A sliding window of size Multimedia information requires large repositories of audio-video data. Retrieval and delivery of video content is a very time-consuming process and is a great challenge for researchers. An efficient approach for faster browsing of large video collections and more efficient content indexing and access is video summarization. Compression of data through extraction of keyframes is a solution to these challenges. A keyframe is a representative frame of the salient features of the video. The output frames must represent the original video in temporal order. The proposed research presents a method of keyframe extraction using the mean of consecutive  Gesture recognition is a giant leap toward the touch-free interface. The information conveyed through gestures is either in the form of static gestures or in the form of continuous gestures . The conThe selection of ”correct” keyframe is based on the application as well as the personal “definition” of what the summary should represent. Researchers have described keyframe extraction into either “sequence-based approaches” or “cluster-based approaches” . The firThe process of selecting keyframes passes through video information analysis, meaningful clip selection, and output generation. For a good summary of video information, we must determine salient features, the descriptors in the visual component, the audio component if any, and the textual components such as closed captions. A shot can change by a “CUT”, which is a sudden change between two adjacent frames, or a “FADE”, which occurs by a steady change in brightness. Another is “DISSOLVE”, which is similar to FADE but is sandwiched between two shots. One scene gets dimmer and the incoming scene gets brighter, and the 2nd shot finally replaces the first one . All theThe video is sampled either uniformly or randomly. The complete video is divided into frames. Out of these frames, one or more will be representative of the content of the video, helping in generating video summaries .k-means clustering are used in making the decision for keyframe selection [These techniques combine similar frames/shots. Some features are then extracted from this group of frames. Based on this, one or more frames are extracted from the cluster. Different features such as luminance, color histogram, a motion vector, and election .This is also called video skimming, which is actually a summary video of all the important scenes from an input stream. It forms an abstraction of the video. Singular Value Decomposition (SVD), and motion model and semantic analysis, are the few techniques that are used for dynamic video summarization .The rest of the paper is organized as follows: A great deal of work has been done on video summarization. Sheena and Narayanan used the histogram of consecutive frames. In this method, the threshold difference of histograms is calculated to find keyframe from video data from the KTH action database. Their algorithm is good both in terms of fidelity value as well as compression ratio . KhattabCahuina et al. proposed a technique based on local descriptors for semantic video summarization and tested the technique on 100 videos. Their technique achieved a recognition level of 99%. They used color information with local descriptors to produce video summaries . Shi et Ciocca et al. proposed an algorithm based on the difference between two consecutive frames of a video sequence and used the visual content changes. They used a color histogram, wavelet statistics, and an edge direction histogram. Similarity measures are determined and combined with the frame difference. The method even detects very minor changes. The proposed method dynamically selects a variable number of keyframes from different shots . Ejaz etZhang et al. used the similarity distance of the adjacent frames to adjust the threshold input adaptive algorithm. They then used the Iterative Self-Organizing Data Analysis Technique (ISODATA) to cluster frames into classes automatically. Their algorithm focuses on different motion types reliably and efficiently. Their results were tested using metrics that analyzed for the reconstructed motion and the mean absolute error value . Dong etMei et al. generated audio streams, compressed images, and metadata for motion information and temporal structure. Their technique works at a very low compression rate. The proposed Near-Lossless Semantic Video Summarization (NLSS) method is effectively used for visualization, indexing, browsing, duplicate detection, concept detection, etc. The NLSS is tested on TREC Video Retrieval Evaluation (TRECVID) and other video collections, showing that it significantly reduces storage consumption while giving high-level semantic fidelity . ShroungWang et al. elaborated the important issues in information theory and discussed the use of these concepts in visualization in relating data communication to data visualization . EntropyDe Avila et al. proposed Video SUMMarization (VSUMM) for producing static video summaries. The method is based on color feature extraction from video frames and a k-means clustering algorithm. The work was compared with manually created static summaries, demonstrating the high accuracy of the proposed VSUMM technique. The technique improves on visual features, their fusion, and the estimation of the number of clusters . Kanehirk images. It then takes a group of k is chosen such that The proposed technique uses the concept of the mean and then applies the median of the entropy to the resultant images for video summarization. The resultant keyframes thus generated will be used for continuous gesture recognition. The technique uses the mean of k frames is defined asThe mean is a very important measure in digital image processing. It is used in spatial filtering and is helpful in noise reduction. The mean of k images. k frames. mth frame.Here, Entropy is the measure of randomness (or uncertainty) in an image. It is a measure of the information transmitted . The conX has a probability distribution i and i, then the multiplier n, while k.l is the total number of gray levels, and k. The value of entropy is highest when samples are equally likely and when Entropy is a measure of the spread of states in which a system can adjust. A system with low entropy will have a small number of such states, while a high entropy system will be spread over a large number of states. Suppose X is a random variable consisting of following he limit . The ter)≤log(l) .Input Video. This is the video that is to be converted into keyframes. It can be in any standard format.Frame Extraction. Every video is basically a sequence of a finite number of still images called frames. These frames occupy a large amount of memory. The frame rate is about 20–30 frames per second (FPS). Movies are shown at a rate of almost 24 fps. In some countries, it is 25 fps. In North America and Japan, the movies are shown at 29.97 fps. In other image processing applications, it is usually at 30 frames per second. Other common frame rates are usually multiples of these [of these . It has Feature Extraction. This process can be based on features such as colors, edges, or motion features. Some algorithms use other low-level features such as color histograms, frame correlations, and edge histograms [stograms .The video summarization process involves the following stages:n to n/k. After this, a sliding window of size k/2 is applied to the resultant frames, and in each window the frame with the median value of entropy is selected.pseudocode:Input: The video.Output: procedure:convert the video to frames resize each frame to an image size of initialize l to 1;increment l by 1;reduce the frame count to consider 1st sliding window of size l, calculate entropy of frame compare the frames in the sliding windows;choose a frame with the median value of entropy;slide window to the next The technique uses the following Algorithm 1: Keyframe Extraction through the proposed MME method.dress in Pakistan Sign Language, which is 3 s long. It consists of almost 90 frames. In the first loop, five frames are averaged at a time, yielding 17 frames. We continued until all frames had been processed. Using computed entropy, we designed a sliding window of size 3 frames. Later on, the median of the entropies of the frames in the window was calculated. Using a 3 s video, we obtained six keyframes. The compression ratio (CR) is determined byThe proposed Algorithm 1 can be used for any type of video, but it has also been tested rigorously for continuous gestures. We tested this algorithm on several videos. The complexity of the algorithm is A low CR represents an efficient technique. Fidelity is another measure to determine the efficiency of the keyframe selection algorithm. It is the maximum of the minimum of the distance between keyframes and the individual frames.Fidelity basically determines how effectively an algorithm maintains the global content of the original video .bird, which is 3 s long.The algorithm was tested on a number of videos, and a few examples are presented here. The technique was applied to the ASL LexiconVideo Dataset, containing thousands of distinct sign classes of American Sign Language . Figure k frames using the video of the gesture for the word bird for bird changes frames at a faster pace. Therefore, for the faster videos, we decreased the value of the k; for the slower videos, we increased the value of k accordingly.dress was converted to frames. It was also 3 s long. It was converted to 90 frames, as shown below in In another scenario, the video of the gesture for the word The mean for these frames was calculated taking 5 frames at a time, so we obtained 17 frames after the process was applied. The entropy was calculated for all frames after taking the mean. A sliding window was applied to three frames at a time. The entropy value of all images was calculated, and the frame representing the median of these frames was selected as the keyframe. Once a keyframe was selected, the sliding window moved to the next three frames. We obtained six frames as the keyframes. letter in Pakistan Sign Language was chosen to test the proposed algorithm. For a video 2 s long, we had approximately 70 frames. letter.In another example, a video of the gesture for the word We obtained 13 frames after applying a mean 5 frames at a time. In the last step, using the sliding window of size 3, we obtained five frames as keyframes. raisins, a 4.5 s long video, the technique generated only one keyframe.The results were also compared with other existing techniques. The proposed technique achieves accuracy comparable to those provided by ,30,38,54k frames with a median of entropy using a sliding window of size The proposed technique uses an average of ced by n . This imk in the range 5–15 is preferential. Selecting a reasonable size of k rules out the possibility of missing frames in the proposed MME technique. Another distinct quality of the proposed technique is the distance of keyframes. We obtained keyframes that were at most Keyframe selection is an active area of research and plays a pivotal role in video summarization. A keyframe is one of the most efficient methods of obtaining a summary of the video content. The temporal order of the frames is maintained by the proposed MME technique. The frame average count k and sliding windows size


Solanum tuberosum L.) is the world’s fourth most important food crop and essential for global food security. The potato chloroplast genomes, the plastomes, are highly conserved and are largely studied for their maternal lineages. In this study, we assembled the complete circular plastome sequences of nine diploid potato clones, with sizes ranging between 155,296 bp and 155,564 bp. Annotation of these plastomes reveals that they each have 141 genes in a similar order. The computational chloroplast DNA typing reveals three plastid DNA types among the nine plastomes and they are grouped according to these types in the phylogeny.Potato ( Solanum tuberosum clones were obtained from the Benton Ridge Substation of Agriculture and Agri-Food Canada in Benton, New Brunswick (https://www.agr.gc.ca/eng/scientific-collaboration-and-research-in-agriculture/agriculture-and-agri-food-research-centres-and-collections/atlantic-provinces/fredericton-research-and-development-centre/?id=1180622499704) (Latitude: 45.923397 Longitude: 66.606842): S. tuberosum cv. 07506-01, S. tuberosum cv. 12120-03, S. tuberosum cv. DW84-1457, S. tuberosum cv. 12625-02, S. tuberosum cv. 08675-21, S. tuberosum cv. H412-1, S. tuberosum cv. W5281-2, S. tuberosum cv. 11379-03, and S. tuberosum cv. 10908-06. Potato plants were propagated in the greenhouse at the Fredericton Research and Development Centre, Fredericton NB, Canada, in six-inch clay pots with potting soil, under conditions of 16 h of light. Leaf tissue was ground and used for DNA extraction using the DNeasy Plant Mini Kit (Qiagen) according to the manufacturer’s instructions for plant tissue. Genomic DNA libraries were prepared using 10X Genomics GemCode technology (https://www.10xgenomics.com/) following the manufacturer’s instructions and whole genome de novo sequencing was carried out using the Novaseq 6000 DNA sequencer at the Génome Québec/Centre d’Expertise et de services Génome Québec  at 89× coverage.The plastid DNA sequences (plastomes) of land plants are highly conserved compared to nuclear and mitochondrial DNA, and are extensively studied for their maternal phylogenetic relationships (Hosaka and Hanneman https://www.10xgenomics.com/) to perform read trimming and barcode error correction. The filtered reads of each plant clone were used to assemble complete plastomes using the NOVOPlasty: de novo organellar genome assembler  , S. phureja Juz. , S. curtilobum Juz. and Bukasov , and S. tuberosum subsp. tuberosum (L.) Hawkes  species as references (Achakkagari et al. The raw reads obtained from the 10× Genomics GemCode technology were run through LongRanger Basic (The assembled sizes range from 155,296 bp to 155,564 bp with the typical quadripartite structure of potato plastomes. All the nine of them have 25,593 bp of inverted repeats. The size of SSC and LSC ranges from 18,373 bp to 18,376 bp and 85,737 bp to 86,005 bp respectively. The plastomes of the W5281.2, 12625-02, 12120-03, and 11379-03 clones have the same size of 155,492 bp. Similarly, the plastomes of clones H412-1, DW84-1457, 07506-01, and 08675-21 have the same size of 155,296 bp. Overall, 141 genes are present in each plastome, with similar gene content and gene order . Of thesFuture studies focusing on the agronomic traits associated with the plastome types in this study can greatly facilitate breeding programs in potato. Also, determining parental origin is trivial to deal with more and more fertility problems in diploid potato breeding. The phylogeny in this study is useful in understanding the evolutionary relationships, hybridization and introgression between these species, when combined with a nuclear phylogeny.


Recent studies have linked compassion with higher vagally mediated heart rate variability (vmHRV), a measure of parasympathetic activity, and meta-analytic evidence confirmed significant and positive associations. Compassion, however, is not to be confused with soothing positive emotions: in order to engage in actions aimed to alleviate (self or others) suffering, the pain should resonate, and empathic sensitivity should be experienced first. The present study examined the association between vmHRV and the empathic sensitivity and action components of trait and state compassion. To do so, several dispositional questionnaires were administered and two videos inducing empathic sensitivity (video 1) and compassionate actions (video 2) were shown, while the ECG was continuously recorded, and momentary affect was assessed. Results showed that (i) scores on subscales assessing the empathic component of trait compassion were inversely related to resting vmHRV; (ii) vmHRV decreased after video 1 but significantly increased after video 2. As to momentary affect, video 1 was accompanied with an increase in sadness and a decrease in positive affect, whereas video 2 was characterized by an increase in anger, a parallel decrease in sadness, and an increase  in positive affect. Overall, present findings support the notion that it is simplistic to link compassion with higher vmHRV. Compassion encompasses increased sensitivity to emotional pain, which is naturally associated with lower vmHRV, and action to alleviate others’ suffering, which is ultimately associated with increased vmHRV. The importance of adopting a nuanced perspective on the complex physiological regulation that underlies compassionate responding to suffering is discussed. Over two decades, studies have shown the health promoting influences of compassion , fosteriCompassion has been defined as a sensitivity to suffering in self and others with a commitment to try to alleviate and prevent it ; it doesAs an evolved prosocial motivation, compassion requires complex social processing systems and evolved competencies which allow approach and engagement with distress signals to help alleviate the distress, such as, a sensitive awareness of suffering, empathic awareness, distress tolerance, a non-judgmental attitude, and the willingness to develop specific skills to enact the motive  , 2019. TOver the past decade, the psychophysiological perspective has contributed significantly to our understanding of compassion in an effort to provide unique insights into its nature and processes. A specific role of the 10th cranial nerve, namely the vagus, has been highlighted in compassion-related processes . EfferenRecent studies  and metaPrevious studies, however, ignored a crucial ingredient of compassion, that is whether the ability to pay sensitive attention to suffering and effectively engage with it is accompanied by the intention and capacity to start the response process (an appropriate action) to alleviate the suffering . If bothIndeed, a phasic decrease in vmHRV could be considered as a signature of the empathic engagement with others’ suffering and it is the prerequisite to be touched by others’ suffering and subsequently act to alleviate it . Heart rBased on such evidence, compassion is expected to be first associated with reduced vmHRV to reflect empathic engagement with suffering, and then by increased vmHRV when the appropriate helpful action is performed. Indeed, in a pilot uncontrolled study, self-compassionate writing has been associated with a significant decrease in vmHRV during the task, and a significant increase in vmHRV during recovery .To date, the physiological signatures of each of the different components of compassion have not been thoroughly investigated, neither when dispositional (trait) nor when induced (state) compassion was examined. The study aimed to fill this gap, assessing resting vmHRV, the specific components of trait compassion, and vmHRV responses to and recovery from videos evoking the different components of compassion . We hypothesized: (i) the association between tonic vmHRV and trait compassion to be negative for the empathic component and positive for the engagement component of compassion; (ii) to see a vmHRV decrease in response to a video eliciting empathetic sensitivity toward others’ suffering, and a vmHRV increase in response to a video depicting intentional actions of giving help. We expected vmHRV reactivity to and recovery from such videos to be moderated by self and other-oriented trait compassion.N = 42, 88% female). Exclusionary criteria were self-reported major psychiatric or cognitive problems, organic illnesses, substance abuse, cardiovascular disease, use of drugs/medications affecting cardiovascular function, body mass index >30 kg/m2, menopause, use of oral contraceptives during the previous 6 months, pregnancy or childbirth within the last 12 months. The protocol was approved by the local Ethics Committee.The sample consisted of 45 students  of an American university based in Rome, Caucasian, and English speaking. Three subjects were not included in the analyses due to unreliable physiological measures , participants rated their current levels of affective states  on several 5-point VAS.Interbeat intervals were continuously recorded throughout the experimental session using the Firstbeat Bodyguard 2 with a standard electrode configuration. Time  and frequency-domain  vmHRV measures were calculated. VmHRV analysis was performed using Kubios HRV software . Artifact-test. The variables that resulted to be significantly associated with vmHRV measures were included in the subsequent analyses as covariate.The data were analyzed using IBM SPSS Statistics version 25 and Mplus 5.1. To evaluate the effects of dispositional variables (socio-demographic factors and trait measures) on the dependent variables, Pearson correlations were performed between BMI, physical activity, trait questionnaires, and vmHRV. Sex differences were evaluated by Student’s Following existing recommendations , to deteModeration analyses were executed using the An exploratory factor analysis on VAS has been then conducted to identify associations within self-reported momentary affect variables. We used Principal Component Analysis (PCA) and Varimax orthogonal rotation as methods to extract the factors. 2p), with η2p = 0.01 referring to a small effect size, 0.06 to a medium effect size and 0.14 to a large effect size  was performed on factorial scores with time  as the within-subjects factor. Effect sizes were calculated using partial eta squares , all the analyses have been performed on HF-HRV only. Correlation analysis showed negative and significant associations between HF-HRV and the following trait measures: Self Compassion total score , Sensitivity to Suffering-Self-Compassion component , Compassion to Others total score , and Compassion to Others-Engagement component .Given the high correlation between the two vmHRV indices  = 7.465; p = 0.009; η2p = 0.151] and significant Time × Video interaction  ; however, recovery from video 2 showed a significant increase in HF-HRV compared to recovery from the video 1 . Given the lack of differences in reactivity to the two videos, moderation analyses were performed only on recovery values.In line with our main hypotheses, the mixed-model ANOVA revealed a main effect of Video for HF-HRV [= 0.138] . ReactivR2 = 0.1447; F = 2.1435; p = 0.1108], whereas a significant effect of Compassion to Others  but not of Self Compassion  emerged for Recovery from video 1, with a significant interaction effect . Overall, the regression model explained the 50% of the observed variance of HF-HRV recovery from Video 1 . The analysis of simple slopes of the interaction effect highlighted that the relationship between Compassion to Others and Recovery 1 was significant for low  and medium Self-Compassion scores (−1 × SD) , while for high scores the relationship was negative and non-significant   .R2 = 0.5247; F = 13.9851; p = 0.0001; interaction effect: β = −0.0025; SE = 0.0006; p = 0.0002]  = 13.0196; p = 0.0001; interaction effect: β = −0.0018; SE = 0.0005; p = 0.0003]  POSITIVE AFFECT ; (b) low arousal NEGATIVE AFFECT ; and (c) high arousal NEGATIVE AFFECT  = 12.106; p = 0.0001; η2p = 0.228; F = 45.798; p = 0.0001; η2p = 0.528; F = 19.982; p = 0.0001; η2p = 0.328; p = 0.0001, M increase = 179%), and less happy and strong  in response to video 1, whereas in response to video 2 they reported to be angrier, and more self-critical compared to baseline  and to video 1  but less sad compared to video 1 . An increase in Positive Affect in response to video 2 also emerged, although not statistically significant  compassion, namely empathic sensitivity and compassionate action. When the dispositional tendency to engage in compassion was examined, data evidenced that only the Compassionate Engagement Actions Scale (CEAS) showed associations with vmHRV. Notably, significant negative associations emerged between resting HF-HRV and dispositional compassion. This finding is not completely unexpected. Indeed, most of the studies that investigated the connection between compassion and vmHRV, used different measurement tools, which reflect different definitions of compassion and do not take into account the subdivision of engagement and action as fundamental components of compassion motivation . In lineConsistently, recent findings show that a more efficient shifting of attention from affective to non-affective aspects of negative information was related to lower resting vmHRV . In a coIn line with our hypothesis, the data evidenced significant greater HF-HRV increase after watching the video depicting the intentional actions of giving help, compared to video eliciting empathic sensitivity toward others’ suffering. Interestingly, most of the participants (88%) labeled the second video as more compassionate. This result replicates previous findings which identified increased vmHRV when individuals effectively engage in compassion interventions , or imprPresent data highlight that the engagement in compassion enables an appropriate autonomic response after seeing compassionate actions, indicative of how efficiently self-regulatory resources have been mobilized and used to overcome the emotional challenge and then return to resting level . This quOur current findings suggest that compassion at first magnifies the saliency of emotional stimuli, consistent with the traditional function of this meditation . Indeed,As to moderation analyses, a lower sensitivity to and motivation to engage with other’s suffering moderated the association between compassion for others and vmHRV recovery from video 1 (empathic stress condition), whereas this moderating role did not emerge for recovery from video 2 (compassionate action condition). Specifically, in the first condition compassion toward others was positively associated with HF-HRV recovery via lower self-compassionate engagement and action.We explored changes in different affective states distinguishing between positive affect, low arousal negative affect, and high arousal negative affect. Results revealed a significant increase in low arousal negative affect and a parallel decrease in positive affect in response to video 1, whereas an increase in high arousal negative affect and parallel decrease in low arousal negative affect emerged in response to video 2. Recently, Gilbert and collaborators highlighted that kindness and compassion are associated with different emotions. Whereas kindness is generally associated with positive feelings, engaging in compassionate actions can give rise to a different emotional experience and affective states, mostly associated with anxiety, sadness, disgust, and anger . ConsistSeveral limitations must be considered when interpreting the current results. First, being the first to explicitly investigate vmHRV in association with the two subcomponents of compassion, the present study was intended to be preliminary and therefore conducted on a relatively small sample. Replication with a larger and more diverse sample is warranted before we can draw any conclusion on this issue. Moreover, there was an unequal sex distribution in our sample comprising of mostly females, and this may have biased the results. Indeed, differences in resting vmHRV have been well-documented , with feLastly, the two videos were not randomly presented. In order to exclude the role of carry-over effects, we statistically compared resting 1 with resting 2 and we found that full recovery occurred before the beginning of video 2. However, we are aware that this is a serious methodological limitation that future studies should avoid.Limitations notwithstanding, current results have potential clinical importance, contributing to inform our comprehension of the processes that are active when one engages in compassion, and although preliminary, highlight the importance of adopting a nuanced perspective on the complex physiological regulation that underlies compassionate responding to suffering. Encouraging finding suggests that this issue could be fruitfully explored by a time series analysis of the vmHRV signal, to disentangle how it fluctuates over the course of the empathic sensitivity condition and across the course of recovery .To conclude, compassion should not be seen as an antidote for negative affect, as it requires a dosage of personal suffering and pain before reaching its emotional and health benefits.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the IRB of Sapienza University of Rome. The patients/participants provided their written informed consent to participate in this study.NP conceptualized and conducted the study. MD analyzed the data and wrote the initial draft of the manuscript. All authors contributed to the interpretation of the results, provided critical feedback, helped shape the analysis and manuscript, and approved the submitted manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The presence of emphysema is relatively common in patients with fibrotic interstitial lung disease. This has been designated combined pulmonary fibrosis and emphysema (CPFE). The lack of consensus over definitions and diagnostic criteria has limited CPFE research.The objectives of this taskforce were to review the terminology, definition, characteristics, pathophysiology, and research priorities of CPFE, and to explore whether CPFE is a syndrome.This research statement was developed by a committee including 19 pulmonologists, 5 radiologists, 3 pathologists, 2 methodologists, and 2 patient representatives. The final document was supported by a focused systematic review that identified and summarized all recent publications related to CPFE.This taskforce identified that patients with CPFE are predominantly male, with history of smoking, severe dyspnea, relatively preserved airflow rates and lung volumes on spirometry, severely impaired diffusion capacity for carbon monoxide, exertional hypoxemia, frequent pulmonary hypertension, and a dismal prognosis. The committee proposes to identify CPFE as a syndrome given the clustering of pulmonary fibrosis and emphysema, shared pathogenetic pathways, unique considerations related to disease progression, increased risk of complications , and implications for clinical trial design. There are varying features of interstitial lung disease and emphysema in CPFE. The committee offers a research definition and classification criteria, and proposes that studies on CPFE include a comprehensive description of radiologic and, when available, pathological patterns including some recently described patterns such as smoking-related interstitial fibrosis.This statement delineates the syndrome of CPFE and highlights research priorities. Despite its clinical significance and a number of published series 3, CPFE remains poorly understood. Imaging features of CPFE vary in both fILD and emphysema, and not all cases correspond to IPF with emphysema. Similarly, the spectrum of pathologic features includes recently described patterns such as airspace enlargement with fibrosis (AEF)4 and smoking-related interstitial fibrosis (SRIF)5. Lack of consensus on criteria for CPFE has limited our ability to compare cohorts and draw consistent conclusions about the features, outcomes, and optimal management of these patients 3. No consensus exists on whether CPFE is a syndrome 6 or a distinct entity. In essence, CPFE remains relatively understudied, with no specific treatment.Emphysema is relatively common in patients with fibrotic interstitial lung disease (fILD), including idiopathic pulmonary fibrosis (IPF), and is designated “combined pulmonary fibrosis and emphysema” (CPFE)The objectives of this taskforce were: 1) to describe the terminology, definition, etiologies, features, comorbidities, and outcomes of CPFE; and 2) to provide a consensus definition and terminology of CPFE, determine whether it represents a syndrome, describe its management, and identify research priorities.This research statement was developed by a committee of experts appointed by the American Thoracic Society (ATS), the European Respiratory Society (ERS), the Japanese Respiratory Society (JRS), and the Asociación Latinoamericana del Tórax (ALAT). The committee included 19 pulmonologists, 5 radiologists, 3 pathologists, 2 methodologists, and 2 patient representatives. Potential conflicts of interest were disclosed and managed in accordance with the ATS policies and procedures. The taskforce communicated during two face-to-face meetings, and via e-mail and teleconferences. Sections of the document were elaborated by subgroups, each with a leader responsible for writing. The final manuscript was approved by all panelists.3 38. The prevalence is also higher in patients with lung cancer and idiopathic interstitial pneumonia, including IPF 40.Emphysema is common in current or former smokers with fILD. Prevalence estimates of CPFE vary depending on the population studied and the definition used, ranging from 8-67% of patients with IPF 1 was identified radiographically in 7.3% of males who underwent high-resolution CT (HRCT) of the chest (indication unknown)41 and in 2.8% of all HRCTs done at a single center in Korea 42. In patients with resected lung cancer, CPFE was found in 3-10% of patients 45. CPFE as previously defined tients 45; however46. Almost all patients with CPFE report a history of smoking, with an average exposure of 40 pack-years, with the notable exceptions of some patients with connective tissue disease (CTD) or fibrotic hypersensitivity pneumonitis (fHP)48 who on average have less smoking exposure 53 who had never smoked 62. Approximately 5-10% of patients with systemic sclerosis-associated ILD have radiological findings of CPFE 64. In 116 never smokers with rheumatoid arthritis-associated ILD (RA-ILD), emphysema was present on HRCT in 27% 52. CPFE is also reported in systemic vasculitis, particularly microscopic polyangiitis 66. Of 150 consecutive patients with RA, 12 (8%) had both ILD and emphysema 67; however, in patients with rheumatoid lung, the reported prevalence of emphysema is as high as 48% 68. Emphysema on HRCT was less extensive in CTD-associated usual interstitial pneumonia (UIP) than in IPF (idiopathic UIP)69. IPF patients with CPFE are more likely to have positive antinuclear antibodies or p-antineutrophil cytoplasmic antibodies than IPF patients without emphysema 25.CPFE can occur in non-smokers especially in CTD, suggesting CTD itself as a risk factor 73 and IPF 112, and are, thus, likely associated with CPFE 46, although this requires further study 113. If confirmed, CPFE would represent a model of smoking-induced, telomere-related, lung disease. Epigenetic alterations may also be important 114.Genetic predisposition in combination with risk factors including smoking or exposure to other aero-contaminants, may predispose individuals to develop both fibrosis and emphysema tant see 94–99 or 46 (comparable to IPF and COPD), with 73-100% male predominance 61. Symptoms include exertional dyspnea and cough 41. Patients with CPFE and pulmonary hypertension (PH) have significant exertional breathlessness, with the majority having a New York Heart Association functional class of III or IV 115.Patients with CPFE have a mean age of approximately 65-70 years 116, although it is not known whether these diseases are more prevalent in CPFE than in IPF without emphysema 60. Differences in sample size, study design (retrospective), and methods for identification and documentation of comorbidities contribute to uncertainties. Prospective studies with standardized data collection methods and case definitions are required.In CPFE, the two most prominent comorbidities are lung cancer and PH, discussed in the outcomes section below. Other comorbidities include coronary artery disease, peripheral vascular disease, and diabetes 119, contrasting with relatively preserved airflow rates and lung volumes. The FVC/DLco ratio is increased in most patients 51.Patients with CPFE have limited exercise capacity, severely impaired DLco and transfer coefficient (Kco)125, even with adjustment for the extent of fibrosis 121120. Comparison of physiology between CPFE and isolated IPF may be hampered by differences between studies in the severity of both emphysema and fibrosis, despite attempts to adjust for severity 24.Compared to isolated IPF, patients with CPFE have higher lung volumes (FVC and TLC), generally comparable FEV1, higher residual volume (RV), lower DLco, lower Kco, and lower PaO2 rosis 121. The mea1 and FEV1/FVC, less hyperinflation, and lower DLco 126. A minority of the 132 patients  from three previous studies had TLC < 80% predicted 115, while only 41% had FEV1/FVC < 0.70. Of these, 11% had FEV1 > 80% predicted, corresponding to Global initiative for Obstructive Lung Disease stage 1, 37% were classified as stage 0 (FEV1/FVC ≥ 0.70 and FEV1 ≥ 80% of predicted), and 22% were unclassified (with FEV1/FVC ≥ 0.70 and FEV1 < 80% of predicted). In another study, smokers with emphysema were less likely to meet functional criteria for COPD if ILD was present on imaging 127. Thus, the relative preservation of spirometric values may lead to underdiagnosis of chronic lung disease if only spirometry is obtained.Compared to COPD, patients with CPFE have relatively preserved FEV1/FVC can actually improve to normal values as fibrotic disease progresses, despite worsening dyspnea and DLco 128, and contrary to COPD 126. TLC correlates positively with emphysema extent on CT, and negatively with fibrosis extent. Conversely, FEV1/FVC correlates negatively with emphysema extent on CT, and positively with fibrosis extent 129. Compared to isolated fILD, patients with CPFE have lower whole-breath inspiratory and expiratory resistance based on analysis of respiratory impedance by multi-frequency forced oscillation technique, further supporting the hypothesis of “normalization” of lung mechanics 130. Conversely, both disease components reduce alveolar capillary gas exchange through either decreased capillary blood volume or alveolar membrane thickening, resulting in greater reductions in DLco.The relative preservation of flow rates and lung volumes is attributed to the counterbalancing effects of the restrictive physiology from pulmonary fibrosis (presumably increased elastic recoil and prevention of expiratory airway collapse by traction forces) and the effects of emphysema on the airways. Thus, in CPFE, FEV119. Hence, exercise limitation with decrease in oxygen saturation 119, and isolated 131 and/or severe 132 reduction in DLco or Kco, contrasting with a mild ventilatory defect, should raise the suspicion of CPFE and/or PH. Compared to isolated IPF, patients with CPFE have lower exercise capacity despite less extensive fibrosis on HRCT 134. Exertional dyspnea is the key limiting factor, related to poor ventilatory efficiency and, presumably, increased dead space in hypoperfused areas 133. Hypercapnia occurs only very late in the disease course. A similar functional profile is observed when CPFE occurs in CTD 52 or fHP 47.Severe decrease in arterial oxygen saturation and hypoxemia at exercise is very common in CPFE, especially when complicated by severe PH 124, whereas decline in DLco and increase in the Composite Physiologic Index (CPI), which quantifies functional impairment due to IPF whilst excluding the functional impact of emphysema, are less affected 60. In an analysis of patients with IPF from two randomized controlled trials, emphysema extent ≥15% was associated with reduced FVC decline over 48 weeks compared to those with either no emphysema or emphysema extent <15% 29.Importantly, the presence of significant emphysema impacts on serial lung volume trends, attenuating serial lung volume decline due to progressive fibrosis. Patients with CPFE experience a slower decline in FVC than patients with isolated IPF 135, are not reliable indicators of disease progression in patients with CPFE 124, which has implications for clinical trial design 136. Serial change in DLco may be a helpful marker of disease progression but is additionally affected by other factors including vasculopathy, hemoglobin concentration, and measurement variation. Serial change in CPI is not validated for monitoring ILD progression. A FEV1%FVC ratio >1.2 at baseline 137 and a decline in FEV1 by 10% or more at 6 or 12 months 138 were associated with a poor outcome, but these observations warrant confirmation. In clinical practice, a decline in one or several of the above-mentioned functional parameters may be observed in individual patients. In summary, the committee therefore suggests that disease progression in CPFE be monitored using a combination of clinical, imaging, and multiple functional parameters, with less emphasis on FVC trends than in the monitoring of ILD without concurrent emphysema.Consequently, no optimal parameter has been validated to monitor disease progression in CPFE. Changes in FVC, commonly used to monitor IPF progression CPFE is characterized by the presence of emphysema and interstitial fibrosis, with a wide variety of appearances on chest HRCT.139. Emphysematous foci can be categorized as centrilobular, paraseptal, or panacinar 140. Interstitial fibrosis is identified as regions of increased parenchymal attenuation, appearing as reticulation and/or ground glass opacities, variably associated with honeycombing and/or traction bronchiectasis , not bounded by visible walls on CT iectasis . Patternasis  time constraints for visual scoring; 3) varying methodologies for HRCT scan interrogation ; 4) varying HRCT spatial resolution; 5) whether emphysema extent alone or both emphysema and fibrosis extents are quantified 162; and 6) variations in emphysema quantification e.g. total extent of emphysema, versus extents of emphysema lying either within or separate to areas of fibrosis163.Disease quantification has predominantly relied on semi-quantitative visual HRCT estimation of emphysema and fibrosis extents. However, this approach is limited by several challenges: 1) interobserver variation 3(see following section), include: >0% 58, >5% 121, >10% 148 and >15% 162 of total lung volume. One study limited assessment of emphysema extent to above the level of the carina 51.The emphysema component of CPFE has been evaluated by imaging rather than lung function tests, given the confounding impact of fibrosis on lung physiology. Reliable estimation of emphysema extent in patients with established pulmonary fibrosis poses significant challenges. Most studies use visual assessment of emphysema by an experienced radiologist, a method that is readily available and has moderate inter-rater agreement. Emphysema thresholds used to characterize a CPFE phenotype on imaging 165, because it fails to discriminate between low density areas due to emphysema and low density due to honeycomb cysts, traction bronchiectasis or non-emphysematous mosaic attenuation due to small airways disease. Until this limitation can be overcome , visual quantification of emphysema extent remains the method of choice in CPFE.Quantitative methods for scoring emphysema using computer-based measurement of lung density (e.g. density masking) are typically used in studies of chronic obstructive pulmonary disease and remove the problem of observer variability. However, this methodology of emphysema quantification is poorly suited to CPFE despite being attempted in some series 147. Large multicentered studies are required to determine whether these morphological CPFE subtypes correlate with distinct functional or prognostic disease groups. The subtypes identified on HRCT imaging could also be confirmed using histopathological correlative studies 151.Differences in morphological patterns of emphysema  have also been used to describe CPFE subtypes 169. This may result in a high prevalence of combined ILAs 170 and emphysema in screening populations.A minimal threshold extent of lung fibrosis on HRCT imaging has rarely been used in CPFE despite the clinical importance of fILD severity . The con171. However, quantitation of fibrosis extent is confounded by volume loss, with lower lobes sometimes greatly contracted to apparently small areas of fibrosis. Yet when considering CTD-related ILD or fHP where ground glass opacities may reflect inflammation rather than fibrosis, there is no consensus on whether ground glass opacities should be considered as part of CPFE fibrosis extent. It has been suggested that to conform to the “fibrosis” element required by a definition of CPFE, ground glass opacities should be quantified only if overlaid by reticular lines or traction bronchiectasis .In the context of IPF, where ground glass opacification on HRCT largely represents fine fibrosis, fibrosis extent in CPFE has been calculated by summing ground glass opacities, reticulation, and honeycomb cysts iectasis  and 91712. Histopathologic studies of patients with severe CPFE defined in this way are limited to small series of autopsy cases or explants given the risk of surgical lung biopsy in this population 151. Overlapping patterns of smoking-related abnormalities are common in lung biopsies from patients undergoing elective lung biopsy for fILD including some for whom a diagnosis of CPFE is uncertain or unanticipated. Here we review patterns of smoking-related abnormalities and pulmonary fibrosis with a focus on features characteristic of CPFE.CPFE was originally defined based on clinical, physiologic, and HRCT features 175. Morphologic studies of carefully inflated lung specimens from explant pneumonectomies and autopsy lungs provided the basis for an anatomical definition of emphysema and continue to inform our understanding of its pathogenesis. However, the coexistence of emphysema and patterns of fILD can be seen in biopsies, a situation in which pathologists need to document the emphysema as well as the fILD. Centrilobular emphysema is an upper lobe predominant form of emphysema caused by cigarette smoking that is often accompanied by paraseptal emphysema in CPFE patients. Emphysema is common in surgical lung specimens and frequently coexists with other smoking-related abnormalities including respiratory bronchiolitis (RB) and SRIF 176.Emphysema is required for a diagnosis of CPFE and is defined as abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, without obvious fibrosis 172–175. 177. RB is a common incidental finding in surgical lung specimens, including biopsies in which it may accompany any pattern of pulmonary fibrosis including especially SRIF, desquamative interstitial pneumonia (DIP), UIP and Langerhans cell histiocytosis given the high prevalence of smoking in these populations. RB-ILD is a diagnosis of exclusion reserved for patients in whom RB is thought to explain diffuse ILD after elimination of diagnostic alternatives, a circumstance histologically indistinguishable from incidental RB. RB by itself is not a fibrotic lesion and therefore an insufficient explanation for fibrosis in patients suspected of having CPFE.RB occurs almost exclusively in cigarette smokers and is defined by the presence of pigmented alveolar macrophages clustered within the lumens of respiratory bronchioles and peribronchiolar air spaces without significant inflammation or fibrosis 177. RB i179. These patterns include a distinctive form of fibrosis linked to cigarette smoking for which Katzenstein proposed the term SRIF 151. SRIF overlaps with previous descriptions of AEF 181, RB-associated ILD with fibrosis 22, RB with fibrosis 182, and DIP5. Some cases with a pattern of fibrotic NSIP may also be related to smoking. SRIF is characterized by densely eosinophilic collagen deposited in expanded alveolar septa with preservation of lung architecture and little or no inflammation  without subpleural honeycomb change (Langerhans cell histiocytosis (LCH) is a potentially fibrotic form of smoking-related ILD that may occur in combination with other smoking-related abnormalities including emphysema, RB, SRIF, and DIP b change .187. Identifying UIP typical of IPF in the setting of emphysema requires recognition of patchy fibrosis, fibroblast foci, and honeycombing without histologic features to suggest an alternative such as LCH, f-HP, or CTD-associated UIP 179. Unique to UIP in CPFE is the presence of thick-walled cysts resulting from the combination of emphysema and SRIF  and differences in statistical modeling 190, and could also be attributable to differing severity of fibrosis and emphysema on HRCT 30. Pathophysiology of PH in CPFE is probably multifactorial 191. Some studies have suggested that the severity of PH is worse among those with CPFE compared to both IPF 32 and COPD 192 or emphysema 149 alone. Estimated systolic pulmonary artery pressures are higher in patients with CPFE than in those with isolated IPF 119. The additional burden of emphysema, over and above a given extent of fibrosis, increases the risk of PH. However, the likelihood of PH does not differ for matched extents of disease (combined fibrosis and emphysema) on HRCT (or when adjusted for DLco) between patients with CPFE and those with fibrosis alone 58.PH has been reported in 15-55% of patients with CPFE 193, with varying methodology . In a meta-analysis 194, patients with CPFE (UIP and emphysema) had a higher risk of lung cancer than those with IPF alone 194. There were similarly increased risks of lung cancer in patients with CPFE and UIP with the presence of any amount of emphysema  and with emphysema in ≥10% of the lung volume , compared to patients who had UIP without emphysema 194.Lung cancer has been reported in 2-52% of patients with CPFE 198. In contrast to the general epidemiology of non-small cell lung cancer with adenocarcinoma accounting for 50% of cases 199, squamous cell carcinomas appear to be more frequent in patients with CPFE 200. The majority of the lung cancers were located in the lower lobes 195. There is greater invasion and the diagnosis is made at a later stage compared to non-small cell lung cancer without CPFE 201.The most common histopathologic subtypes of lung cancer in CPFE are squamous cell carcinoma and adenocarcinoma 200, a systematic review and meta-analysis concluded that the presence of CPFE is associated with worse survival in patients with non-small cell lung cancer198. 200Among patients with CPFE and lung cancer, the presence of honeycombing, later cancer stage, and reduced feasibility of surgical resection are predictors of mortality 202. The poor outcome is at least in part related to increased morbidity and mortality of cancer treatments in CPFE, which often limits standard therapy 204.Although individual studies differ in their conclusions 207. Risk factors for acute exacerbation in CPFE may be similar to IPF, including worse gender-age-physiology score and the presence of lung cancer, particularly following surgical resection 205. Diffuse ground glass and/or consolidation on chest HRCT help to differentiate exacerbations of fibrosis from exacerbations of emphysema in CPFE 208. The prognosis of acute exacerbation in CPFE might be better than that of isolated IPF 207.Acute exacerbations of IPF have been reported in patients with CPFE with varying prevalence 209, which probably reflect differences in sample size, follow-up time, and comorbidities. Patients with CPFE have worse survival than patients with emphysema alone on HRCT 42. As compared to patients with IPF alone, patients with CPFE were reported to have worse 56, comparable 212, or better survival 147. Possible explanations for this discrepancy include diagnostic contamination , attrition bias 60, differences in the relative extent of emphysema versus fibrosis in different cohorts 213, and a ‘healthy smoker’ effect 214. A positive correlation was found in some series between the extent of emphysema and the extent of fibrosis 32, however a negative correlation was found in others 215. In some series, an attempt was made to examine CPFE specifically in sub-groups mostly or wholly made up of IPF 212. However, this goal is complicated by the lack of histologic confirmation of UIP in most CPFE patients with suspected IPF, and difficulties discriminating between true honeycomb change (required for an HRCT pattern of UIP) and the admixture of emphysema and pulmonary fibrosis (“pseudohoneycomb change”) on HRCT 217.CPFE is associated with poor survival, with different estimates between series 212, using both visual analysis to the nearest 5% 212 and computer-based analysis with the CALIPER software 58. The global disease extent on HRCT (i.e. the combined extent of fibrosis and of emphysema) and the baseline DLco both predicted mortality, reflecting the overall severity of parenchymal lung destruction 212. After correction for baseline severity using DLco, the presence or extent of emphysema did not impact on survival 58. 214Prognostic evaluation of CPFE, with particular reference to comparisons between CPFE and isolated IPF, requires quantification of both pulmonary fibrosis and emphysema. This was conducted in two retrospective cohorts of patients with IPF 164. It is likely that the lower rate of FVC decline in CPFE 29 is related to the preservation of volumes by emphysema, especially when admixed with fibrosis 58, rather than to slower progression of fibrosis. Further studies should compare progression of fibrosis using serial HRCT, DLco, CPI, and symptom assessment in patients with or without emphysema.There is no evidence that disease progression, FVC trends apart, differs between patients with IPF who have and do not have emphysema 115, CPI 187, age 27, and the presence of specific co-morbidities such as PH 115 and lung cancer 218. However, the risk of mortality and of developing PH does not differ in patients with both IPF and emphysema compared to those with fibrosis alone when adjusting for severity using baseline DLco or total disease extent on HRCT The pathogenetic mechanisms leading to the coexistence of emphysema with IPF and other fILDs remain unclear. Likewise, it is uncertain whether IPF and non-IPF/ILD are causally linked with emphysema or if they represent different lung disorders running in parallel and sharing some mechanisms.222, supports the notion of a shared pathophysiology. There is bidirectional interaction between emphysema and fibrosis through mechanical forces 225. Many pathways and pathogenetic mechanisms are shared between fibrosis and emphysema, including gene expression and pathways, gene variants, telomere dysfunction and shortening, alveolar alterations, epigenomic reprogramming, and enzymatic activity, especially matrix metalloproteinases  of all eligible studies 3(202. The majority of studies (75%) diagnosed CPFE if there was any emphysema present on chest HRCT, while 25% used a specific threshold: >5% 124, >10% 206, >15% 162, >20% 145, and >25% 151 of total lung volume. Quantitative HRCT was used to evaluate fibrosis extent in 7 studies . Fifty two studies required that emphysema be upper lung predominant, 10 studies included emphysema in all locations, and 34 studies did not specify location criteria. The extent of emphysema was assessed visually in 85/96 studies, with 4 studies using the Goddard method of quantifying emphysema 280, and the remaining 11 studies using quantitative HRCT . Few studies used values from pulmonary function tests to define CPFE.A recent systematic review identified the heterogeneous definitions and diagnostic criteria previously used in 72 previous studies on CPFE studies 3. A diagnResearch in CPFE has primarily been driven by observational studies that have led to an appreciation that CPFE possesses unique clinical, radiologic, and physiologic features. However, a major limitation of previous CPFE research is the heterogeneity of study populations and criteria used to define CPFE, prohibiting direct comparison of different cohorts and validation of key findings.245. A potential approach to reconcile these conflicting priorities is to carefully and transparently define CPFE in a manner that reflects the clinical setting and/or research objectives. For example, studies evaluating prognosis are likely to require separation of IPF and non-IPF patients, while studies evaluating lung physiology may not require such stratification.Both imaging and histopathologic studies indicate that CPFE can encompass a variety of fILDs. IPF and COPD share common risk factors of older age and a history of smoking, resulting in this definition likely capturing the largest and most clinically relevant subgroup of patients with ILD who have concurrent emphysema, while also ensuring a relatively homogeneous population. Allowing CPFE to include a variety of ILD subtypes has the advantage of capturing all patients with these two diseases; however, this approach results in a heterogeneous population that complicates assessment of disease biology that might vary across ILD subtypes. An inclusive definition that encompasses all ILD subtypes can also introduce bias in comparison to control populations given the common risk factors for emphysema (e.g. older age and a history of smoking) that also predispose to some ILD subtypes (most notably IPF). Given its association with smoking, IPF is more frequently associated with emphysema than are CTD-ILD or fHP, even if there is now acceptance that smoking can also cause fibrosis distinct from IPF 127 offers the best opportunity to learn more about the natural history of CPFE and important biological processes that underlie both of these diseases. Future definitions and diagnostic criteria should allow for identification and study of these patients with early disease, particularly when studying biological mechanisms of disease.Furthermore, few studies have quantified the extent of fibrosis and of emphysema on chest HRCT. Automated quantification is challenging when both components are present (see section on imaging), hampering the development of imaging criteria and consistency between studies. Hence, the term CPFE does not specify extent thresholds for either pulmonary fibrosis or emphysema, with some previous studies including patients with any amount of each abnormality, and other studies setting higher thresholds based on supposed clinical relevance. When used, specific extent thresholds are more commonly applied to emphysema than to pulmonary fibrosis. It is also debated as to whether disease extent should be quantified by visual or quantitative methods. The designation of CPFE only if certain thresholds for emphysema and/or fibrosis are exceeded has the advantage of excluding subclinical disease that may be of no or minimal clinical consequence, and selecting subjects who are at risk of outcomes typical of CPFE. Using such thresholds increases specificity for CPFE, but at the expense of excluding patients with lesser extent of either component. Decisions regarding the use of specific thresholds have, thus, been partially driven by the purposes of individual studies, with biological studies on disease mechanisms potentially not needing high severity thresholds, but such thresholds viewed as more appropriate for clinical or physiological studies in which trivial disease is unlikely to have a meaningful impact. Studying patients with early disease research definition for CPFE that will enable future research, and provisional classification criteria of CPFE clinical syndrome intended to serve clinicians managing patients with CPFE , whilst the research definition of CPFE delineates a larger group of patients that should continue to be studied with the ultimate goal of reviewing the syndrome threshold as further clinical and pathogenetic data emerge.The lack of diagnostic criteria and inability to directly compare study populations has hampered the study of the biology, management, and prognosis of CPFE. There is a need to establish specific criteria for CPFE, including standardized and reproducible methods of quantifying both emphysema and fibrosis. The committee proposes a common terminology , a proviith CPFE . TherefoThe committee acknowledged the absence of clear justification to deviate from the entrenched historical term of “CPFE”, recognizing that this is the simplest and broadest label for this group of patients. Similarly, the committee proposes retention of the literal definition of CPFE as the coexistence of both pulmonary fibrosis and emphysema. All subtypes of fILD and emphysema are thus included in the overall CPFE population, but with an important requirement that the fILD subtype be clearly described given the potential biases that can be introduced by including multiple ILDs in this definition. However, it was proposed that studies on CPFE include a comprehensive description of the radiologic and, when available, of the pathological patterns  or the underlying disease when known (e.g. CPFE – fHP or CPFE – RA). This would facilitate comparison between studies through a common terminology, and emphasize the heterogeneity of what can be grouped under the umbrella of CPFE.The most common definition of CPFE is the presence of lung fibrosis and upper-lobe predominant emphysema. The requirement for emphysema in many studies to be upper-lobe predominant minimizes potential confounding by the presence of honeycombing, which is typically lower-lobe predominant and can be difficult to distinguish from paraseptal emphysema. However, the committee proposed that in CPFE, emphysema may be present in other areas of the lung, may be admixed with fibrosis, or may be replaced by thick-walled large cysts greater than 2.5-cm in diameter .29, and 10% being a more commonly used threshold 148. For research purposes, the committee proposed to define CPFE based on emphysema extent ≥ 5% of total lung volume  is required to defined CPFE. The committee, however, recommended that fibrosis extent and emphysema extent should both be assessed in future studies, using visual assessment, and that the association of the study end points with the presence of emphysema above and below thresholds of emphysema extent should be analyzed, as well as their association with patterns of fILD. The committee also emphasized that there should be generally no restriction on the cause of emphysema  or of fILD  unless a study is focused on emphysema of a particular etiology. Future research is required to determine the reproducibility and relevance for research of the CPFE 19, CPFE had been viewed as the coincidental coexistence of IPF and emphysema, with a common linkage to smoking. In 2005, the description of the characteristic functional profile of CPFE in a series of 61 patients 1, taken together with the observation of a high prevalence of PH, provided support for “the individualization of CPFE as a discrete clinical entity apart from both IPF and pulmonary emphysema”. The authors considered that “CPFE was not just a distinct phenotype of IPF, but deserved the terminology of syndrome as a result of the association of symptoms and clinical manifestations, each with a probability of being present increased by the presence of the other” 2. However, no consensus exists on whether CPFE is a syndrome or distinct entity.Current management and future study of CPFE will be facilitated by a clearer understanding of whether this entity has clinical relevance  or if it is biologically unique (pathogenic utility). In early descriptions two coincident diseases); 2) coexistence of two diseases with clinically relevant implications and/or major pathogenetic significance (a syndrome); 3) a single biologically unique entity distinct from both IPF and emphysema (one distinct disease).The committee considered the following options for CPFE: 1) coexistence of two diseases with no clinically relevant implications or major pathogenetic significance  and/or pathogenetic utility . In 2005, Cottin et al proposed CPFE as a discrete entity, arguing that “it deserves the terminology of syndrome as a result of the association of symptoms and clinical manifestations, each with a probability of being present increased by the presence of the other” 2.In a seminal article The main arguments in favor and against CPFE being a syndrome are summarized in There are multiple pathways common to both pulmonary fibrosis and emphysema; however, no primary pathogenetic pathways unique to CPFE have been identified. One argument in favor of CPFE being a syndrome is the clustering of pulmonary fibrosis and emphysema, e.g. that the presence of emphysema on HRCT is more prevalent than expected in several fILDs (see section on pathogenesis). Taken together, these observations suggest that CPFE may result from involvement of shared pathways in at least some patients.141. The pattern of SRIF or AEF may also represent a unique histopathologic pattern of CPFE 180. Much work therefore remains to define CPFE morphologic subtypes and potential identification of signature pathogenetic pathways.However, if CPFE represents a biologically distinct syndrome, it is questionable whether it will be applicable to all patients with CPFE. Despite the phenomenon of clustering of emphysema with pulmonary fibrosis, the two diseases will inevitably co-exist in some patients as coincidental smoking-related processes. The definition of a patient group with a unique pathogenetic pathway, if it exists, is likely to require careful morphologic evaluation of histopathologic and HRCT features. Thick-walled cystic lesions  may represent a unique imaging pattern of CPFE, as they were present histologically in an autopsy study in over 70% of patients with CPFE, but never in patients with either isolated pulmonary fibrosis or isolated emphysema 281.For the present, the acceptance of CPFE as a syndrome is mostly dependent on its perceived clinical utility. The strongest argument is that monitoring of disease progression cannot be reliably based on FVC in patients with CPFE: serial FVC trends, generally viewed as the cardinal monitoring measure in IPF, are less reliable in CPFE-IPF, with a lower prognostic significance than in the remaining IPF patients without emphysema. The high prevalence of lung cancer and PH further supports the designation of CPFE as a syndrome, especially with the perspective of therapeutic consequences 190. In addition, patients with CPFE have a higher risk of lung cancer than those with IPF alone 198.Another approach to address whether the syndrome of CPFE is a distinct condition would be to demonstrate that its outcome differs from that of IPF alone. However, challenges in the diagnosis and quantification of CPFE hamper prognostic evaluation. As discussed above, difficulties comparing outcomes between patients with CPFE and those with fibrosis alone stem from the heterogeneity of CPFE, both for the emphysema and the fILD components, and from the need to quantify both components to adjust for severity of disease when studying outcome. However, in general, additional emphysema alerts the clinician of a greater likelihood of PH and greater mortality than might be expected for a given extent of fILD syndrome based on distinct clinical features and pathogenetic considerations and to facilitate further potentially crucial pathogenetic research. Whether it might correspond to a single biologically unique entity in a proportion of cases warrants further study.Taken in their entirety, the considerations summarized above indicate that CPFE should be considered a 282. Although some have advocated management based on a “treatable traits” approach  284, there are no high-quality data indicating that treatment of emphysema or PH in the context of CPFE improves health outcomes of these patients. Management of CPFE as summarized in There is a paucity of controlled data and no clinical practice guidelines to inform treatment decisions in patients with CPFE 285, and may also have benefits when prescribed only for hypoxemia that occurs during exercise and nocturnally, even in those patients who are normoxemic at rest 286. Regular exercise and pulmonary rehabilitation are recommended for most patients with CPFE 192. Although no studies have evaluated pulmonary rehabilitation in CPFE, pulmonary rehabilitation and regular exercise are a cornerstone of management of patients with emphysema and are increasingly used in patients with fILD. As most exacerbations of both COPD and fILD are thought to be triggered by a respiratory tract infection (either from a virus or bacteria), influenza, pneumococcal, and COVID-19 vaccination are also recommended as per standard intervals, unless contraindicated 288. Referral for consideration of lung transplantation should be made early in the disease course for appropriate patients due to the progressive natural history of CPFE 289, particularly when complicated by PH.Smoking cessation is appropriate in all patients who continue to smoke, as well as avoidance of any other potential inhalational exposures. Supplemental oxygen therapy is recommended in the context of resting hypoxemia 288. Management of pulmonary fibrosis in the setting of CPFE is informed by the landmark clinical trials of nintedanib and pirfenidone 296. Both antifibrotic medications slow progression of mild-to-moderate IPF and other subtypes of progressive pulmonary fibrosis by approximately 50% at 12 months. While patients with significant emphysema (greater than the volume of fibrosis on HRCT) and those with significant airflow obstruction have generally been excluded from these studies, the presence of emphysema in a proportion of patients might have contributed to slow decline in FVC in the placebo arm in CAPACITY 1 291. A subgroup analysis of the IPF INPULSIS trials with nintedanib found no difference in the magnitude of the treatment effect with regards to the presence of mild-to-moderate emphysema 297. Importantly, in the INBUILD trial of nintedanib in fibrotic lung disease other than IPF, progressing despite management 294, the treatment effects were uniform across individual ILDs 298. Therefore, antifibrotic medications may have benefit in IPF patients with CPFE, and in other forms of pulmonary fibrosis with CPFE, progressing despite management. In patients with fILD other than IPF, combined with emphysema, including fHP and CTD-ILD, glucocorticoids and/or immunosuppressive therapy may be beneficial 288. However, there is a need to specifically study CPFE in future trials given its unique physiology. Specifically, the preserved FVC 24 and slower rates of FVC progression 29 indicate that FVC, the traditional endpoint for IPF trials, may be seriously flawed as a primary endpoint in CPFE, as discussed earlier.Decisions about pharmacologic treatment are guided by the underlying diagnosis of fILD 35. Inhaled bronchodilators may have benefit in select patients with CPFE who have significant airflow limitation (ie. COPD)299, and one uncontrolled cohort study has suggested a possible improvement in FEV1 following the use of a combination of inhaled corticosteroid and long-acting bronchodilator 299. Further studies of inhaled bronchodilators with/without corticosteroids are needed in patients with CPFE due to the relatively well-preserved spirometric values 24.Recognition of the individual phenotype of each patient is recommended given the lack of controlled data specific to the treatment of CPFE 300. Bronchoscopic approach with endobronchial valves is generally safer, although no direct comparison with surgery was performed 301. It is uncertain, however, whether removal of emphysematous tissue will lead to improvements or worsening of lung mechanics in those with CPFE.Surgical or bronchoscopic lung volume reduction therapy removes emphysematous tissue, enabling relatively normal tissue to expand; however, most patients with CPFE would be precluded from such procedure given the frequently severe reduction in DLco 115. Controlled data do not support the use of oral PH specific therapies 302, including endothelin receptor antagonists , phosphodiesterase-5 inhibitors , or stimulator of soluble guanylate cyclase (riociguat)303, although uncontrolled observational studies show possible benefit from PH therapies 305, and there are encouraging secondary endpoint trends in trials using sildenafil in IPF 307. Particular caution should be exercised, as treatment with ambrisentan and riociguat may be detrimental in patients with fILD 309 and especially those with CPFE 310. Recently, nebulized treprostinil improved 6-minute walk distance, decreased NT-pro-brain natriuretic peptide levels, improved FVC, and reduced the risk of clinical worsening compared to placebo in patients with ILD and group 3 precapillary PH confirmed by right heart catheterization 311; however, clinical implementation remains limited due to multiple challenges. To date, retrospective data have not demonstrated any survival benefit of PH therapy in patients with CPFE, and further research is required to specifically evaluate these therapies, particularly in those patients with preserved spirometry and “out of proportion PH”.Management of PH in the presence of CPFE is based upon managing the underlying respiratory disorder, treating hypoxemia with supplemental oxygen, and ensuring optimal timing for lung transplant referral 312. Unfortunately, relatively more patients with CPFE are not candidates for various forms of treatment and complication rates are generally higher for those who are treated, with harm likely driven by the combined severity of emphysema and underlying fILD. For example, standard of care cancer treatment could not be instituted in 17% of patients with CPFE and lung cancer due to limitations in treatment directly attributable to CPFE 116.The overall approach to management of lung cancer in CPFE is similar to other populations, with prioritization of surgical resection where possible , multiple additional options considered in other situations , and palliation appropriate for many patients 203, with high rates of acute lung injury 200, acute disease exacerbations 204, and tumor recurrence 201. The risk of treatment-associated acute exacerbation of ILD is of particular concern in patients with CPFE, with increased rates of exacerbation following surgical resection, radiation, and many forms of chemotherapy. Lung-preserving resection options, improved anesthetic considerations, targeted medications, and stereotactic ablative radiotherapy may conceivably all reduce this risk to some extent 312, although there are currently limited direct data to guide risk estimation. Additional studies will continue to test the safety and efficacy of these treatment options in patients with fILD, with these results likely to be generalizable to patients with CPFE.CPFE is a risk factor for post-surgical morbidity and mortality compared to lung cancer without CPFE 29, despite disease progression and a high risk of mortality. The use of DLco is limited by the general functional severity of disease (i.e. floor effect), variability of measurement, and its multiple determinants 313. CPI is not validated as an endpoint. Mortality has been considered impracticable as a primary endpoint 314. Consideration could be given to a composite endpoint . However, composite endpoints are usually driven by, and are only as meaningful as, their least severe component 315. HRCT analysis of fibrosis either using visual methods, or future quantitative computer tools that can discriminate emphysema accurately, and/or blood biomarkers may be particularly useful if validated as endpoints.There have been a limited number of clinical trials on CPFE, in part due to its complicated pathophysiology and the lack of a standardized definition. The potential impact of emphysema (CPFE) on commonly used outcomes in COPD and ILD and the change of these variables over time is uncertain and presents difficulty when considering how to include and study these patients in clinical trials. In particular, the use of FVC as an endpoint is hampered in CPFE by its relative stability 138. Although further study is needed, these limited data may have important implications during the design and execution of future clinical trials.One retrospective series suggesting that change in FEV1 (decline in FEV1 > 10% over 12 months) was the best physiologic predictor of increased risk of mortality in patients with at least moderate CPFE 316, is confounded by concurrent emphysema, has major implications for future IPF trial design 29. In future IPF trials, patients with a significant functional impact from concurrent emphysema are likely to be excluded. The approach taken in the CAPACITY and ASCEND trials of pirfenidone was to exclude patients with obstructive lung disease based on FEV1/FVC ratio < 0.7 or < 0.8, respectively 293. Thus, the effect of pirfenidone on patients with IPF and airflow obstruction is unknown. However, physiology variables are insensitive in excluding patients with emphysema in the setting of IPF 29, and imaging criteria such as extent of emphysema on HRCT may be more appropriate.The observation that serial change in FVC, now the favored primary endpoint in IPF treatment trials 292. A post-hoc analysis found that 39.6% of patients had emphysema (scored yes/no at baseline) and 38.8% had a FEV1/FVC ratio > 0.7 and ≤ 0.8 297. The treatment effect of nintedanib versus placebo was similar between patients with and without emphysema, and when comparing different thresholds of FEV1/FVC  and their association with restrictive lung deficits that can obscure features of airflow obstruction by spirometry 282. Consultation with, or referral to, an ILD specialist may be helpful to determine if the patient is a candidate for ILD specific therapy, although further research is needed to better understand the optimal treatment of this patient population. In general, the presence of emphysema is associated with a worse outcome and a greater likelihood of PH than might be expected for a given extent of ILD. Future research is also needed for the evaluation of lung cancer risk in this population. While both IPF and COPD increase the risk for lung cancer compared to the general population, lung cancer risk for patients with CPFE (or ILAs and emphysema) may be elevated beyond emphysema or IPF alone 198. Such patients also have generally poor prognosis 198.After identifying CPFE, additional history and diagnostic testing may be warranted as outlined in this document, similar to what is appropriate in patients with isolated ILD The CPFE taskforce committee identified several gaps in our knowledge that need to be addressed, including: 1) to understand the pathogenetic mechanisms in CPFE; 2) to understand the pathobiology, disease behavior, and natural history of CPFE; 3) to improve methods that allow an early diagnosis; and 4) to evaluate potential therapeutic opportunities. Questions and statements identifying some of the topics that were considered important for research are listed in CPFE is characterized by a wide variety of appearances and patterns on chest HRCT and when available on histopathology. Clustering of pulmonary fibrosis and emphysema (regardless of the type of fILD), the frequency of associated comorbidities and complications especially PH and lung cancer, the relevance for disease progression monitoring, and the involvement of pathogenetic pathways shared by both components, suggest that CPFE should be considered a syndrome. Despite numerous case series and studies, many important questions remain unanswered. This ATS/ERS/JRS/ALAT Research Statement offers research definition and classification criteria and identifies major research priorities that will better delineate this entity, understand its pathogenesis, and guide its management.Supplemenary data