RATIONALE:Familial pulmonary fibrosis (FPF), defined as fibrosing interstitial lung disease (ILD) affecting two or more family members, is associated with earlier-onset and a more aggressive disease phenotype. Imaging findings may vary between relatives, complicating diagnosis. While genetic testing exists, it is limited by accessibility and the rarity of monogenic causes. Patient-reported family history may serve as a valuable adjunct prognostic marker. OBJECTIVES:This study aimed to characterize the clinical and radiological features of patients with FPF using a multicenter ILD registry. We compared lung function and transplant-free survival between patients with FPF and sporadic ILD, overall and by radiologic pattern. METHODS:The multicenter Canadian Registry for Pulmonary Fibrosis includes patients with fibrotic ILD. Demographics, forced vital capacity (FVC%), diffusion capacity for carbon monoxide (DLCO%), and death or lung transplant data were collected. Family history was determined via physician or patient documentation. A subset underwent re-evaluation where baseline radiologic features and patterns were described. Statistical comparisons used chi-square tests, Cox proportional hazards, omnibus test and mixed models to assess outcomes. RESULTS:Of 5375 patients, 719 (13%) had FPF. Demographics were similar between FPF and sporadic ILD. When grouping idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis and unclassifiable ILD together, those with FPF were younger (P < .001), more likely female (P < .001), less likely to have smoked (P = .007), and had higher baseline DLCO% (P < .001). Antifibrotics were more often prescribed to FPF patients with fibrotic hypersensitivity pneumonitis, unclassifiable ILD, and systemic autoimmune rheumatic disease-ILD versus their sporadic counterparts. The mean annual rate of FVC% decline was greater in patients with FPF compared to those with sporadic ILD (P = .024). FPF more frequently received referral for transplant (P < .001), but transplant-free survival did not differ between FPF and sporadic disease. In the radiologic cohort (n = 1519) those with FPF had a higher likelihood of radiologic usual interstitial pneumonia than those with sporadic ILD (P = .004). CONCLUSIONS:FPF accounts for a meaningful proportion of ILD cases and exhibits distinct clinical features in certain disease subtypes. Although survival outcomes were similar in this study, earlier onset and accelerated progression highlight the need for refined diagnostic and prognostic approaches to familial disease.

BACKGROUND:Combined pulmonary fibrosis and emphysema (CPFE) is an important phenotype in patients with fibrotic interstitial lung disease (ILD). RESEARCH QUESTION:What is the prevalence of CPFE? What is the predictive performance of the CPFE index and of physiologic airflow obstruction for CT imaging emphysema extents? Is the extent of emphysema on CT imaging associated with outcomes in patients with fibrotic ILD? STUDY DESIGN AND METHODS:Consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who underwent a standardized visual assessment of the baseline high-resolution CT imaging of the chest from a prospective registry were included. CPFE was defined as emphysema extent of ≥ 15% on CT imaging, with sensitivity analyses using different thresholds: ≥ 5%, ≥ 10%, and ≥ 20%. Emphysema subtypes were categorized based on their predominant distribution: centrilobular, paraseptal, or panlobular. The CPFE index was derived using measurements of spirometry and diffusion capacity of the lungs for CO2. RESULTS:The prevalence of CPFE at baseline was 20% for IPF (92/455) and 7% in non-IPF fibrotic ILD (84/1121). Both FEV1 to FVC ratio less than the lower limit of normal and < 0.70 showed poor sensitivity (IPF, 11.1%-18.9%; non-IPF fibrotic ILD, 13.1%-23.7%) for detecting emphysema on CT imaging, although high specificity (IPF, 96.2%-98.8%; non-IPF fibrotic ILD, 92.8%-95.8%). The CPFE index was correlated moderately with extent of emphysema on CT imaging in both IPF (r = 0.48) and non-IPF fibrotic ILD (r = 0.41), but with poor agreement and wide limits of agreement on Bland-Altman analysis. Extent of emphysema on CT imaging of ≥ 20% was associated consistently with differences in lung function trajectories and worse transplant-free survival in IPF and non-IPF fibrotic ILD. No significant relationships were noted between emphysema subtypes and health outcomes. INTERPRETATION:Our results show that coexisting emphysema is important in both IPF and non-IPF fibrotic ILD, with extent of emphysema on CT imaging of ≥ 20% being associated with worse health outcomes. Both physiologic and radiologic assessments are needed to identify coexistent emphysema in patients with fibrotic ILD.

BACKGROUND:Currently available pharmacotherapies for interstitial lung disease (ILD) are limited to systemic glucocorticoids, steroid-sparing immunosuppressive medications and antifibrotic medications. Each of these treatments target major components of ILD biology. OBJECTIVE:This review presents the relevant evidence to the pharmacological management of ILD that is based on a treatable traits approach. We further highlight major knowledge gaps that should be the focus of future research that moves patient care toward a more precision-medicine approach. SUMMARY OF REVIEW:The previous treatment paradigm for the pharmacotherapy of ILD is based on the integration of several clinical, laboratory, radiological and pathological features to an underlying biology that is more likely to respond to a given medication strategy. Patients with more acute presentations and suggestion of significant inflammation are typically treated with systemic glucocorticoid therapy, with the route and initial dose decided primarily based on the severity of disease. Patients with ILD who have chronic disease with suggestion of inflammatory features are typically treated with long-term steroid-sparing immunosuppression. Patients with ILD who have chronic disease with progressive fibrotic features are typically treated with antifibrotic medication. Emerging therapies include nerandomilast, a phosphodiesterase 4B inhibitor with antifibrotic and immunomodulatory effects that has recently been approved in the USA. A major goal is future integration of molecular endotypes to support a transition towards precision-based management of ILD. CONCLUSIONS:Pharmacotherapy of ILD has previously focused on a morphology-based treatable traits approach that uses various clinical, laboratory, radiological and pathological clues to suggest a preferred treatment. We describe this approach and highlight specific questions that need to be addressed in future studies as we move toward a precision-based approach to patient management.

Extent of fibrosis, defined by the amount of honeycombing and traction bronchiectasis, was consistently associated with death or lung transplant across all interstitial lung disease subtypes in a dose-dependent fashion.

Rationale: Guidelines have defined a "typical hypersensitivity pneumonitis (HP)" imaging pattern for fibrotic HP (fHP); however, the frequency, characteristics, and outcomes of different multidisciplinary diagnoses within this pattern are unknown. Objectives: The goal of this study was to describe the frequency at which different multidisciplinary diagnoses present with a typical fHP pattern and to identify clinically relevant differences across these diagnoses. Methods: Patients with a typical fHP pattern on chest computed tomography (CT) were identified from a prospective registry. Multidisciplinary diagnoses were established by consensus during a research-dedicated standardized multidisciplinary discussion of all available data. Prespecified diagnostic categories of interest included fHP with an exposure identified, fHP without an exposure identified, and connective tissue disease-associated interstitial lung disease (CTD-ILD), with each diagnosis defined by >50% likelihood after this structured multidisciplinary discussion. Clinical and radiological features and outcomes were compared across multidisciplinary diagnoses. Measurements and Main Results: Of 164 patients with CT patterns of typical fHP, 49 had multidisciplinary diagnoses of fHP with probable or possible exposures identified (30%), 56 had fHP without exposures identified (34%), 36 had CTD-ILD (22%), and 23 had other multidisciplinary diagnoses (14%). Clinical and CT features differed across multidisciplinary diagnoses. Lung function decline and time to death or transplantation were worse in patients with fHP without probable or possible exposures. Positive autoimmune serologies or new rheumatologist-confirmed CTD diagnoses developed in 14% of patients with fHP without exposures identified during follow-up. Conclusions: Patients with a typical fHP pattern on chest CT frequently have non-HP diagnoses (most often CTD-ILD), have differences in baseline characteristics and disease behavior across multidisciplinary diagnoses, and more frequently develop features of CTD during follow-up when an initial HP exposure is not identified.

Rationale Familial pulmonary fibrosis (FPF) is defined by two or more family members within the same family being affected by interstitial lung disease (ILD). It has been found that patients with FPF may present earlier and with a more aggressive phenotype than other ILD patients. Patient-reported family history may be used as an adjunct prognostic marker, as patient-reported family history predicts reduced transplant free survival and performs well to identify at-risk individuals, even in the absence of predisposing genetic variants. The objective of this study was to characterize the prevalence, characteristics and prognosis of FPF from a large, multicenter national ILD registry. Methods The Canadian Registry for Pulmonary Fibrosis is a prospective, multicentre ILD registry. All patients with ILD (idiopathic pulmonary fibrosis (IPF), connective tissues disease ILD (CTD-ILD), hypersensitivity pneumonitis (HP), unclassifiable ILD, and other ILDs) were eligible for inclusion. Family history was ascertained by patient questionnaire or physician documentation, kinship was not recorded. In a subset, baseline CT scans were scored for radiologic patterns, blinded to clinical data. Continuous variables are presented as mean ± standard deviation (SD). Death and transplant free survival were evaluated using mixed effects Cox regression model, adjusted for age, sex, smoking, baseline lung function, and treatment. Categorical variables were analyzed using Pearson's chi-square test. Results Of 5454 eligible patients 731 (13%) had patient or physician reported FPF (Table 1). In IPF, HP and unclassifiable ILD, familial versus sporadic ILD was associated with an earlier age at diagnosis. Compared to sporadic IPF, patients with familial IPF were more likely to be female (p<0.001), never smokers (p=0.001) and be referred for lung transplant assessment (p=0.024). Physician reported FPF was associated with increased mortality in adjusted models (HR 1.33, 95%CI 1.09 to 1.62). Of the 1519 participants with radiologic data, 197 (15%) had FPF. Radiologist defined NSIP (p<0.001) and UIP (p=0.014) were more common in FPF compared to sporadic ILD. Conclusions In this multicentre registry, FPF was prevalent in 13% of registry participants and was associated with specific clinical characteristics, including sex, earlier age at diagnosis and a higher likelihood of non-smoking status, and prognosis including mortality. These findings emphasize the importance of ascertaining family history in ILD assessments, as it may offer valuable insights for identifying at-risk individuals and refining management strategies. Further research is warranted to investigate the genetic and environmental factors contributing to FPF and its varied phenotypic presentations.

Transbronchial cryobiopsies (CB) are increasingly replacing surgical biopsies (video-assisted thoracoscopic/VATS biopsies) for diagnosing diffuse parenchymal lung disease (interstitial lung disease, ILD), but there is very little guidance for pathologists on CB interpretation. Here we propose a fairly simple approach. First, if the diagnosis can be made on a traditional forceps biopsy, it can be made on a cryobiopsy. Many diseases with specific features will fall into this category (eg, sarcoidosis or Langerhans cell histiocytosis). More problematic are patterns such as usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP), in which low-power architecture is the key to diagnosis. In this circumstance, an adequate sample is crucial to look for features such as fibroblast foci, because a combination of fibroblast foci plus any patchy old fibrosis, fibrotic architectural remodeling, or honeycombing, allows a diagnosis of a UIP pattern. However, in most instances, CB will not separate the UIP patterns seen in idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis, or connective tissue disease-interstitial lung disease (CTD-ILD), although giant cells/granulomas (uncommon findings) in this setting favor fibrotic hypersensitivity pneumonitis. Fibroblast foci can be difficult to differentiate from organizing pneumonia (OP), but granulation tissue plugs clearly in airspaces favor OP. Absent fibroblast foci, patchy old fibrosis, architectural distortion, and honeycombing by themselves do not allow a specific diagnosis. NSIP in CB microscopically looks like NSIP in VATS biopsies, and the presence of an NSIP or an NSIP+OP pattern is typical of CTD-ILD. All the above diagnoses require correlation with clinical and radiologic findings.

AimTransbronchial cryobiopsies are increasingly used for the diagnosis of interstitial lung disease (ILD), but there is a lack of published information on the features of specific ILD in cryobiopsies. Here we attempt to provide pathological guidelines for separating usual interstitial pneumonia (UIP) of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease‐associated ILD (CTD–ILD) in cryobiopsies.MethodsWe examined 120 cryobiopsies from patients with multidisciplinary discussion (MDD)‐established CTD–ILD and compared them to a prior series of 121 biopsies from patients with MDD‐established IPF or FHP.ResultsA non‐specific interstitial pneumonia (NSIP) pattern alone was seen in 36 of 120 (30%) CTD–ILD, three of 83 (3.6%) FHP and two of 38 (5.2%) IPF cases, statistically favouring a diagnosis of CTD–ILD. The combination of NSIP + OP was present in 29 of 120 (24%) CTD–ILD, two of 83 (2.4%) FHP and none of 38 (0%) IPF cases, favouring a diagnosis of CTD–ILD. A UIP pattern, defined as fibroblast foci plus any of patchy old fibrosis/fibrosis with architectural distortion/honeycombing, was identified in 28 of 120 (23%) CTD–ILD, 45 of 83 (54%) FHP and 27 of 38 (71%) IPF cases and supported a diagnosis of FHP or IPF. The number of lymphoid aggregates/mm2 and fibroblast foci/mm2 was not different in IPF, CTD–ILD or FHP cases with a UIP pattern. Interstitial giant cells supported a diagnosis of FHP or CTD–ILD over IPF, but were infrequent.ConclusionsIn the correct clinical/radiological context the pathological findings of NSIP, and particularly NSIP plus OP, favour a diagnosis of CTD–ILD in a cryobiopsy, but CTD–ILD with a UIP pattern, FHP with a UIP pattern and IPF generally cannot be distinguished.

Objectives Interstitial lung disease (ILD) in CTDs has highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality, and immunosuppression response.Methods Patients with CTD-ILD had high-resolution chest CT (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern [usual interstitial pneumonia (UIP); non-specific interstitial pneumonia (NSIP); organizing pneumonia (OP); fibrotic hypersensitivity pneumonitis (fHP); and other]. Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed-effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment.Results Among 645 CTD-ILD patients, the most frequent CTDs were SSc (n = 215), RA (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with the case for patients with UIP, FVC decline was slower in patients with NSIP (by 1.1%/year, 95% CI 0.2, 1.9) or OP (by 3.5%/year, 95% CI 2.0, 4.9), and mortality was lower in patients with NSIP [hazard ratio (HR) 0.65, 95% CI 0.45, 0.93] or OP (HR 0.18, 95% CI 0.05, 0.57), but higher in fHP (HR 1.58, 95% CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95% CI 1.4, 2.8), with no change for UIP or fHP.Conclusion Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP.

BACKGROUND: Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without di-rection on whether or how to apply these approaches concurrently within a single patient.RESEARCH QUESTION: How can we integrate guideline-defined radiologic patterns to diagnose interstitial lung disease (ILD) and what are the pitfalls associated with described patterns that require reassessment in future guidelines?STUDY DESIGN AND METHODS: Patients from the Canadian Registry for Pulmonary Fibrosis underwent detailed reevaluation in standardized multidisciplinary discussion. CT scan fea-tures were quantified by chest radiologists masked to clinical data, and guideline-defined patterns were assigned. Clinical data then were provided to the radiologist and an ILD clinician, who jointly determined the leading diagnosis.RESULTS: Clinical-radiologic diagnosis in 1,593 patients was idiopathic pulmonary fibrosis (IPF) in 26%, fHP in 12%, connective tissue disease-associated ILD (CTD-ILD) in 34%, idiopathic pneumonia with autoimmune features in 12%, and unclassifiable ILD in 10%. Typical and probable UIP patterns corresponded to a diagnosis of IPF in 66% and 57% of patients, respectively. Typical fHP pattern corresponded to an fHP clinical diagnosis in 65% of patients, whereas compatible fHP was nonspecific and associated with CTD-ILD or IPAF in 48% of patients. No pattern ruled out CTD-ILD. Gas trapping affecting > 5% of lung parenchyma on expiratory imaging was an important feature broadly separating compatible and typical fHP from other patterns (sensitivity, 0.77; specificity, 0.91).INTERPRETATION: An integrated approach to guideline-defined UIP and fHP patterns is feasible and supports > 5% gas trapping as an important branch point. Typical or probable UIP and typical fHP patterns have moderate predictive values for a corresponding diagnosis of IPF and fHP, although occasionally confounded by CTD-ILD; compatible fHP is nonspecific.

Background Prognosis in connective tissue disease associated interstitial lung disease (CTD-ILD) is influenced by the underlying diagnosis and chest imaging pattern. Usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), and fibrotic hypersensitivity pneumonitis (fHP) patterns can be found across all CTD-ILD subtypes although their impact on disease evolution and treatment response is unclear. Objectives Our goal was to examine the association of lung imaging pattern with CTD-ILD progression, mortality, and immunosuppression response. Methods 615 patients with CTD-ILD enrolled in the Canadian Registry for Pulmonary Fibrosis had high-resolution chest computed tomography (HRCT) from their first ILD clinic visit reviewed in standardized multidisciplinary discussion. All CTD diagnoses were rheumatologist-confirmed. Experienced chest radiologists blinded to clinical data categorized each case into five groups: UIP, NSIP, organizing pneumonia (OP), fHP, and other patterns. Longitudinal percent-predicted forced vital capacity (FVC) and transplant-free survival were compared between imaging groups using linear mixed effects and Cox proportional hazards models adjusted for age, sex, smoking pack-years, and baseline FVC. Linear mixed effects models were used to compare pre- and post-treatment rate of FVC decline in patients with ≥6 months follow-up before and after treatment with mycophenolate, azathioprine, rituximab, cyclophosphamide, and/or tocilizumab. UIP was the reference group for all comparisons. Results The most frequent CTD subtypes were systemic sclerosis (SSc) (33%), rheumatoid arthritis (RA) (20%), and idiopathic inflammatory myopathy (IIM) (16%) with NSIP pattern present in 54% of all CTD-ILD (Table 1). On multivariable analyses among all CTD-ILD patients, NSIP was associated with a slower rate of FVC decline by 1.1%/year (0.2, 1.9) and a lower mortality HR (95%CI) of 0.65 (0.45, 0.93) compared to UIP. OP was also associated with a slower rate of FVC decline by 3.5%/year (2.0, 4.9) and a lower mortality HR (95%CI) of 0.18 (0.05, 0.57) compared to UIP. In contrast, fHP had a higher mortality HR (95%CI) of 1.58 (1.01, 2.40). The rate of FVC decline after treatment was not significantly different compared to pre-treatment in the UIP group but was slower in the NSIP group by 2.1%/year (1.4, 2.8). Subgroup analyses in RA-ILD and SSc-ILD showed the persistence of fHP having a higher mortality compared to UIP in RA-ILD. Conclusion The presence of an NSIP pattern was associated with improved outcomes and immunosuppression response compared to UIP in the overall CTD-ILD group. The findings of fHP associated with worse survival compared to UIP in CTD-ILD and in the RA-ILD are novel. These findings need to be further confirmed in disease specific cohorts and randomized trials of immunosuppression in patients with CTD-ILD. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests Boyang Zheng: None declared, Daniel-Costin Marinescu: None declared, cameron hague: None declared, Nestor Muller: None declared, darra murphy: None declared, Andrew Churg: None declared, Joanne Wright: None declared, Amna Al-Arnawoot: None declared, Ana-Maria Bilawich: None declared, patrick bourgouin: None declared, Gerald Cox: None declared, celine durand: None declared, Tracy Elliot: None declared, Jen Ellis: None declared, Jolene Fisher Consultant of: Boehringer-Ingelheim, AstraZeneca, Derek Fladeland: None declared, Amanda Grant-Orser: None declared, Gillian Goobie Grant/research support from: Boehringer Ingelheim, Zachary Guenther: None declared, Ehsan Haider: None declared, Nathan Hambly Speakers bureau: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Janssen, Roche, James Huynh: None declared, Kerri Johannson Consultant of: Boehringer-Ingelheim, Hoffman-La Roche Ltd, geoff karjala: None declared, Nasreen Khalil: None declared, Martin Kolb Speakers bureau: Roche, Novartis, Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Pieris, Roche, Jonathon Leipsic Speakers bureau: GE Healthcare, Philips Healthcare, Stacey Lok Speakers bureau: Boehringer Ingelheim, sarah macisaac: None declared, micheal mcinnis: None declared, Helene Manganas Grant/research support from: Boehringer Ingelheim Canada, Hoffmann La Roche, Galapagos, BMS, Veronica Marcoux Grant/research support from: Astra Zeneca,Roche,Boehringer Ingelheim, John Mayo: None declared, julie morisset Speakers bureau: Roche, Boehringer Ingelheim, Ciaran Scallan: None declared, Tony Sedlic: None declared, shane shapera Consultant of: AstraZeneca, Boehringer Ingelheim, Hoffman LaRoche, Kelly Sun: None declared, victoria tan: None declared, Alyson Wong: None declared, Christopher Ryerson Speakers bureau: Boehringer Ingelheim, Hoffmann-La Roche, Astra Zeneca, Consultant of: Boehringer Ingelheim, Hoffmann-La Roche, Astra Zeneca.

Transbronchial cryobiopsy (TBCB) is increasingly used for the diagnosis of fibrosing interstitial pneumonias, but there are few detailed descriptions of the pathologic findings in such cases. It has been proposed that a combination of patchy fibrosis and fibroblast foci with an absence of alternative features is diagnostic of usual interstitial pneumonia (UIP; ie, idiopathic pulmonary fibrosis [IPF]) in TBCB. In this study, we reviewed 121 TBCB in which a diagnosis of fibrotic hypersensitivity pneumonitis (FHP; n = 83) or IPF (n = 38) was made by multidisciplinary discussion and evaluated a range of pathologic features. Patchy fibrosis was found in 65 of 83 (78%) biopsies from FHP and 32of 38 (84%) biopsies from UIP/IPF cases. Fibroblast foci were present in 47 of 83 (57%) FHP and 27 of 38 (71%) UIP/IPF cases. Fibroblast foci/patchy fibrosis combined did not favor either diagnosis. Architectural distortion was seen in 54 of 83 (65%) FHP and 32 of 38 (84%) UIP/IPF cases (odds ratio [OR] for FHP, 0.35; P = .036) and honeycombing in 18 of 83 (22%) and 17 of 38 (45%), respectively (OR, 0.37; P = .014). Airspace giant cells/granulomas were present in 13 of 83 (20%) FHP and 1 of 38 (2.6%) UIP/IPF cases (OR for FHP, 6.87; P = .068), and interstitial giant cells/granulomas in 20 of 83 (24%) FHP and 0 of 38 (0%) UIP/IPF (OR, 6.7 x 106; P = .000). We conclude that patchy fibrosis plus fibroblast foci can be found in TBCB from both FHP and UIP/IPF. The complete absence of architectural distortion/honeycombing favors a diagnosis of FHP, as does the presence of airspace or interstitial giant cells/granulomas, but these measures are insensitive, and many cases of FHP cannot be separated from UIP/IPF on TBCB.

Background Bronchoalveolar lavage (BAL) cellular analysis is often recommended during the initial diagnostic evaluation of fibrotic ILD. Despite recommendation for its use, between-center heterogeneity exists and supportive data concerning the clinical utility and correlation of BAL findings with radiologic features or patterns remains sparse. Research Question In patients with fibrotic ILD, are BAL findings associated with radiologic features, patterns, and clinical diagnoses? Methods Patients with fibrotic ILD who underwent BAL for diagnostic evaluation and enrolled in the prospective Canadian Registry for Pulmonary Fibrosis were re-reviewed in a standardized multidisciplinary discussion (MDD). BAL was categorized according to guideline-recommended thresholds, and also using thresholds of lymphocytosis>20% and neutrophils>4.5%. High-resolution computed tomography (HRCT) scans were scored (blinded to clinical data) for specific features and percentage lung involvement. Radiologists classified HRCTs according to guideline-defined patterns for idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP), then MDD diagnoses were assigned, considering all available data. Results Bronchoscopy with cellular analysis was performed in 209/1593 (13%) patients. Lymphocyte% was weakly negatively correlated with total fibrosis% (r=-0.16, p=0.023) but not statistically significantly correlated with ground glass opacity% (r=0.01, p=0.94). A mixed BAL pattern was the most frequent in all radiologic patterns (range 45% to 69%), with a minority classifiable according to BAL guidelines. BAL lymphocytosis appeared with similar frequency across HRCT patterns of fHP (21%) and UIP (18%). Only 5% of patients with MDD-based fHP had a guideline defined isolated lymphocytosis >15%. Interpretation BAL cellular analyses did not significantly correlate with radiologic features, guideline patterns, or MDD-based diagnoses. Ground glass opacities are often interpreted to represent pulmonary inflammation, but were not associated with BAL lymphocytosis in this cohort.

BackgroundLung imaging findings vary among subtypes of connective tissue disease-associated interstitial lung disease (CTD-ILD), leading to both diagnostic and therapeutic challenges.ObjectivesWe performed a comprehensive assessment of ILD morphology across CTD-ILD subtypes by examining the presence of overall imaging patterns and specific morphological features.MethodsHigh-resolution chest computed tomography (HRCT) of patients with CTD-ILD enrolled in the multicentre Canadian Registry for Pulmonary Fibrosis from their first ILD clinic visit were re-reviewed in standardized multidisciplinary discussion. All CTD diagnoses were rheumatologist-confirmed. An experienced chest radiologist blinded to clinical data quantified the percentage of lung parenchyma affected by honeycombing, reticulation, ground glass opacity (GGO), hypoattenuating lobules, consolidation, and emphysema. Gas trapping was evaluated on expiratory CT. Each case was categorized into an overall disease pattern including usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), fibrotic hypersensitivity pneumonitis (fHP), lymphocytic interstitial pneumonia (LIP), and unclassifiable.Results615 patients with CTD-ILD were assessed with 215 (33%) having systemic sclerosis (SSc), 127 (20%) rheumatoid arthritis (RA), 100 (16%) idiopathic inflammatory myopathy (IIM), 61 (9%) mixed connective tissue disease (MCTD), 40 (6%) Sjogren’s syndrome (SS), 19 (3%) lupus (SLE), and 83 (13%) undifferentiated connective tissue disease (UCTD). NISP was most predominant in SSc (76%), IIM (62%), and MCTD (66%), while UIP was most common in RA (47%) and SS (33%). A fHP pattern was most common in RA (15%), SLE (21%), and MCTD (12%) (Figure 1a). There was substantial variability in the extent of fibrotic (honeycombing, reticulations) and non-fibrotic (pure GGO, consolidation) parenchymal features within and across each CTD (Figure 1b).ConclusionThere is considerable variation in imaging features across subtypes of CTD-ILD, with NSIP generally most common, UIP most frequent in RA and SS, and fHP less frequent but most common in RA, SLE, and MCTD. This variability highlights the need for additional data on management of CTD-ILD that considers the potential for variable treatment responses across major CTD-ILD subtypes and phenotypes.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsBoyang Zheng: None declared, Daniel-Costin Marinescu: None declared, cameron hague: None declared, Nestor Muller: None declared, darra murphy: None declared, Andrew Churg: None declared, Joanne Wright: None declared, Amna Al-Arnawoot: None declared, Gerald Cox: None declared, Zachary Guenther: None declared, Amanda Grant-Orser: None declared, James Huynh: None declared, Tracy Elliot: None declared, Derek Fladeland: None declared, Jen Ellis: None declared, geoff karjala: None declared, Gillian Goobie Grant/research support from: Boehringer Ingelheim. Pulmonary Fibrosis Foundation, Kerri Johannson Paid instructor for: Boehringer-Ingelheim, Hoffman-La Roche Ltd, Consultant of: Boehringer-Ingelheim, Hoffman-La Roche Ltd, Pliant Therapeutics, Stacey Lok Speakers bureau: Boehringer Ingelheim, Tony Sedlic: None declared, Nasreen Khalil: None declared, Veronica Marcoux Grant/research support from: Astra Zeneca, Roche, Boehringer Ingelheim, Martin Kolb Speakers bureau: Roche, Novartis, Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Pieris, Roche, Ciaran Scallan: None declared, Nathan Hambly Speakers bureau: Boehringer Ingelheim, Janssen, Roche, Grant/research support from: Boehringer Ingelheim, Janssen, Roche, sarah macisaac: None declared, Jonathon Leipsic Speakers bureau: GE Healthcare, Philips Healthcare, victoria tan: None declared, celine durand: None declared, Helene Manganas Grant/research support from: Boehringer Ingelheim Canada, Hoffmann La Roche, Galapagos, BMS, Ehsan Haider Speakers bureau: Boerhinger Ingelheim, Jolene Fisher Speakers bureau: Boehringer-Ingelheim, Consultant of: Boehringer-Ingelheim, AstraZeneca, micheal mcinnis: None declared, shane shapera Consultant of: AstraZeneca, Boehringer Ingelheim, Hoffman LaRoche, Ana-Maria Bilawich: None declared, John Mayo: None declared, patrick bourgouin: None declared, julie morisset Speakers bureau: Roche, Boehringer Ingelheim, Kelly Sun: None declared, Alyson Wong: None declared, Christopher Ryerson Speakers bureau: Boehringer Ingelheim, Hoffmann-La Roche, Astra Zeneca, Consultant of: Boehringer Ingelheim, Hoffmann-La Roche, Astra Zeneca.

Recent clinical practice guidelines have addressed the diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). These disease-specific guidelines were developed independently, without clear direction on how to apply their respective recommendations concurrently within a single patient, where discrimination between these two fibrotic interstitial lung diseases represents a frequent diagnostic challenge. The objective of this review, created by an international group of experts, was to suggest a pragmatic approach on how to apply existing guidelines to distinguish IPF and fHP. Key clinical, radiologic, and pathologic features described in previous guidelines are integrated in a set of diagnostic algorithms, which then are placed in the broader context of multidisciplinary discussion to guide the generation of a consensus diagnosis. Although these algorithms necessarily reflect some uncertainty wherever strong evidence is lacking, they provide insight into the current approach favored by experts in the field based on currently available knowledge. The authors further identify priorities for future research to clarify ongoing uncertainties in the diagnosis of fibrotic interstitial lung diseases.

To the Editor.—Although many pulmonologists are adopting transbronchial cryobiopsy, there is a remarkable dearth of information on the specific pathologic features used to diagnose various forms of interstitial lung disease in such specimens. Cooper et al1 have recently published pathologic criteria for usual interstitial pneumonia (UIP); they suggest that the combination of fibroblast foci and patchy fibrosis, along with the absence of features suggesting an alternative diagnosis, strongly support a diagnosis of UIP in a cryobiopsy.We2 reported in Archives of Pathology & Laboratory Medicine an in-silico exercise in which we created “cryobiopsies” by outlining multiple circles on the pathology slides of 15 video-assisted thoracoscopic surgery (VATS) biopsies from cases that had been given a 60% or greater probability of fibrotic hypersensitivity pneumonitis (fibrotic HP) during a specialty devised multidisciplinary discussion exercise.3 We found a low probability of detecting granulomas or giant cells, features acknowledged to be markers in this context of fibrotic HP and not UIP. However, the probability of finding peribronchiolar metaplasia affecting 50% or greater of bronchioles, a feature that also supports a diagnosis of fibrotic HP,3 was considerably higher, and the frequency of these features within an individual case generally increased with increasing numbers of “cryobiopsies.”Here, we went back to our previously used VATS biopsy slides and asked whether the features described by Cooper et al1 as favoring a diagnosis of UIP could be found in our fibrotic HP-derived “cryobiopsies.” We used the same “cryobiopsies” previously selected for analysis of granulomas/giant cells and peribronchiolar metaplasia, and counted the number of samples showing fibroblast foci, and patchy fibrosis in 1 to 8 “cryobiopsies” for each case; these features had not been evaluated in our previous study.2 For comparison, the total biopsy area of 86.4 mm2 for 4 of our “cryobiopsies” is identical to the mean total area of 87 mm2 reported in the COLDICE study.4Results are shown in the Table. Fibroblast foci were frequently found, from 8 of 15 (53%) cases if a single “cryobiopsy” was evaluated for each case, to 12 of 15 (80%) if 4 biopsies were evaluated, and 12 of 13 (92%) with 8 biopsies (2 cases did not have enough VATS biopsy area to create 8 “cryobiopsies”). Patchy fibrosis ranged from 4 of 15 (27%) single biopsies, to 8 of 15 (53%) with 4 biopsies, and 12 of 13 (92%) with 8 biopsies. The combination of fibroblast foci and patchy fibrosis was found in 1 of 15 (6.7%) cases with a single biopsy and increased to 7 of 15 (47%) cases when 4 biopsies were reviewed and 10 of 13 (77%) with 8 biopsies, suggesting the potential to misclassify almost half of fibrotic HP biopsies as UIP with 4 biopsies and the majority of patients with 8 biopsies using these criteria alone. This situation is improved by also looking for giant cells/granulomas or peribronchiolar metaplasia affecting more than 50% of bronchioles, but still leaves a significant number of fibrotic HP cases misclassified as UIP (Table).This is obviously a small series that uses a somewhat artificial system. Nonetheless, these data emphasize the idea that a combination of fibroblast foci and patchy fibrosis is a feature not only of UIP but also of fibrotic HP, and used by themselves, these features will lead to misclassification of a proportion of fibrotic HP cases as UIP.Although it may be surprising to nonspecialist pathologists (and to many clinicians), the exact pathologic features that define UIP, even in VATS biopsies, are not universally agreed upon, as discussed in detail in 2 recent position papers,5,6 and this is a problem that needs to be addressed. That being so, it is even harder to determine the features that should be used to separate conditions, such as fibrotic HP, which often have considerable morphologic overlap with UIP.Granulomas/giant cells are generally accepted as features against a diagnosis of UIP; extensive peribronchiolar metaplasia, in our view, favors fibrotic HP,3 and fibrosis that is predominantly peribronchiolar rather than subpleural also is in favor of fibrotic HP. But how to quantify and apply these criteria to actual cryobiopsies, and where one draws the line between UIP and fibrotic HP in such biopsies, is an important unanswered question, a problem also acknowledged by Cooper et al.1

Sarcomatoid mesothelioma is an aggressive malignancy that can be challenging to distinguish from benign spindle cell mesothelial proliferations based on biopsy, and this distinction is crucial to patient treatment and prognosis. A novel deep learning based classifier may be able to aid pathologists in making this critical diagnostic distinction. SpindleMesoNET was trained on cases of malignant sarcomatoid mesothelioma and benign spindle cell mesothelial proliferations. Performance was assessed through cross-validation on the training set, on an independent set of challenging cases referred for expert opinion (‘referral’ test set), and on an externally stained set from outside institutions (‘externally stained’ test set). SpindleMesoNET predicted the benign or malignant status of cases with AUC's of 0.932, 0.925, and 0.989 on the cross-validation, referral and external test sets, respectively. The accuracy of SpindleMesoNET on the referral set cases (92.5%) was comparable to the average accuracy of 3 experienced pathologists on the same slide set (91.7%). We conclude that SpindleMesoNET can accurately distinguish sarcomatoid mesothelioma from benign spindle cell mesothelial proliferations. A deep learning system of this type holds potential for future use as an ancillary test in diagnostic pathology.