boehringer Ingelheim and consultancy fees from Aileron Therapeutics, PureTech LYT-100 Inc., United Therapeutics Corporation and Veracyte. Chad A. Newton reports consultancy fees from Boehringer Ingelheim. Dr. Newton is supported by the National Heart, Lung, and Blood Institute (K23 HL148498). Sachin Gupta is an employee of Genentech, Inc. Katerina Samara is an employee of F. Hoffmann-La Roche, Ltd. Elana J. Bernstein reports grants, consultancy fees and support for meeting attendance from Boehringer Ingelheim. Dr. Bernstein is also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant number K23 AR075112), the National Heart, Lung, and Blood Institute (grant number R01 HL164758), and the Department of Defence (grant number W81XWH2210163).

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Prior Presentation: Some of the results presented in this manuscript were previously presented as a poster at the ATS 2022 International Conference (13–18 May 2022; San Francisco, CA) and the ERS 2022 International Congress (4–6 September 2022; Barcelona, Spain).

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Kulkarni, T., Newton, C.A., Gupta, S. et al. The Impact of Autoantibodies on Outcomes in Patients with Idiopathic Pulmonary Fibrosis: Post-Hoc Analyses of the Phase III ASCEND Trial. Pulm Ther (2024). https://doi.org/10.1007/s41030-024-00267-x

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DOI : https://doi.org/10.1007/s41030-024-00267-x

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The role of transforming growth factor-β (tgf-β) in asthma and chronic obstructive pulmonary disease (copd).

1. Introduction

1.1. canonical (smad) pathway, 1.2. non-canonical (non-smad) pathway, 1.3. aims of the study, 2. the role of tgf-β in chronic obstructive pulmonary disease (copd), 2.1. the levels of tgf-β in copd, 2.2. genetic background of tgf-β and copd association, 2.3. tgf-β takes part in the development of emphysema in copd, 2.4. protective role of club cells, 2.5. the role of tgf-β in airway remodeling in copd, 3. the role of tgf-β in asthma pathogenesis, 3.1. the levels of tgf-β in asthma, 3.2. genetic background of tgf-β and asthma association, 3.3. the role of tgf-β in asthma, 3.4. the role of tgf-β in airway remodeling in asthma, 3.5. the interactions of corticosteroids on tgf-β expression in asthma, 3.6. the summary of tgf-β role in asthma, 4. putative compounds altering tgf-β activity, 4.1. natural compounds, 4.1.1. yu-ping-feng-san (ypfs), 4.1.2. berberine, 4.1.3. betalains, 4.1.4. osthole, 4.1.5. nerolidol, 4.1.6. diosmetin, 4.1.7. amygdalin, 4.1.8. epigallocatechin gallate (egcg), 4.1.9. aloin, 4.1.10. quercetin, 4.1.11. kaempferol, 4.2. synthetic compounds, 4.2.1. nintedanib, 4.2.2. tranilast, 4.2.3. pan-pde inhibitors, 6. conclusions, author contributions, conflicts of interest.

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Kraik, K.; Tota, M.; Laska, J.; Łacwik, J.; Paździerz, Ł.; Sędek, Ł.; Gomułka, K. The Role of Transforming Growth Factor-β (TGF-β) in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Cells 2024 , 13 , 1271. https://doi.org/10.3390/cells13151271

Kraik K, Tota M, Laska J, Łacwik J, Paździerz Ł, Sędek Ł, Gomułka K. The Role of Transforming Growth Factor-β (TGF-β) in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Cells . 2024; 13(15):1271. https://doi.org/10.3390/cells13151271

Kraik, Krzysztof, Maciej Tota, Julia Laska, Julia Łacwik, Łukasz Paździerz, Łukasz Sędek, and Krzysztof Gomułka. 2024. "The Role of Transforming Growth Factor-β (TGF-β) in Asthma and Chronic Obstructive Pulmonary Disease (COPD)" Cells 13, no. 15: 1271. https://doi.org/10.3390/cells13151271

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• v.12(7); 2024 Jul
• PMC11233258

Development of allergic bronchopulmonary aspergillosis in a patient with nontuberculous mycobacterial‐pulmonary disease successfully treated with dupilumab: A case report and literature review

Ryuta onozato.

1 Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo Japan

Takanori Asakura

2 Department of Respiratory Medicine, Kitasato University Kitasato Institute Hospital, Tokyo Japan

3 Department of Clinical Medicine (Laboratory of Bioregulatory Medicine), Kitasato University School of Pharmacy, Tokyo Japan

Ho Namkoong

4 Department of Infectious Diseases, Keio University School of Medicine, Tokyo Japan

Koichiro Asano

5 Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Kanagawa Japan

Naoki Hasegawa

Koichi fukunaga, associated data.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Pulmonary manifestations in patients with allergic bronchopulmonary aspergillosis (ABPA) and nontuberculous mycobacterial‐pulmonary disease (NTM‐PD) include bronchiectasis and mucus plugging. A 68‐year‐old woman, treated with antibiotics and inhaled corticosteroids for NTM‐PD and asthma, presented with fever and wheezing. ABPA was diagnosed based on laboratory findings (elevated peripheral blood eosinophil counts and serum total IgE levels and positive Aspergillus ‐specific IgE and IgG) and imaging observation of a high‐attenuation mucus plug. Systemic prednisolone was avoided to prevent NTM‐PD progression. Dupilumab, a monoclonal antibody that blocks IL‐4/13, was introduced to improve the clinical findings. Herein, we discuss the pathophysiological mechanisms underlying this rare comorbidity.

The patient with allergic bronchopulmonary aspergillosis and nontuberculous mycobacterial‐pulmonary disease was successfully treated with dupilumab.

INTRODUCTION

Allergic bronchopulmonary aspergillosis (ABPA) is characterized by central bronchiectasis and recurrent pulmonary infiltrates and manifests as poorly controlled asthma, affecting an estimated 4 million patients worldwide. 1 , 2 It is a well‐recognized complication of asthma and cystic fibrosis. Therapeutic strategies include using systemic corticosteroids and antifungal agents during the initiation. Although multiple environmental factors play an important role, their pathophysiological mechanisms remain unclear.

The incidence and prevalence of nontuberculous mycobacterial‐pulmonary disease (NTM‐PD) are increasing worldwide. 3 Pulmonary manifestations include bronchiectasis and mucus plugging, similar to those observed in ABPA. Neutrophilic inflammation occurs in NTM‐PD, whereas ABPA is characterized by eosinophilic inflammation. 4 , 5 Patients with NTM‐PD often present with secondary infections by various microorganisms, including Aspergillus species. 6 Herein, we describe a patient who developed ABPA during NTM‐PD and was successfully treated with dupilumab.

CASE REPORT

A 68‐year‐old woman has been allergic to Japanese cedar and house dust mite since reaching adulthood. The patient was diagnosed with bullous pemphigoid 16 years ago, and treatment with systemic corticosteroids was initiated 13 years ago. Serum Aspergillus ‐specific IgE antibody was positive 12 years ago. Asthma was diagnosed 10 years ago based on the findings of cough and rhinitis that improve with inhaled corticosteroids/long‐acting β2‐agonist. A bacteriological examination of the sputum revealed Mycobacterium avium 8 years ago, and a diagnosis of NTM‐PD was made. Imaging findings of NTM‐PD on chest radiography and computed tomography (CT) worsened 6 years ago (Figure  1A,B ), and treatment with antibiotics combined with clarithromycin (800 mg/day), ethambutol (500 mg/day), and rifampicin (600 mg/day) was initiated. However, NTM‐PD was difficult to treat despite the use of multidrug therapy with the addition of amikacin and sitafloxacin to this treatment.

Imaging findings of chest CT at the diagnosis of NTM‐PD, at the diagnosis of ABPA, and after the initiation of dupilumab. CT showed cavities with their wall thickness and bronchiectasis in the upper and lower lobe of the left lung (A, B). At the diagnosis of ABPA, CT showed a high attenuation mucus plug in the lower lobe of the right lung (C, D). After initiating dupilumab, mucus plugging improved, and bronchiectasis was observed in the same lesion (E, F). ABPA, allergic bronchopulmonary aspergillosis; CT, computed tomography; NTM‐PD, nontuberculous mycobacterial‐pulmonary disease.

Serum Aspergillus ‐specific IgG antibody became positive 3 years ago. Sputum culture revealed the presence of filamentous fungi in the previous year. This patient presented with wheezing and fever. Respiratory function test showed normal vital capacity (VC, 2.04 L; %VC, 80.3%) and forced expiratory volume in 1 s (FEV1, 1.78 L; %FEV1, 93.7%; FEV1%, 87.3%) with a high level of fractional exhaled nitric oxide (FeNO, 42 ppb). The laboratory findings are summarized in Table  1 . Serum total IgE levels and peripheral blood eosinophil counts were high. Chest CT revealed a high‐attenuation mucus plug (HAM) (Figure  1C,D ). Based on these findings, ABPA was diagnosed according to its diagnostic criteria. 7

Results of blood test.

The use of systemic corticosteroids was avoided to prevent the exacerbation of NTM‐PD. Antifungal agents were also excluded because of their pharmacological interactions with rifampicin. Single inhaler triple therapy using inhaled corticosteroid/long‐acting β2‐agonist/long‐acting muscarinic antagonist (ICS/LABA/LAMA, fluticasone furoate (200 μg/day)/umeclidinium (62.5 μg/day)/vilanterol (25 μg/day)) and dupilumab, an anti‐IL‐4 receptor α monoclonal antibody, were initiated to treat comorbid severe eosinophilic asthma. The clinical symptoms and imaging findings improved after treatment initiation (Figure  1E,F ), while serum total IgE levels and peripheral blood eosinophil counts slightly decreased (2236 IU/mL and 977/μL, respectively). Of note, there was no transient eosinophilia. No worsening of NTM‐PD has been observed following treatment with dupilumab; however, residual shadows, including bronchiectasis, remain visible on the chest CT. Figure  2 summarizes the clinical course of the disease.

Clinical course of NTM‐PD and ABPA in the present patient. ABPA, allergic bronchopulmonary aspergillosis; ICS/LABA, inhaled corticosteroid/long‐acting β2‐agonist; ICS/LABA/LAMA, inhaled corticosteroid/long‐acting β2‐agonist/long‐acting muscarinic antagonist; IgE, immunoglobulin E; NTM‐PD, nontuberculous mycobacterial‐pulmonary disease.

This is a valuable case report of ABPA in a patient with NTM‐PD that describes the long‐term follow‐up period involving the onset of both diseases. Previous reports have shown that NTM‐PD is associated with a higher frequency of ABPA. 8 , 9 Among patients with cystic fibrosis, the incidence of ABPA is higher in those with NTM‐PD than in those without. 8 Patients with bronchiectasis also have a higher incidence of ABPA than those without NTM‐PD. 9 In contrast, the cumulative incidence of NTM‐PD increased over time in patients with ABPA and allergic bronchopulmonary mycosis (ABPM) who received oral corticosteroids as a risk factor for this complication. 10

In this case, the patient developed asthma with sensitization to Aspergillus fumigatus prior to the diagnosis of NTM‐PD. IgE‐mediated A. fumigatus sensitization aggravates respiratory conditions in patients with asthma who do not meet ABPA diagnostic criteria. Patients with A. fumigatus sensitization frequently exhibit impaired pulmonary function, mucus plugging, and bronchiectasis. 11 The positivity rate of A. fumigatus ‐specific IgE increases over time in patients with asthma, and risk factors include the use of medium‐to high‐dose inhaled corticosteroids and high serum levels of total IgE. 12 Inhaled or systemic steroids are known risk factors for the development of NTM‐PD. 13 , 14 A. fumigatus may induce a Th2‐mediated immune response and reduce cytokines involved in NTM eradication. 15 These findings suggest that airway inflammation, therapeutic agents used in asthma, and sensitization to A. fumigatus may trigger the development of NTM‐PD.

Bronchiectasis often coexists with severe asthma, and A. fumigatus is frequently isolated from cultured microorganisms in such cases. 16 Bronchiectasis in NTM‐PD is associated with enhanced airway inflammation and increased cytokine levels, including IL‐1 and GM‐CSF. 17 , 18 Animal studies have demonstrated that these cytokines induce sensitization to allergens. 19 Based on these findings, NTM‐PD and bronchiectasis may promote further sensitization to Aspergillus in the airways.

A. fumigatus ‐specific IgG is frequently detected in patients with NTM‐PD. A previous report showed that Aspergillus precipitating antibody‐positive patients presented with a longer duration, more severe bronchiectasis, and lower pulmonary function, and 5 of 109 patients developed ABPA. 20 Another study demonstrated that Aspergillus precipitating antibody‐positive cases were characterized by male sex, emphysema, and interstitial pneumonia, and 3 of 109 cases developed ABPA. 21 Additionally, the accumulation of neutrophils in the airways due to NTM‐PD may enhance the migratory response of eosinophils. 4 , 22 It has been reported that some patients with bronchiectasis exhibit a mixed phenotype of neutrophilic and eosinophilic inflammation. 23 These findings indicate that Aspergillus sensitization aggravates the pathogenesis of NTM‐PD and may trigger the development of ABPA.

Biologics are not currently available for ABPM cases. Case reports and series have reported that the use of biologics targeting IgE, 24 IL‐5, 25 IL‐4/IL‐13, 26 , 27 , 28 , 29 , 30 , 31 , 32 and TSLP 33 improves the disease status of ABPA complicated by severe asthma. Monoclonal antibodies against IgE have therapeutic efficacy in patients with ABPA and severe asthma, including 12 of the 25 patients with NTM‐PD. 24 Anti‐IL‐5/IL‐5 receptor antibodies are highly effective in patients with ABPA, especially for improving mucus plugging. 25 Previous case reports suggested that dupilumab is effective when switching from other biologics to this drug. 26 , 27 , 28 , 29 , 30 Similar to the present case, the therapeutic efficacy of dupilumab in patients with NTM‐PD 31 and the discontinuation of oral steroids during the use of dupilumab 32 were also observed in patients with ABPA. Of note, dupilumab treatment was associated with a reduced incidence of respiratory infections in patients with moderate‐to‐severe asthma or severe CRSwNP. 34 Since IL‐4 suppresses Th1 cells, this inhibition by dupilumab may contribute to the eradication of NTM in the lung by normalizing type 1 inflammation. 35 , 36 , 37 These findings suggestive of its usefulness in patients with infectious diseases. ABPA cases that were successfully treated with dupilumab are summarized in Table  2 . It may be necessary to consider the phenotype of ABPA when selecting a specific biologic. 38

Summary of the cases with ABPA successfully treated with dupilumab.

Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; NTM‐PD, non‐tuberculous mycobacterial‐pulmonary disease; OCS, oral corticosteroid.

Based on our experience with this patient, we speculated that the pathogenesis of NTM‐PD is associated with the development of ABPA in asthma. Bronchiectasis and/or inhaled/systemic corticosteroid use may be the potential causes of this comorbidity. Clinical practitioners should know about this association to decide the appropriate therapeutic management for both conditions, including biologics.

AUTHOR CONTRIBUTIONS

Ryuta Onozato and Jun Miyata conceived the idea. Koichi Fukunaga overviewed the project. Ryuta Onozato and Jun Miyata wrote the paper. Takanori Asakura, Ho Namkoong, Koichiro Asano, Naoki Hasegawa critically contributed to the accomplishment of this report.

FUNDING INFORMATION

This study did not receive any funding from any source.

CONFLICT OF INTEREST STATEMENT

Jun Miyata received lecture fees from Sanofi S.A..

ETHICS STATEMENT

The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.

Onozato R, Miyata J, Asakura T, Namkoong H, Asano K, Hasegawa N, et al. Development of allergic bronchopulmonary aspergillosis in a patient with nontuberculous mycobacterial‐pulmonary disease successfully treated with dupilumab: A case report and literature review . Respirology Case Reports . 2024; 12 ( 7 ):e01432. 10.1002/rcr2.1432 [ CrossRef ] [ Google Scholar ]

Associate Editor: Young Ae Kang

DATA AVAILABILITY STATEMENT

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A Patient-Driven Mobile Health Innovation in Cystic Fibrosis Care: Comparative Cross-Case Study

Affiliations.

• 1 Department of Learning, Informatics, Management and Ethics, Medical Management Centre, Karolinska Institutet, Stockholm, Sweden.
• 2 Södertälje Hospital, Södertälje, Sweden.
• 3 Participatory e-Health and Health Data, Department of Women's and Child's Health, Uppsala University, Uppsala, Sweden.
• 4 Upstream Dream, Bromma, Sweden.
• 5 Pulmonary, Allergy and Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States.
• PMID: 39083342
• DOI: 10.2196/50527

Background: Patient-driven innovation in health care is an emerging phenomenon with benefits for patients with chronic conditions, such as cystic fibrosis (CF). However, previous research has not examined what may facilitate or hinder the implementation of such innovations from the provider perspective.

Objective: The aim of this study was to explain variations in the adoption of a patient-driven innovation among CF clinics.

Methods: A comparative multiple-case study was conducted on the adoption of a patient-controlled app to support self-management and collaboration with health care professionals (HCPs). Data collection and analysis were guided by the nonadoption, abandonment, spread, scale-up, and sustainability and complexity assessment tool (NASSS-CAT) framework. Data included user activity levels of patients and qualitative interviews with staff at 9 clinics (n=8, 88.9%, in Sweden; n=1, 11.1%, in the United States). We calculated the maximum and mean percentage of active users at each clinic and performed statistical process control (SPC) analysis to explore how the user activity level changed over time. Qualitative data were subjected to content analysis and complexity analysis and used to generate process maps. All data were then triangulated in a cross-case analysis.

Results: We found no evidence of nonadoption or clear abandonment of the app. Distinct patterns of innovation adoption were discernable based on the maximum end-user activity for each clinic, which we labeled as low (16%-23%), middle (25%-47%), or high (58%-95%) adoption. SPC charts illustrated that the introduction of new app features and research-related activity had a positive influence on user activity levels. Variation in adoption was associated with providers' perceptions of care process complexity. A higher perceived complexity of the value proposition, adopter system, and organization was associated with lower adoption. In clinics that adopted the innovation early or those that relied on champions, user activity tended to plateau or decline, suggesting a negative impact on sustainability.

Conclusions: For patient-driven innovations to be adopted and sustained in health care, understanding patient-provider interdependency and providers' perspectives on what generates value is essential.

Keywords: adaptability; adoption; chronic illness; health care provider; implementation; innovation; interdependency; mHealth; mobile health; motivation; patient-driven innovation; spread.

©Pamela Mazzocato, Jamie Linnea Luckhaus, Moa Malmqvist Castillo, Johan Burnett, Andreas Hager, Gabriela Oates, Carolina Wannheden, Carl Savage. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 31.07.2024.

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