Acute exacerbations of fibrotic interstitial lung diseases.

BACKGROUND AND OBJECTIVE: Acute exacerbation (AE) is a severe complication of idiopathic pulmonary fibrosis (AE-IPF). In 2016, an international working group revised its definition and diagnostic criteria; however, few studies have assessed the frequency and prognosis of AE in patients with other fibrotic interstitial lung diseases (FILD). METHODS: We used data from 1019 consecutive interstitial lung disease (ILD) patients initially evaluated between January 2008 and July 2015. All subject diagnoses were made by multidisciplinary discussion in December 2018. ILD was categorized as IPF (n = 462) and other FILD which included non-specific interstitial pneumonia (n = 22), chronic hypersensitivity pneumonitis (n = 29), connective tissue disease-associated ILD (n = 205) and unclassifiable ILD (n = 209). Using the 2016 definition of AE-IPF, we identified all subjects with an AE. RESULTS: During the observational period, 193 patients experienced a first AE (AE-FILD n = 69, AE-IPF n = 124). The time to first AE was significantly longer in FILD than IPF (log-rank test, P < 0.001). After adjusting for potentially influential confounders, FILD remained a significant predictor of longer time to first AE compared with IPF (hazard ratio: 0.453; 95% CI: 0.317-0.647, P = 0.006). In a multivariate Cox proportional analysis, baseline disease severity was closely associated with the incidence of AE-ILD. Even after adjustment for other clinical variables, AE had a negative impact on overall survival. AE-FILD and AE-IPF showed similar poor short-term outcomes. CONCLUSION: All forms of ILD are at risk of AE and have a similar outcome to AE-IPF.

Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally.

CONTEXT: Three distinct patterns of pulmonary fibrosis, including usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis, can be identified on surgical lung biopsies. OBJECTIVES: To compare the pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and prognoses of usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis patterns, and to address the challenges and controversies related to pulmonary fibrosis. DATA SOURCES: Data were derived from published literature and clinical experience. CONCLUSIONS: Although there may be overlap, identification of the dominant form of fibrosis in a particular case can provide a general category of disease and assist in identifying an etiology.

Pulmonary fibrosis in dyskeratosis congenita: report of 2 cases.

Dyskeratosis congenita (DC) is a disorder of poor telomere maintenance and is related to 1 or more mutations that involve the vertebrate telomerase RNA component. Most affected patients develop mucocutaneous manifestations and cytopenias in the peripheral blood between 5 and 15 years of age. DC patients may also develop pulmonary complications including fibrotic interstitial lung disease and pulmonary vascular abnormalities. The radiologic and pathologic features of pulmonary fibrosis associated with DC are poorly defined. Herein, we report 2 new DC cases and suggest that the radiologic and histopathologic findings may resemble usual interstitial pneumonia but may not neatly fit into the current classification of interstitial lung disease.

Idiopathic pleuroparenchymal fibroelastosis: consideration of a clinicopathological entity in a series of Japanese patients.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported group of disorders characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes. We report five Japanese cases fulfilling the criteria of IPPFE and address whether it should be considered a separate clinicopathologic entity. And this study was an attempt to identify features in common between IPPFE and previously described idiopathic upper lobe fibrosis (IPUF), allowing IPPFE to be considered as a distinct entity in our Japanese series. METHODS: Five consecutive cases of idiopathic interstitial lung disease confirmed as IPPFE by surgical lung biopsy were studied. RESULTS: There were four males and one female, aged 70±2.76 yr. No associated disorder or presumed cause was found in any case. Lung function tests found a restrictive ventilatory defect (4/5) and/or impairment of DLco (4/5). Chest X-ray showed marked apical pleural thickening in all cases. Computed tomography of the chest in all cases mainly showed intense pleural thickening and volume loss associated with evidence of fibrosis, predominantly in the upper lobes. In all cases in this study, markedly thickened visceral pleura and prominent subpleural fibrosis characterized by both elastic tissue and dense collagen were clearly shown. All cases were alive at the last follow-up, 17.6±13.59 months after diagnosis; however, all had deteriorated both clinically and radiologically. CONCLUSIONS: IPPFE deserves to be defined as a separate, original clinicopathologic entity owing to its uniformity and IPPFE has some features in common with previously described idiopathic upper lobe fibrosis (IPUF). Our limited experience with a cohort of 5 subjects suggests that IPPFE can be rapidly progressive.

Epithelial-mesenchymal transition in chronic hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis (HP) causes progressive and irreversible pulmonary fibrosis, a disease also observed in conjunction with idiopathic pulmonary fibrosis (IPF). Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition (EMT), may play a role in the pathogenesis of IPF. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic HP. Lung specimens from a chronic HP model and from patients with chronic HP were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells (AECs) were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of IL-13 and TGF-ß1, the fibrosis score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with usual interstitial pneumonia pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of fibrosis. In conclusion, EMT may play an important role in the fibrotic process of chronic HP under the Th2-biased environment.

[Idiopathic interstitial pneumonia: classification and diagnostic work-up]. / Les pneumopathies interstitielles diffuses idiopathiques: classification et démarche diagnostique.

Idiopathic interstitial pneumonias represent a group of complex lung diseases among which the most frequent types are idiopathic pulmonary fibrosis (IPF), idiopathic non-specific interstitial pneumonia (idiopathic NSIP), and cryptogenic organizing pneumonia (COP). Clinicians may rely on a precise classification of these diseases from an America-European consensus that has been published in 2002. However it appears that diagnosis should always be confirmed by a multidisciplinary team discussion with experience in the field. There are generally tremendous prognostic and therapeutic implications for the patient.

Antioxidants as potential therapeutics for lung fibrosis.

Interstitial lung disease encompasses a large group of chronic lung disorders associated with excessive tissue remodeling, scarring, and fibrosis. The evidence of a redox imbalance in lung fibrosis is substantial, and the rationale for testing antioxidants as potential new therapeutics for lung fibrosis is appealing. Current animal models of lung fibrosis have clear involvement of ROS in their pathogenesis. New classes of antioxidant agents divided into catalytic antioxidant mimetics and antioxidant scavengers are being developed. The catalytic antioxidant class is based on endogenous antioxidant enzymes and includes the manganese-containing macrocyclics, porphyrins, salens, and the non-metal-containing nitroxides. The antioxidant scavenging class is based on endogenous antioxidant molecules and includes the vitamin E analogues, thiols, lazaroids, and polyphenolic agents. Numerous studies have shown oxidative stress to be associated with many interstitial lung diseases and that these agents are effective in attenuating fibroproliferative responses in the lung of animals and humans.

Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms?

Idiopathic pulmonary fibrosis (IPF) is a devastating condition that carries a prognosis worse than that of many cancers. A recent classification of the idiopathic interstitial pneumonias has redefined the diagnostic criteria necessary to determine a diagnosis of IPF. The present authors believe that this redefinition is incorrect, relying as it does on subtle histological differences for the definition of separate disease categories. A further issue affecting IPF research is the polarisation of views around two competing pathogenetic hypotheses. One argues for the primacy of inflammation as the trigger that initiates fibrosis, and the other proposes that fibrosis arises as a consequence of chronic epithelial injury and failure of repair due to aberrant epithelial-mesenchymal interactions. The present authors believe that this schism is hampering understanding of IPF and skewing research priorities. It is argued here, instead, that abnormalities in multiple pathways involved in wound healing and inflammation lead to the development of idiopathic pulmonary fibrosis, and it is suggested that a new rationale for clinical classification and pathogenesis may be more productive in driving the search for novel therapies in the future.

Reassessment of the classification of the severity in idiopathic pulmonary fibrosis using SF-36 questionnaire.

OBJECTIVE: To investigate whether or not the newly revised classification of the severity of idiopathic interstitial pneumonia (IIP) is appropriate with respect to quality of life (QOL). METHODS: The association between the subscale of Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and pulmonary function or serum marker was analyzed using Pearson's correlation coefficient. The association between the subscale of SF-36 and the previous or newly revised classification of the severity of IIP was analyzed using Spearman's rank correlation test. PATIENTS: Forty patients with idiopathic pulmonary fibrosis (IPF) were enrolled. RESULTS: The mean deviation value scores for 7 items, excluding bodily pain (BP) in SF-36 were below the national reference values. % vital capacity (VC) was correlated with the 7 items excluding BP. However, neither serum LDH nor KL-6 values were correlated with any item in SF-36. According to the new or previous classification of the severity, severity was correlated with physical function, limitation of role functioning related physical problems and general health (GH); the correlation coefficient with the new one was slightly higher than the previous one. Based on these results, we established a unique draft on the classification of the severity. %VC <70% was added as an item for the newly revised classification in our draft. In our draft, there was rank correlation between the 7 items, excluding BP, in SF-36 and severity. CONCLUSION: With respect to QOL, the newly revised classification of the severity of IIP was not satisfactory, but the hypoxemia during exercise in patients with resting PaO(2) >80 Torr and reduction of VC were found to be important factors.

[Pulmonary fibrosis. Classification, diagnosis, therapy]. / Lungenfibrosen. Klassifikation, Diagnostik, Therapie.

A new classification of the idiopathic interstitial pneumonia has recently been proposed, defining idiopathic pulmonary fibrosis (IPF) more rigorously and in contrast to further subentities. The new classification is of prognostic and clinical relevance. Diagnosis requires a combined clinical, radiological and pathological effort. In patients with characteristic clinical and HR-CT findings, the diagnosis of IPF can be made with sufficient confidence without surgical lung biopsy. Recent evidence suggests that the primary pathogenetic event in IPF involves epithelial injury and abnormal wound heeling. This explains the ineffectiveness of the usual anti-inflammatory therapy in the majority of patients. Since no antifibrotic drugs are available at present, the recommended standard therapy is a combination of prednisone with azathioprine or cyclophosphamide. New antifibrotic molecules are already tested in clinical trials.

[Interstitial pulmonary siderofibrosis: requirements for acceptance as new occupational disease]. / Schweisserlungenfibrose: Begründung für die Aufnahme als neue Berufskrankheit.

BACKGROUND: Pulmonary siderosis is a well established disorder in welders. Internationally more than 150 cases of interstitial pulmonary siderofibrosis are associated with long-standing and heavy exposure to welding fumes at poorly ventilated working places. PATIENTS: Characteristic job histories, lung function analyses and histological examinations as well as elemental microanalysis by energy dispersive X-ray analysis (EDX) are demonstrated from 3 welders with pulmonary siderofibrosis. RESULTS: Histological examinations show a patchy interstitial fibrosis with accumulations of particulate material typical for welding fumes. EDX disclose an increase of iron-load in activated macrophages as well as in lung tissue and a close topographical relationship of welding fume particles and interstitial fibrotic reactions. Lung function analysis showed predominantly loss of pulmonary performance during spiroergometry. CONCLUSIONS: Regarding the actual knowledge about the pathomechanisms of ultrafine particles on lung tissue, the evidence from animal experiments, the histological and electron microscopical results, our own clinical examinations of welders and some epidemiological evidence, we assume a causal relationship of interstitial pulmonary siderofibrosis in welders with long-standing exposure to high concentrations of welding fumes under poor working conditions.

Relevância da lesão da unidade epitélio/membrana basal epitelial no remodelamento arquitetural precoce de pneumonias intersticiais idiopáticas / Relevance of the epithelial cell/epithelial basement membrane unity lesion in idiopathic interstitial pneumonias early achitectural

Foi feito um estudo retrospectivo qualitativo e quantitativo, por técnicas histoquímicas e imuno-histoquímicas, do remodelamento arquitetural precoce em padrões histológicos de pneumonia intersticial idiopática em 81 biopsias pulmonares a céu aberto realizadas no Hospital das Clínicas da FMUSP. A forma de remodelamento dependeu da extensão da lesão da unidade epitélio-membrana basal e da configuração espacial do ácino pulmonar, obedecendo a mesma seqüência básica de eventos morfológicos observada na cicatrização de feridas. Todos padrões histológicos apresentaram as várias formas de remodelamento, cuja magnitude se correlacionou com seus respectivos cursos clínicos naturais / Early architectural remodelling in idiopathic interstitial pneumonia histologic patterns were retrospectively studied in 81 open lung biopsies performed at the Hospital das Clínicas da FMUSP. Morphological parameters were qualitative and quantitatively analysed after histochemical and immunohistochemical procedures. The type of remodelling depended on the injury extension to the epithelial cell/epithelial basement membrane unity and on the acinar spatial configuration, obeying the basic sequence of morphological events observed in wound healing. All histologic patterns showed the different types of remodelling, which amounts correlated with their respective natural clinical histories...

Overview of pulmonary fibrosis.

Pulmonary fibrosis is a component of over 200 interstitial lung diseases. Some have known etiologies, however, for many diseases, the etiology remains unknown or obscure. This brief review examines the prevalence and classification of these diseases, the approach to be taken for the investigation of a patient suspected of having pulmonary fibrosis, the indications for the performance of lung biopsy, and current thoughts concerning the pathogenesis of the idiopathic forms of fibrotic lung disease. A brief review of established and emerging therapeutic strategies is included.

The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia.

BACKGROUND: The prognosis of pulmonary fibrosis associated with scleroderma (PF-SSc) has been reported to be significantly better than that of IPF. Because the nonspecific interstitial pneumonia-pattern (NSIP), a newly defined subgroup of idiopathic interstitial pneumonias (IIP), has better prognosis than the usual interstitial pneumonia pattern (UIP), we postulated that NSIP may occur more frequently than UIP in patients with scleroderma who develop fibrosis. METHOD: We reviewed the pathologic, radiologic and clinical outcomes in 19 patients with PF-SSc. Two pulmonary pathologists reclassified the histopathology of surgical lung biopsies (SLBx) and consensus diagnosis was achieved in all patients. RESULTS: Thirteen patients had NSIP, five had UIP, and remained one showed only nondiagnostic honeycombing. No significant difference was noted in the initial pulmonary function test (PFT), bronchoalveolar lavage (BAL) findings, or other clinical parameters between UIP and NSIP groups. Comparison of the clinical outcome of 12 patients who were followed for more than 12 months (mean: 34.5 +/- 26.0 months) suggested a better prognosis for NSIP than UIP. Five of the eight NSIP patients improved and three were stable, whereas in patients with UIP, one worsened and three were stable. CONCLUSION: NSIP seems to be the major histopathologic pattern in patients with PF-SSc.

Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder.

Idiopathic pulmonary fibrosis is a chronic and usually progressive lung disorder of unknown etiology. A growing body of evidence suggests that, in contrast to other interstitial lung diseases, IPF is a distinct entity in which inflammation is a secondary and non-relevant pathogenic partner. Evidence includes the presence of similar mild/moderate inflammation either in early or late disease, and the lack of response to potent anti-inflammatory therapy. Additionally, it is clear from experimental models and some human diseases that it is possible to have fibrosis without inflammation. An evolving hypothesis proposes that IPF may result from epithelial micro-injuries and abnormal wound healing.