The six-minute walk test (6MWT) is a simple test that is widely used to assess functional exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Patients with IPF have reduced ...exercise capacity due to a number of factors, such as impaired respiratory mechanics and circulatory problems. As a self-paced and usually submaximal exercise test, the 6MWT reflects the exercise level of everyday activities. Variables measured during the 6MWT, such as six-minute walk distance (6MWD) and desaturation, are strong predictors of mortality in patients with IPF. However, the results of a 6MWT are affected by numerous factors, including age, body size, comorbidities and the use of supplemental oxygen during the test, and these need to be borne in mind when interpreting the results of individual and serial tests. Clinical studies, including trials of potential therapies for IPF, have differed in the methodology used to implement the 6MWT, hindering the comparison of results across studies. In this review, I describe the utility of the 6MWT in patients with IPF and provide recommendations for standardisation of the test for use both in clinical practice and research. A brief video on how to set up and administer the 6MWT is available at http://www.usscicomms.com/respiratory/lancaster/6mwt/.
Although in some cases clinical and radiographic features may be sufficient to establish a diagnosis of diffuse parenchymal lung disease (DPLD), surgical lung biopsy is frequently required. Recently ...a new technique for bronchoscopic lung biopsy has been developed using flexible cryo-probes. In this study we describe our clinical experience using bronchoscopic cryobiopsy for diagnosis of diffuse lung disease.
A retrospective study of subjects who had undergone bronchoscopic cryobiopsy for evaluation of DPLD at an academic tertiary care center from January 1, 2012 through January 15, 2013 was performed. The procedure was performed using a flexible bronchoscope to acquire biopsies of lung parenchyma. H&E stained biopsies were reviewed by an expert lung pathologist.
Twenty-five eligible subjects were identified. With a mean area of 64.2 mm(2), cryobiopsies were larger than that typically encountered with traditional transbronchial forceps biopsy. In 19 of the 25 subjects, a specific diagnosis was obtained. In one additional subject, biopsies demonstrating normal parenchyma were felt sufficient to exclude diffuse lung disease as a cause of dyspnea. The overall diagnostic yield of bronchoscopic cryobiopsy was 80% (20/25). The most frequent diagnosis was usual interstitial pneumonia (UIP) (n = 7). Three of the 25 subjects ultimately required surgical lung biopsy. There were no significant complications.
In patients with suspected diffuse parenchymal lung disease, bronchoscopic cryobiopsy is a promising and minimally invasive approach to obtain lung tissue with high diagnostic yield.
We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication ...analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.1 × 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.
Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent
analyses have demonstrated that pirfenidone ...reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs.
In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses ...or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks.
We did a pooled analysis of the combined patient populations of the three global randomised phase 3 trials of pirfenidone versus placebo-Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006; trial durations 72-120 weeks) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016; 52 weeks)-for all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at weeks 52, 72, and 120. We also did meta-analyses of these data and data from two Japanese trials of pirfenidone versus placebo-Shionogi Phase 2 (SP2) and Shionogi Phase 3 (SP3; trial durations 36-52 weeks).
At week 52, the relative risk of death for all four mortality outcomes was significantly lower in the pirfenidone group than in the placebo group in the pooled population (all-cause mortality hazard ratio HR 0·52 95% CI 0·31-0·87; p=0·0107; treatment-emergent all-cause mortality 0·45 0·24-0·83; 0·0094; idiopathic-pulmonary-fibrosis-related mortality 0·35 0·17-0·72; 0·0029; treatment-emergent idiopathic-pulmonary-fibrosis-related mortality 0·32 0·14-0·76; 0·0061). Consistent with the pooled analysis, meta-analyses for all-cause mortality at week 52 also showed a clinically relevant and significant risk reduction in the pirfenidone group compared with the placebo group. Over 120 weeks, we noted significant differences in the pooled analysis favouring pirfenidone therapy compared with placebo for treatment-emergent all-cause mortality (p=0·0420), idiopathic-pulmonary-fibrosis-related mortality (0·0237), and treatment-emergent idiopathic-pulmonary-fibrosis-related (0·0132) mortality; similar results were shown by meta-analyses.
Several analytic approaches demonstrated that pirfenidone therapy is associated with a reduction in the relative risk of mortality compared with placebo over 120 weeks.
F Hoffmann-La Roche/Genentech.
•Drug-related interstitial lung disease (ILD)/pneumonitis diagnosis is challenging.•Careful monitoring, prompt diagnosis, and appropriate management are important.•Most events are low grade and can ...be managed safely.•Education is critical to ensure potential ILD/pneumonitis is proactively identified.•We suggest using a multidisciplinary approach.
Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd–related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd–related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd–related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms.
References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors’ own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.
Despite Food and Drug Administration approval of 2 new drugs for idiopathic pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high. Preclinical and clinical data ...support the safety of human mesenchymal stem cells as a potential novel therapy for this fatal condition. The Allogeneic Human Cells (hMSC) in patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) trial was the first study designed to evaluate the safety of a single infusion of bone marrow-derived mesenchymal stem cells in patients with idiopathic pulmonary fibrosis.
Nine patients with mild to moderate IPF were sequentially assigned to 1 of 3 cohorts and dosed with a single IV infusion of 20, 100, or 200 × 10
human bone marrow-derived mesenchymal stem cells per infusion from young, unrelated, men. All baseline patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis. The primary end point was the incidence (at week 4 postinfusion) of treatment-emergent serious adverse events, defined as the composite of death, nonfatal pulmonary embolism, stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test abnormalities. Safety was assessed until week 60 and additionally 28 days thereafter. Secondary efficacy end points were exploratory and measured disease progression.
No treatment-emergent serious adverse events were reported. Two nontreatment-related deaths occurred because of progression of IPF (disease worsening and/or acute exacerbation). By 60 weeks postinfusion, there was a 3.0% mean decline in % predicted FVC and 5.4% mean decline in % predicted diffusing capacity of the lungs for carbon monoxide.
Data from this trial support the safety of a single infusion of human mesenchymal stem cells in patients with mild-moderate IPF.
ClinicalTrials.gov; No.: NCT02013700; URL: www.clinicaltrials.gov.
The preclinical natural history of progressive lung fibrosis is poorly understood.
Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed ...tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia.
Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study time to complete 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated.
Among 336 subjects, the mean age was 53.1 (SD, 9.9) years. Those with ILA (early/mild
= 74 or extensive
= 3) were older, were more likely to be ever smokers, had shorter peripheral blood mononuclear cell telomeres, and were more likely to carry the
risk allele. Self-reported occupational or environmental exposures, including aluminum smelting, lead, birds, and mold, were independently associated with ILA. Among 129 subjects with sufficient study time, 25 (19.4%) had an ILD event by 5 years after enrollment; of these, 12 met the study endpoint and another 13 had radiologic progression of ILA. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs. 6.1%;
< 0.0001).
Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.
Summary Background Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm ...the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis. Methods In two concurrent trials (004 and 006), patients (aged 40–80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov , numbers NCT00287729 and NCT00287716. Findings In study 004, 174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006, 171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0·001). Mean FVC change at week 72 was −8·0% (SD 16·5) in the pirfenidone 2403 mg/day group and −12·4% (18·5) in the placebo group (difference 4·4%, 95% CI 0·7 to 9·1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0·0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0·501). Mean change in FVC at week 72 was −9·0% (SD 19·6) in the pirfenidone group and −9·6% (19·1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0·6%, −3·5 to 4·7); however, a consistent pirfenidone effect was apparent until week 48 (p=0·005) and in an analysis of all study timepoints (p=0·007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 36% of 345 vs 60 17% of 347), dyspepsia (66 19% vs 26 7%), vomiting (47 14% vs 15 4%), anorexia (37 11% vs 13 4%), photosensitivity (42 12% vs 6 2%), rash (111 32% vs 40 12%), and dizziness (63 18% vs 35 10%) than did those in the placebo group. Fewer overall deaths (19 6% vs 29 8%) and fewer deaths related to idiopathic pulmonary fibrosis (12 3% vs 25 7%) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups. Interpretation The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis. Funding InterMune.
IL-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing ...disease.
Investigate efficacy and safety of tralokinumab, a human anti-IL-13 monoclonal antibody, in subjects with mild to moderate IPF.
Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention-to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median.
The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least-squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: -1.77 (-4.13 to 0.59) (P = 0.140) and -1.41 (-3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC greater than or equal to 10% at Week 52 was numerically greater for tralokinumab-treated subjects compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively.
Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).
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