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Previous studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients < 65 years old, in the elderly it may occur without germline mutations and could negatively affect prognosis. Physicians should be aware for possible IPF deterioration and therapeutic options for MDS should be wisely considered. © 2019 The Author(s).

Introduction: Controversy exists about the pathogenesis of idiopathic pulmonary fibrosis acute exacerbations (IPF-AEs). According to one hypothesis IPF-AEs represent the development of any etiology diffuse alveolar damage (DAD) upon usual interstitial pneumonia (UIP), whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated IPF patients. Methods: Consecutive IPF patients referred to our department were included. Diagnoses of IPF and IPF-AE were based on international guidelines and consensus criteria. The interleukins (IL)-4, IL-6, IL-8, IL-10, and IL-13 as well as active transforming growth factor-beta (TGF-β) were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12 months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. Results: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The IL-6 and IL-8 levels were significantly higher in exacerbated patients (p = 0.002 and p = 0.046, respectively). An increase in either IL-6 or IL-8 by 1 pg/ml increases the odds of death by 5.6% (p = 0.021) and 6.7% (p = 0.013), respectively, in all patients. No differences were detected for the other cytokines. Conclusion: High levels of IL-6 and IL-8 characterize early-on IPF-AEs and an increase in the levels of IL-6 and IL-8 associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-β IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of IL-6 further studies are necessary to clarify the enigma of IPF-AEs etiopathogenesis. © 2017 Elsevier Ltd

We hypothesized that cardiovascular events and/or indices of cardiac dysfunction may be increased in pulmonary alveolar proteinosis (PAP). Systemic and pulmonary arterial hypertension, arrhythmias, pulmonary embolism, stroke and ischemic heart attack were reported. Patients underwent serum anti-GM-CSF antibodies, disease severity score (DSS), Doppler transthoracic echocardiograph, glucose, thyroid hormones, lipids, troponin and pro-Brain natriuretic peptide (BNP) examination. Thirteen patients (8 female) were studied, median age of 47. Pro-BNP inversely related to DLCO% and TLC%; troponin directly related to DSS, age, P(A-a)O2, left atrium-, left ventricle-end-diastole diameter and BMI. On multiple regression analysis DSS was the only parameter significantly and strongly related with troponin (R2 = 0.776, p = 0.007). No cardiovascular event was reported during follow-up. In PAP cardiovascular risk indices relate to lung disease severity. Therefore, PAP patients could be at increased risk for cardiovascular events. Quantitation of its magnitude and potential links to lungs physiologic derangement will be addressed in future studies. © 2015 © 2015 Taylor & Francis.

Subacute-acute, hyperacute, or even catastrophic and fulminant respiratory events occur in almost all classic connective tissue disorders (CTDs); they may share systemic life-threatening manifestations, may precipitously lead to respiratory failure requiring ventilatory support as well as a combination of specific therapeutic measures, and in most affected patients constitute the devastating end-of-life event. In CTDs, acute respiratory events may be related to any respiratory compartment including the airways, lung parenchyma, alveolar capillaries, lung vessels, pleura, and ventilatory muscles. Acute respiratory events may also precipitate disease-specific extrapulmonary organ involvement such as aspiration pneumonia and lead to digestive tract involvement and heart-related respiratory events. Finally, antirheumatic drug-related acute respiratory toxicity as well as lung infections related to the rheumatic disease and/or to immunosuppression complete the spectrum of acute respiratory events. Overall, in CTDs the lungs significantly contribute to morbidity and mortality, since they constitute a common site of disease involvement; a major site of infections related to the 'mater' disease; a major site of drug-related toxicity, and a common site of treatment-related infectious complications. The extreme spectrum of the abovementioned events, as well as the 'vicious' coexistence of most of the aforementioned manifestations, requires skills, specific diagnostic and therapeutic means, and most of all a multidisciplinary approach of adequately prepared and expert scientists. Avoiding lung disease might represent a major concern for future advancements in the treatment of autoimmune disorders. © 2016 S. Karger AG, Basel.

Lung involvement in connective tissue disorders (CTDs) may present as pleomorphic since any lung compartment may be involved such as airways, exocrine secretory and alveolar epithelia, interstitial lung structure, pulmonary vasculature and pleura as well as, in specific disorders, several tissues of the thoracoabdominal ventilator pump. Any combination of the above anatomic structures may be involved concomitantly although some specific combinations may include a determinant of rheumatic disorders. The diagnosis of a specific CTD requires the fulfilment of clearly defined clinical and laboratory criteria including in most cases positivity for autoantibodies, mostly specific serologic combinations. In this setting, serologic investigation targets mainly, although not exclusively, the detection of antinuclear antibodies. A specific serologic positivity or a combination of autoantibodies constitutes not only a diagnostic criterion for a specific CTD, but may also characterize the pattern of respiratory manifestation in a determinant rheumatic disorder. Therefore, the investigation of lung involvement in CTDs requires adequate skills in the ambit of a multidisciplinary approach and an extended spectrum of diagnostic tools and modalities able to detect both early clinical clues and serologic conversion as well as any pathophysiologic alteration that regards the complexity of respiratory functional status. Although many patients with CTDs suffer from a 'vicious' combination of lung involvement, lung drug toxicity and infections related to the above two as well as to the 'mater' disease, for space reasons this review will focus on the established lung manifestations that regard the 7 major CTDs. © 2015 S. Karger AG, Basel.

Background: Idiopathic pulmonary fibrosis acute exacerbation (IPF-AE) constitutes IPF's most devastating event, representing the unexpected superimposition of diffuse alveolar damage of unknown etiology. Guidelines recommend high-dose steroids treatment despite unproven benefit. We hypothesized that previous immunosuppression and the administration of high-dose steroids adversely affect IPF-AE outcome. Methods: We studied all consecutive patients hospitalized in our department for IPF deterioration from 2007 to June 2013. Our protocol consisted of immediate cessation of immunosuppression (if any), best supportive care, broad-spectrum antimicrobials and thorough evaluation to detect reversible causes of deterioration. Patients were followed-up for survival; post-discharge none received immunosuppression. Results: Twenty-four out of 85 admissions (28 %) fulfilled IPF-AE criteria. IPF-AE were analyzed both as unique events and as unique patients. As unique events 50 % survived; 3 out of 12 (25 %) in the group previously treated with immunosuppression whereas nine out of 12 (75 %) in the group not receiving immunosuppression (p=0.041). As unique patients 35.3 % survived; 3 out of 6 (50 %) in the never treated group whereas three out of 11 (27.3 %) in the group receiving immunosuppression (p=0.685). The history of immunosuppression significantly and adversely influenced survival (p=0.035). Survival was greater in the never treated group compared to the immunosuppressed patients (p=0.022). Post-discharge, our IPF-AE survivors had an 83 % 1-year survival. Conclusions: By applying the above mentioned protocol half of our patients survived. The history of immunosuppression before IPF-AE adversely influences survival. Avoiding steroids in IPF patients may favor the natural history of the disease even at the moment of its most devastating event. © 2015 Papiris et al.

Pulmonary alveolar proteinosis (PAP) is categorized into hereditary, secondary and autoimmune PAP (aPAP) types. The common pathogenesis is the ability of the alveolar macrophages to catabolize phagocytized surfactant is affected. Hereditary PAP is caused by mutations involving the GM-CSF signaling, particularly in genes for the GM-CSF receptor and sometimes by GATA2 mutations. Secondary PAP occurs in hematologic malignancies, other hematologic disorders, miscellaneous malignancies, fume and dust inhalation, drugs, autoimmune disorders and immunodeficiencies. aPAP is related to the production of GM-CSF autoantibodies. PAP is characterized morphologically by the inappropriate and progressive 'occupation' of the alveolar spaces by an excessive amount of unprocessed surfactant, limiting gas exchange and gradually exhausting the respiratory reserve. Myeloid cells' immunity deteriorates, increasing the risk of infections. Treatment of PAP is based on its etiology. In aPAP, recent therapeutic advances might shift the treatment option from the whole lung lavage procedure under general anesthesia to the inhalation of GM-CSF 'as needed'. © 2015 Informa UK, Ltd.

Background and Objectives: Granulocyte macrophage-colony-stimulating factor (GM-CSF) causes variable improvement in autoimmune pulmonary alveolar proteinosis (aPAP). Upon response to short-term treatment, patients are divided into responders and non-responders. The aim of this study was to test the hypothesis that long-term inhaled GM-CSF (iGM-CSF) is effective in all patients and that attainment of remission permits gradual de-escalation of the dose to the lowest effective safe dose. Methods: Patients were treated with iGM-CSF 250 μg once a day given 4 days on and 4 days off for as long as necessary (the "as far as it takes" protocol). Upon remission, defined as absence of symptoms, oxygen desaturation

Fibrotic interstitial lung diseases (ILDs) are commonly encountered in scleroderma where they significantly influence prognosis. The mainstay of treatment in idiopathic fibrotic ILDs for the past 30 years was based on the combined administration of prednisone and cyclophosphamide (CYC) or prednisone, azathioprine plus N-acetyl cysteine, recently proved ineffective and harmful. Rheumatologists also despite "facts" showing that CYC treatment has no beneficial impact on fibrotic ILDs in scleroderma continue to commit the same, in a manner of speaking, "faults" by "treating their fibrotic ILDs by immunosuppressants." In this issue of the journal, Panopoulos et al. (Lung, 191, 483-489, 2013) recognizing the minimal effect of CYC on fibrotic ILDs in scleroderma patients and the increased use in clinical practice of mycophenolate mofetil (MMF) as an alternative, report that MMF use to replace CYC in this setting is not supported, confirming that restoration of purely fibrotic damage in the lungs remains one of the most challenging fields in medicine. © 2013 Springer Science+Business Media.

Considerable controversy is haunting the treatment of IPF 'acute exacerbation', its most devastating complication. The consensus coined term 'acute exacerbation' implies that on an unknown etiology disease such as IPF, an unknown etiology superimposed acute lung injury/acute respiratory distress syndrome (ALI/ARDS) represents the end-life event in a consistent proportion of patients and are treated by high dose steroids despite unproven benefit. Inversely, ALI/ARDS treatment recommendations are based on the provision of excellent supportive care plus an extensive search and appropriate treatment of the etiologic precipitant and all intensive care clinicians in the absence of an obvious etiology, considering that occult infection is the most probable and also the most treatable underlying condition, universally administer extensive spectrum antimicrobials. Viewing the persistent high mortality in IPF 'acute exacerbations' treated with steroids we strongly believe that a study comparing the two arms of the steroid and non-steroid approach is greatly awaited by scientists and owed to the patients. © Informa Uk, Ltd.

Background: Recent studies suggest poor sleep quality in patients with idiopathic pulmonary fibrosis (IPF). However, so far, the impact of IPF-related sleep breathing disorders (SBDs) on survival has not been extensively studied. Methods: In a cohort of 31 (24 males) treatment-naïve, newly diagnosed consecutive IPF patients, we prospectively investigated the relationship of SBD parameters such as apnea-hypopnea index (AHI), maximal difference in oxygen saturation between wakefulness and sleep (maxdiff SpO2), and lowest sleep oxygen saturation (lowest SpO2) with clinical (survival, dyspnea, daytime sleepiness), pulmonary function, submaximal (6-min walk test [6MWT]) and maximal exercise variables (cardiopulmonary exercise test [CPET]), and right ventricular systolic pressure (RVSP). Results: Sleep oxygen desaturation exceeded significantly that of maximal exercise (p < 0.001). Maxdiff SpO2 was inversely related to survival, DLCO%, and SpO 2 after 6MWT, and directly with dyspnea, AHI, and RVSP. The lowest SpO2 was directly related to survival and to functional (TLC%, DLCO%) as well as submaximal and maximal exercise variables (6MWT distance, SpO 2 after 6MWT, peak oxygen consumption/kg, SpO2 at peak exercise), while an inverse association with dyspnea score, AHI, and RVSP was observed. Conclusions: Our findings provide evidence that intermittent sleep oxygen desaturation significantly exceeds that of maximal exercise and is associated with survival in IPF patients. Furthermore, they imply the existence of a link between lung damage and apnea events resulting to the induction and severity of intermittent sleep oxygen desaturation that aggravate pulmonary arterial hypertension and influence IPF survival.

Bronchiolitis is an inflammatory and potentially fibrosing condition affecting mainly the intralobular conducting and transitional small airways. Secondary bronchiolitis participates in disease process of the airways and/or the surrounding lobular structures in the setting of several already defined clinical entities, mostly of known etiology, and occurs commonly. Primary or idiopathic bronchiolitis dominates and characterizes distinct clinical entities, all of unknown etiology, and occurs rarely. Secondary bronchiolitis regards infections, hypersensitivity disorders, the whole spectrum of smoking-related disorders, toxic fumes and gas inhalation, chronic aspiration, particle inhalation, drug-induced bronchiolar toxicities, sarcoidosis and neoplasms. Idiopathic or primary bronchiolitis defines clinicopathologic entities sufficiently different to be designated as separate disease entities and include cryptogenic constrictive bronchiolitis, diffuse panbronchiolitis, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, neuroendocrine hyperplasia in infants, bronchiolitis obliterans syndrome in lung and allogeneic hematopoietic cell transplantation, connective tissue disorders, inflammatory bowel disease and bronchiolitis obliterans organizing pneumonia. Most of the above are pathological descriptions used as clinical diagnosis. Acute bronchiolitis, though potentially life threatening, usually regresses. Any etiology chronic bronchiolitis contributes to morbidity and/or mortality if it persists and/or progresses to diffuse airway narrowing and distortion or complete obliteration. Bronchiolitis in specific settings leads to bronchiolectasis, resulting in bronchiectasis. © 2013 2013 Expert Reviews Ltd.

The advent of computed tomography permitted recognition of the coexistence of pulmonary fibrosis and emphysema (CPFE). Emphysema is usually encountered in the upper lobes preceding fibrosis of the lower lobes, and patients are smokers, predominantly male, with distinct physiologic profile characterized by preserved lung volumes and markedly reduced diffusion capacity. Actually, the term CPFE is reserved for the coexistence of any type and grade of radiological pulmonary emphysema and the idiopathic usual interstitial pneumonia computed tomography pattern as well as any pathologically confirmed case. CPFE is complicated by pulmonary hypertension, lung cancer and acute lung injury and may present different outcome than that of its components. © 2013 2013 Expert Reviews Ltd.

Background. In IPF, defects in lung mechanics and gas exchange manifest with exercise limitation due to dyspnea, the most prominent and disabling symptom. Aim. To evaluate the role of exercise testing through the 6MWT (6-minute walk test) and CPET (cardiopulmonary exercise testing) in the survival of patients with IPF. Methods. This is a prospective, observational study evaluating in 25 patients the relationship between exercise variables through both the 6MWT and CPET and survival. Results. By the end of the observational period 17 patients were alive (33% mortality). Observation ranged from 9 to 64 months. VE/VCO2 slope (slope of relation between minute ventilation and CO2 production), VO2 peak/kg (peak oxygen consumption/kg), VE/VCO2 ratio at anaerobic threshold, 6MWT distance, desaturation, and DLCO% were significant predictors of survival while VE/VCO2 slope and VO2 peak/kg had the strongest correlation with outcome. The optimal model for mortality risk estimation was VO2 peak/kg + DLCO% combined. Furthermore, VE/VCO2 slope and VO2 peak/kg were correlated with distance and desaturation during the 6MWT. Conclusion. The integration of oxygen consumption and diffusing capacity proved to be a reliable predictor of survival because both variables reflect major underlying physiologic determinants of exercise limitation. © 2013 Christina Triantafillidou et al.

PURPOSE OF REVIEW: Diagnosis of idiopathic interstitial pneumonias (IIPs) requires the exclusion of, among others, concomitant connective tissue diseases (CTDs), which may present as interstitial lung disease (ILD). This review focuses on the evaluation required to separate these entities through serology, although not exclusively. RECENT FINDINGS: Several recent data suggest that patients diagnosed with IIPs can show evidence of CTDs on follow-up. This is especially true for nonspecific interstitial pneumonia but may also be seen with other forms of ILD. SUMMARY: ILDs may occur alone, IIPs, or in association with, among others, CTDs. In the latter case, they may present before, during or even several months or years after the fulfillment of undisputed criteria for CTDs. If present before, their presentation presupposes their occurrence in early undiagnosed, undefined or undifferentiated CTD, which occasionally indefinitely maintains this status of diagnostic uncertainty, especially if ILD is empirically treated by immunosuppressants. Serologic evaluation for autoantibodies assisted by serum inflammatory biomarkers, detailed search for clinical clues of CTDs and suggestive histopathologic features on lung specimens may provide a framework to build the correct diagnosis. Obtaining a diagnosis of ILD associated with CTD exceeds semantics as this subset of patients may present different natural history, pathobiology, treatment and prognosis. Copyright © 2012 Lippincott Williams & Wilkins.

Background: In Idiopathic pulmonary fibrosis (IPF) irreversibly progressive fibrosing parenchymal damage, leads to defects in mechanics and gas exchange, manifesting with disabling exertional dyspnea. Previous studies have shown a relationship between fibroblast foci (FF) profusion and severity and survival and a relationship between dyspnea grade and severity and outcome. We hypothesized a relationship between Medical Research Council (MRC) dyspnea scale with FF, and a relationship between FF and functional parameters and survival.Methods: We retrospectively reviewed 24 histologically documented IPF patients. Profusion of FF was semiquantitatively evaluated by two scores, Brompton and Michigan. Survival analysis was performed by fitting Cox regression models to examine the relationship of the two scores with survival and the non-parametric Spearman correlation coefficient was calculated to describe the relationships of FF scores with dyspnea scores and functional parameters.Results: No statistically significant correlation between FF scores and the MRC scores was observed (p = 0.96 and p = 0.508 respectively). No significant correlation between FF scores and survival (p = 0.438 and p = 0.861 respectively) or any functional parameter was observed.Conclusions: The lack of relationship between the MRC dyspnea scale and the FF might relate to the fact that dyspnea in IPF better reflects the overall of lung damage and its related consequences on mechanics and gas exchange whereas FF, one of its histological hallmarks, may not reflect its entire histology derangement also constrained by the geographically limited sampled tissue. This might be also valid for the observed lack of association between FF and survival or functional parameters. © 2011 Triantafillidou et al; licensee BioMed Central Ltd.

Idiopathic pulmonary fibrosis (IPF) is a dreadful, chronic, and irreversibly progressive fibrosing disease leading to death in all patients affected, and IPF acute exacerbations constitute the most devastating complication during its clinical course. IPF exacerbations are subacute/acute, clinically significant deteriorations of unidentifiable cause that usually transform the slow and more or less steady disease decline to the unexpected appearance of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) ending in death. The histological picture is that of diffuse alveolar damage (DAD), which is the tissue counterpart of ARDS, upon usual interstitial pneumonia, which is the tissue equivalent of IPF. ALI/ARDS and acute interstitial pneumonia share with IPF exacerbations the tissue damage pattern of DAD. 'Treatment' with high-dose corticosteroids with or without an immunosuppressant proved ineffective and represents the coup de grace for these patients. Provision of excellent supportive care and the search for and treatment of the 'underlying cause' remain the only options. IPF exacerbations require rapid decisions about when and whether to initiate mechanical support. Admission to an intensive care unit (ICU) is a particular clinical and ethical challenge because of the extremely poor outcome. Transplantation in the ICU setting often presents insurmountable difficulties. © 2010 BioMed Central Ltd.