Lung imaging patterns in connective tissue disease-associated interstitial lung disease impact prognosis and immunosuppression response.

OBJECTIVES: Interstitial lung disease (ILD) in connective tissue diseases (CTD) have 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 computed tomography (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: Of 645 CTD-ILD patients, the frequent CTDs were systemic sclerosis (n = 215), rheumatoid arthritis (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 UIP, FVC decline was slower for NSIP (1.1%/year, 95%CI 0.2, 1.9) and OP (3.5%/year, 95%CI 2.0, 4.9), and mortality was lower for NSIP (HR 0.65, 95%CI 0.45, 0.93) and 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.

Pathologic Criteria for the Diagnosis of Usual Interstitial Pneumonia vs Fibrotic Hypersensitivity Pneumonitis in Transbronchial Cryobiopsies.

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.

A genomic history of Aboriginal Australia.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.

Deep-learning based classification distinguishes sarcomatoid malignant mesotheliomas from benign spindle cell mesothelial proliferations.

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.

Pathologic separation of idiopathic pulmonary fibrosis from fibrotic hypersensitivity pneumonitis.

Accurate separation of idiopathic pulmonary fibrosis from fibrotic (chronic) hypersensitivity pneumonitis is crucial to patient management, but is frequently a difficult problem. Our objective was to identify pathologic variables that help make this separation. Clinical, radiological, and pathologic data were re-reviewed for 23 patients with a fibrotic interstitial lung disease and biopsy suggesting idiopathic pulmonary fibrosis or fibrotic hypersensitivity pneumonitis. Clinical features, high-resolution computed tomography, and surgical lung biopsies were each examined independently using a prespecified approach. This was followed by a multidisciplinary discussion in which the likelihood of an idiopathic pulmonary fibrosis diagnosis was assigned by the clinician alone based only on clinical data, by the clinician and radiologist based on integrated clinical and radiologic data, and by the clinician, radiologist, and pathologist based on all three domains. A higher multidisciplinary discussion-based confidence of idiopathic pulmonary fibrosis was associated with older age at diagnosis, male sex, higher forced vital capacity, and absence of ground glass changes. Pathologic variables associated with a higher multidisciplinary discussion-based confidence of idiopathic pulmonary fibrosis included increased number of fibroblast foci/cm2 and increased subpleural fibrosis. Pathologic variables associated with a higher multidisciplinary discussion-based confidence of hypersensitivity pneumonitis included an increased fraction of bronchioles with peribronchiolar metaplasia, increased foci of peribronchiolar metaplasia/cm2, and presence of giant cells/granulomas. These results provide guidance in separating idiopathic pulmonary fibrosis from hypersensitivity pneumonitis; however, a third of cases could not be confidently classified even when using these pathologic features combined with clinical and radiologic information in a multidisciplinary discussion.

Sex differences in lymphoid follicles in COPD airways.

BACKGROUND: Female smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. Tertiary lymphoid follicles are often found in the lungs of patients with severe COPD but sex-related differences have not been previously investigated. We determined the impact of female sex hormones on chronic cigarette smoke-induced expression of lymphoid aggregates in mice with COPD-like pathologies. METHODS: Lymphoid aggregate counts, total aggregate cross-sectional area and foamy macrophage counts were determined morphometrically in male, female, and ovariectomized mice exposed to air or cigarette smoke for 6 months. B-cell activating factor (BAFF) protein expression and markers of oxidative stress were evaluated in mouse lung tissues by immunofluorescence staining and gene expression analyses. Quantitative histology was performed on lung tissue sections of human COPD lungs to evaluate follicle formation. RESULTS: Lymphoid follicle and foamy macrophage counts as well as the total follicle cross-sectional area were differentially increased in lung tissues of female mice compared to male mice, and these differences were abolished by ovariectomy. These lymphoid aggregates were positive for CD45, CD20, CD21 and BAFF expression. Differential increases in Mmp12 and Cxcl2 gene expression correlated with an increase in foamy macrophages in parenchymal tissues of female but not male mice after smoke exposure. Parenchymal tissues from female mice failed to induce antioxidant-related genes in response to smoke exposure, and this effect was restored by ovariectomy. 3-nitrotyrosine, a stable marker of oxidative stress, positively correlated with Mmp12 and Cxcl2 gene expression. Hydrogen peroxide induced BAFF protein in mouse macrophage cell line. In human lung tissues, female smokers with severe COPD demonstrated increased numbers of lymphoid follicles compared with males. CONCLUSIONS: Chronic smoke exposure increases the risk of lymphoid aggregate formation in female mice compared with male mice, which is mediated female sex hormones and BAFF expression in an oxidative environment.

Ancient mtDNA sequences from the First Australians revisited.

The publication in 2001 by Adcock et al. [Adcock GJ, et al. (2001) Proc Natl Acad Sci USA 98(2):537-542] in PNAS reported the recovery of short mtDNA sequences from ancient Australians, including the 42,000-y-old Mungo Man [Willandra Lakes Hominid (WLH3)]. This landmark study in human ancient DNA suggested that an early modern human mitochondrial lineage emerged in Asia and that the theory of modern human origins could no longer be considered solely through the lens of the "Out of Africa" model. To evaluate these claims, we used second generation DNA sequencing and capture methods as well as PCR-based and single-primer extension (SPEX) approaches to reexamine the same four Willandra Lakes and Kow Swamp 8 (KS8) remains studied in the work by Adcock et al. Two of the remains sampled contained no identifiable human DNA (WLH15 and WLH55), whereas the Mungo Man (WLH3) sample contained no Aboriginal Australian DNA. KS8 reveals human mitochondrial sequences that differ from the previously inferred sequence. Instead, we recover a total of five modern European contaminants from Mungo Man (WLH3). We show that the remaining sample (WLH4) contains ∼1.4% human DNA, from which we assembled two complete mitochondrial genomes. One of these was a previously unidentified Aboriginal Australian haplotype belonging to haplogroup S2 that we sequenced to a high coverage. The other was a contaminating modern European mitochondrial haplotype. Although none of the sequences that we recovered matched those reported by Adcock et al., except a contaminant, these findings show the feasibility of obtaining important information from ancient Aboriginal Australian remains.

Cicatricial organising pneumonia mimicking a fibrosing interstitial pneumonia.

AIMS: Organising pneumonia (OP) is composed of loose granulation tissue plugs in distal airspaces; these disappear with steroid treatment. Recently a variant labelled 'cicatricial' OP has been described in which the granulation tissue organised to much denser fibrous tissue but still retained the usual pattern of OP. Here we report 10 patients thought to have an interstitial lung disease, and who on biopsy had a variant of cicatricial OP characterised by linear bands or small nodular masses of dense fibrous tissue that does not resemble ordinary OP. METHODS AND RESULTS: The bands/nodules were usually distributed randomly but occasionally resembled fibrotic non-specific interstitial pneumonia in local areas. Small foci of loose granulation tissue at the edge of the fibrotic bands sometimes mimicked fibroblast foci. Recognisable conventional OP was always present, but often in very small amounts. Four cases, including one patient with Ehlers-Danlos syndrome, showed formation of bone in the fibrotic bands and nodules. On computerised tomography (CT) scan of the chest some cases looked like typical OP, but some demonstrated only irregularly distributed linear opacities, sometimes with associated calcification. Follow-up imaging on six cases showed that the process either markedly improved or remained stable over time; no case had progressive disease. CONCLUSIONS: Cicatricial OP with this pathological pattern represents an uncommon form of OP that appears to be a generally benign process which may have persisting linear opacities on CT scan but that does not progress; however, it can be confused on biopsy and CT with a fibrosing interstitial pneumonia.

Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease.

RATIONALE: After adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown. OBJECTIVES: To characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD. METHODS: Airway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-ß-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography. MEASUREMENTS AND MAIN RESULTS: Small airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-ß1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls. CONCLUSIONS: The excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-ß1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers.

Lung exposure to lipopolysaccharide causes atherosclerotic plaque destabilisation.

Epidemiological studies have implicated lung inflammation as a risk factor for acute cardiovascular events, but the underlying mechanisms linking lung injury with cardiovascular events are largely unknown.Our objective was to develop a novel murine model of acute atheromatous plaque rupture related to lung inflammation and to investigate the role of neutrophils in this process.Lipopolysaccharide (LPS; 3 mg·kg(-1)) or saline (control) was instilled directly into the lungs of male apolipoprotein E-null C57BL/6J mice following 8 weeks of a Western-type diet. 24 h later, atheromas in the right brachiocephalic trunk were assessed for stability ex vivo using high-resolution optical projection tomography and histology. 68% of LPS-exposed mice developed vulnerable plaques, characterised by intraplaque haemorrhage and thrombus, versus 12% of saline-exposed mice (p=0.0004). Plaque instability was detectable as early as 8 h post-intratracheal LPS instillation, but not with intraperitoneal instillation. Depletion of circulating neutrophils attenuated plaque rupture.We have established a novel plaque rupture model related to lung injury induced by intratracheal exposure to LPS. In this model, neutrophils play an important role in both lung inflammation and plaque rupture. This model could be useful for screening therapeutic targets to prevent acute vascular events related to lung inflammation.

Fibroblast signal transducer and activator of transcription 4 drives cigarette smoke-induced airway fibrosis.

Cigarette smoke-induced emphysema and small airway remodeling are the anatomic bases of chronic obstructive pulmonary disease (COPD), but the pathogenesis of these changes is unclear, and current treatments for COPD are minimally effective. To evaluate the role of signal transducer and activator of transcription (STAT)-4 in cigarette smoke-induced small airway remodeling, we used C57BL/6J (wild type [WT]) and STAT4-/- mice exposed to air or cigarette smoke for 6 months and isolated airway and parenchymal fibroblasts. We also compared the results with those obtained with human fibroblasts. We found that STAT4-/- mice were protected against smoke-induced small airway remodeling but not emphysema. STAT4 is abundantly expressed in airway compared with parenchymal-derived fibroblasts isolated from normal human and murine lung. WT airway fibroblasts proliferate faster than STAT4-/- airway fibroblasts, whereas there is no difference between strains for parenchymal fibroblasts. IL-12 is up-regulated in the lung after smoke exposure, and IL-12 receptor B2 is expressed on airway and parenchymal fibroblasts in mouse and human lung. Treatment with IL-12 causes phosphorylation of STAT4 in WT airway fibroblasts. Exposure of WT airway, but not parenchymal, fibroblasts to IL-12 causes increased expression of collagen 1α1 and transforming growth factor ß1, factors involved in small airway remodeling, whereas STAT4-/- fibroblasts are unresponsive to IL-12. These results indicate that IL-12 can drive small airway remodeling via STAT4 signaling and suggest that treatment with clinically available anti-IL-12p40 drugs might provide a new approach to preventing small airway remodeling in cigarette smokers.

Club cell protein 16 and disease progression in chronic obstructive pulmonary disease.

RATIONALE: Club (Clara) cell protein 16 (CC-16) is a protein that is synthesized predominantly in the lungs and is detectable in serum. Its expression decreases with lung injury and smoking, and is thus a marker of bronchial cell dysfunction. OBJECTIVES: To evaluate the possibility of using serum CC-16 as a biomarker for disease progression in chronic obstructive pulmonary disease (COPD). METHODS: We measured serum CC-16 levels from 4,724 subjects with mild-to-moderate airflow limitation in the Lung Health Study. Using a linear regression model, we determined the relationship of serum CC-16 concentrations to decline in lung function over 9 years. In addition, to determine whether CC-16 plays a major role in the pathogenesis of mild COPD, we exposed CC-16-deficient (-/-) mice to 6 months of cigarette smoke. MEASUREMENTS AND MAIN RESULTS: Reduced serum concentrations of CC-16 were associated with accelerated decline in FEV1 over 9 years (P < 0.0001), and this association persisted after adjustments for age, sex, race, smoking status, airway reactivity, body mass index, and baseline FEV1 (P = 0.0002). However, CC-16(-/-) mice did not demonstrate an enhanced risk of emphysema or small airway remodeling in response to cigarette smoke. CONCLUSIONS: Serum CC-16 is associated with disease progression, and may assist in the identification of "rapid progressors." However, the absence of CC-16 does not appear to modify the risk of cigarette-related COPD in mice.

Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease.

RATIONALE: Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation. OBJECTIVES: To determine the role of MPO in COPD. METHODS: We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure. RESULTS: At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding. CONCLUSIONS: We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.

Integration and Application of Radiologic Patterns From Clinical Practice Guidelines on Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without direction 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 features 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.

Statin reverses smoke-induced pulmonary hypertension and prevents emphysema but not airway remodeling.

RATIONALE: the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect. OBJECTIVES: to determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension. METHODS: we exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate. MEASUREMENTS AND MAIN RESULTS: cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation. CONCLUSIONS: simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke-induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD.

Integration and Application of Clinical Practice Guidelines for the Diagnosis of Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis.

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.

Everything prevents emphysema: are animal models of cigarette smoke-induced chronic obstructive pulmonary disease any use?

There is a very large number of experimental approaches that prevent cigarette smoke-induced emphysema in laboratory animals, but the few similar treatments that have been tried in humans have had minimal effects, leading to questions of whether animal models of chronic obstructive pulmonary disease (COPD) are of any use in developing treatments for human disease. We review possible reasons for this problem. First, humans usually get treated when they have severe (Global Initiative for Chronic Obstructive Lung Disease III/IV) COPD, but animal models only produce mild (Global Initiative for Chronic Obstructive Lung Disease I/II) disease that never progresses after smoking cessation, and never develops spontaneous exacerbations (i.e., animal models are not models of severe human disease, and probably can't be used to model treatment of severe disease). Second, animal models have concentrated on emphysema and largely ignored small airway remodeling, but small airway remodeling is an equally important cause of airflow obstruction. In addition, small airway remodeling and emphysema are independent responses to smoke, and some experimental animal treatments prevent both lesions, but many do not. Third, animal models are typically Day 1 of smoke exposure "prevention" models, but humans are always treated well along in the course of their disease; thus, any human treatment will be an intervention, and not a prevention. We propose that animal models should examine both emphysema and small airway remodeling, and that experiments should include a relatively late intervention arm. This approach, combined with the realization that human COPD probably needs early rather than late treatment, may make development of treatments based on animal models more relevant.

Fibrosis with emphysema.

The concept of fibrosis with emphysema is confused by the existence of two very different clinical/pathological scenarios: first, cases in which a diffuse fibrosing interstitial pneumonia, most commonly usual interstitial pneumonia (UIP), occurs in a patient with emphysema. This combination is largely of clinical interest because of its effects on pulmonary function and pulmonary hypertension, but can produce unusual appearances in surgical lung biopsies when the fibrotic areas are wrapped around emphysematous spaces. However, the underlying morphology of emphysema and UIP or other interstitial lung disease remains unchanged. Radiological consultation is often helpful to show that the patient has both lesions; secondly, cases in which there is localized fibrosis that is part of emphysema, or related to respiratory bronchiolitis, or both. These lesions have been called 'respiratory bronchiolitis' (RB), 'respiratory bronchiolitis-interstitial lung disease' (RB-ILD), 'airspace enlargement with fibrosis', 'RB-ILD with fibrosis' and 'clinically occult interstitial fibrosis in smokers', but are probably all the same entity. Such changes are associated only rarely with the physiological or radiological features of an interstitial lung disease. Care should be taken when describing these lesions in biopsies so as not to give the impression that a diffuse interstitial lung disease is present.

Desquamative interstitial pneumonia.

Desquamative interstitial pneumonia (DIP) is one of the rarest of the idiopathic interstitial pneumonias. It is characterized by the accumulation of macrophages in large numbers in the alveolar spaces associated with interstitial inflammation and/or fibrosis. The macrophages frequently contain light brown pigment, and because of their association with smoking have been called 'smoker's macrophages'. Lymphoid nodules are common, as is a sparse but distinct eosinophil infiltrate. Most cases of DIP are caused by cigarette smoking, but drugs and other inhaled agents, including marijuana smoke, can also produce the same disease. Although respiratory bronchiolitis-interstitial lung disease (RB-ILD) is a closely related process, there are prognostic reasons for continuing to separate it from DIP when possible. The proposed relationship of DIP to fibrotic non-specific interstitial pneumonia (NSIP) remains uncertain. The prognosis of DIP appears to be significantly better than that of fibrotic NSIP, so while there can be morphological overlap between the two, merging them into one disease may hide important prognostic information. Although the majority of DIP patients improve on treatment, some patients develop progressive irreversible fibrosis.

Acute exacerbations of fibrotic interstitial lung disease.

An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre-existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non-specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high-dose steroid therapy.