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Background: Pleuroparenchymal fibroelastosis (PPFE) has a variable disease course with dismal prognosis in the majority of patients with no validated drug therapy. This study is to evaluate the effect of nintedanib in patients with idiopathic and secondary PPFE. Patients admitted to a tertiary care center (2010-2019) were included into this retrospective analysis if they had a multidisciplinary diagnosis of PPFE, had been followed-up for 3 months or more, and had lung function tests and chest CTs available for review. Changes in pulmonary function tests were assessed using non-parametric tests and linear mixed effect model. Lung volumes were measured with lobar segmentation using chest CT., Results: Out of 21 patients with PPFE, nine had received nintedanib, six had received another treatment and another six patients were monitored without drug therapy. Annual FVC (% of predicted) relative decline was - 13.6 ± 13.4%/year before nintedanib and - 1.6 ± 6.02%/year during nintedanib treatment (p = 0.014), whereas no significant change in FVC% relative decline was found in patients receiving another treatment (- 13.25 ± 34 before vs - 16.61 ± 36.2%/year during treatment; p = 0.343). Using linear mixed effect model, the slope in FVC was - 0.97%/month (95% CI: - 1.42; - 0.52) before treatment and - 0.50%/month (95% CI: - 0.88; 0.13) on nintedanib, with a difference between groups of + 0.47%/month (95% CI: 0.16; 0.78), p = 0.004. The decline in the upper lung volumes measured by CT was - 233 mL/year ± 387 mL/year before nintedanib and - 149 mL/year ± 173 mL/year on nintedanib (p = 0.327). Nintedanib tolerability was unremarkable., Conclusion: In patients with PPFE, nintedanib treatment might be associated with slower decline in lung function, paving the way for prospective, controlled studies., (© 2021. The Author(s).)

Background: Interstitial pneumonia with autoimmune features (IPAF) has recently been defined by an international Taskforce to characterize interstitial lung disease associated with systemic manifestations limited to subtle serological and clinical autoimmune abnormalities and not fulfilling the international criteria for the diagnosis of a given connective tissue disease., Objective: to report on a series of patients with IPAF, and to compare their outcome to that of a cohort of patients with idiopathic pulmonary fibrosis (IPF)., Methods: Retrospective analysis of consecutive patients in a single institution over a 3-year period., Results: Out of 778 consecutive patients with interstitial lung disease, 55% had idiopathic interstitial pneumonia (including 20.1% with IPF), 21.5% had connective tissue disease, and 7.3% had IPAF. Patients (49% of females) had a mean FVC of 64% and a mean DLco of 49%. Serologic criteria for IPAF were the most frequent (93%), followed by "morphologic" criteria (79%), and clinical criteria (47%). Fifty three percent of patients had a NSIP pattern on CT. Nailfold capillaroscopy found giant capillaries in 13/30 patients tested (23%). No significant was found in overall survival between patients with IPAF and those with IPF., Conclusion: The recently defined criteria for IPAF are fulfilled by a significant proportion of patients referred for interstitial lung disease. As compared to those with IPF, patients with IPAF are more frequently females, have distinctive characteristics, have relatively frequent abnormalities at nailfold capillaroscopy, with no difference in age or in overall survival. Prospective studies are needed to guide the management of IPAF., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes [STING]-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

As the bronchioles have a strategic position between the airways and the alveolar structures, they are at a site where disorders of many origins may develop, including infections, inflammatory and/or fibrosing processes of immune, occupational, environmental, tumoral, and iatrogenic origin, which may result in predominant bronchiolitis and/or organizing pneumonia. This etiologic variety results in many distinct entities and syndromes, common or rare, with new or renewed faces such as bronchiolocentric interstitial pneumonia or organizing pneumonia primed by radiation to the breast., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines., (©ERS 2014.)

Bakers are exposed daily to flour and may be susceptible to immunologic occupational diseases. A 30-year-old, nonsmoking, female baker was referred for progressive dyspnea on exertion, basal crackles on auscultation, restrictive lung function, decreased diffusing capacity of the lung for carbon monoxide, ground glass hyperdensities with a mosaic pattern on high-resolution CT scan, 25% lymphocytosis by BAL, and cellular chronic bronchiolitis with peribronchiolar interstitial inflammation by lung biopsy specimen. Cultures from flours isolated nine species, including Aspergillus fumigatus. Twenty-six antigens were tested. Serum-specific precipitins were found against A fumigatus, the flour mite Acarus siro, and total extracts from maize and oat. Outcome was favorable with cessation of occupational exposure to flours and transient therapy with prednisone and immunosuppressive agents. To our knowledge, this report is the first of a well-documented case of hypersensitivity pneumonitis due to sensitization to fungi- and mite-contaminated flours. Hypersensitivity pneumonitis--and not only asthma and allergic rhinitis--should be suspected in bakers with respiratory symptoms.

Biopsy-proven cases of eosinophilic bronchiolitis have only been reported in isolation, and all come from Japan. We present six patients with hypereosinophilic obliterative bronchiolitis (HOB), defined by the following criteria: 1) blood eosinophil cell count >1 G·L(-1) and/or bronchoalveolar lavage eosinophil count >25%; 2) persistent airflow obstruction despite high-dose inhaled bronchodilators and corticosteroids; and 3) eosinophilic bronchiolitis at lung biopsy (n=1) and/or direct signs of bronchiolitis (centrilobular nodules and branching opacities) on computed tomography (n=6). Chronic dyspnoea and cough which was often severe, without the characteristic features of asthma, were the main clinical manifestations. Atopy and asthma were present in the history of three and two patients, respectively. One patient met biological criteria of the lymphoid variant of idiopathic hypereosinophilic syndrome. Mean blood eosinophil cell count was 2.7 G·L(-1) and mean eosinophil differential percentage at bronchoalveolar lavage was 63%. Mean initial forced expiratory volume in 1 s/forced vital capacity ratio was 50%, normalising with oral corticosteroid therapy in all patients. HOB manifestations recurred when oral prednisone was decreased to 10-20 mg·day(-1), but higher doses controlled the disease. HOB is a characteristic entity deserving to be individualised among the eosinophilic respiratory disorders. Thorough analysis is needed to determine whether unrecognised and/or smouldering HOB may further be a cause of irreversible airflow obstruction in chronic eosinophilic respiratory diseases.

Objective: To compare anti-PM/Scl autoantibody-associated interstitial lung disease (ILD) with anti-aminoacyl-tRNA synthetases (anti-ARS) autoantibody-associated ILD., Methods: We retrospectively studied 21 patients with ILD from a department of respiratory medicine, including 9 with anti-PM/Scl autoantibodies (6 women, median age 55 yrs, followup 5.5 yrs) and 12 with anti-ARS autoantibodies (6 women, median age 59 yrs, followup 2.3 yrs)., Results: Pulmonary manifestations in patients with anti-PM/Scl autoantibody-associated ILD usually followed the extrapulmonary manifestations of the connective tissue disease (CTD) (7/9 cases). The predominant imaging features on initial high resolution computed tomography were ground-glass attenuation and reticular opacities, and mainly suggested nonspecific interstitial pneumonia in both groups. CTD was classified as dermatomyositis (DM; 2), undifferentiated CTD (2), cutaneous limited systemic sclerosis (2), rheumatoid arthritis (RA; 1), and overlap syndrome (1) in the anti-PM/Scl group; and polymyositis (4), undifferentiated CTD (5), DM (1), amyopathic DM (1), and RA (1) in the anti-ARS group. Frequencies of arthralgia, Raynaud phenomenon, cutaneous rash, and mechanic's hands were comparable in both groups. Myalgia or muscle weakness was present in 0/9 PM/Scl and 5/12 ARS patients (p < 0.05). More than 1 autoantibody was present in 11 patients. ILD worsened despite treatment in 4 patients with anti-PM/Scl autoantibodies and 2 with anti-ARS autoantibodies, and included 1 death., Conclusion: Anti-PM/Scl and anti-ARS antibodies are associated with similar clinical manifestations, with the exception only of more overt myositis in the latter, therefore challenging the clinical specificity of the antisynthetase syndrome.

Ovine pulmonary adenocarcinoma (OPA) is a lung cancer strikingly similar to the pneumonic-type mixed invasive adenocarcinoma with a predominant bronchioloalveolar component in humans. Telomerase activity in OPA and the potential involvement of the kinase Akt in telomerase activation and regulation of cell proliferation were investigated. Lung tissues were collected from sheep with a histopathological diagnosis of OPA or controls. Epithelial cell cultures were derived in vitro from lung tissues. Telomerase activity was evaluated using the telomeric repeat amplification protocol method. Phosphorylation of Akt was detected by Western blotting. Telomerase activity was significantly higher in OPA lung tissues compared to control lung tissues. A high telomerase activity was detected in eight out of 12 (67%) primary cell cultures derived from tumours. A high level of expression of phosphorylated Akt was found in 10 out of 27 (37%) tumours, with abolition of Akt activation in response to epidermal growth factor stimulation demonstrated in primary cell cultures derived from tumours. Telomerase activation takes place in ovine pulmonary adenocarcinoma tumour cells and may be partly attributable to Akt activation. Telomerase may inhibit cellular senescence and contribute to the accumulation of tumour cells in mixed adenocarcinoma with a bronchioloalveolar component. Further work is necessary to identify alternative signalling pathways of telomerase activation in tumours.

Objective: Many changes have occurred in the natural history and the management of active infectious endocarditis (AIE) in recent years. Therefore, the records of patients admitted in a tertiary care specialized hospital presenting with the Duke criteria were reviewed., Methods: Adults operated on to treat AIE were included during a 3-year period. Patients presenting with AIE associated with a pacemaker were not included. Bacteriologic investigations included blood cultures, intraoperative samplings (including polymerase chain reaction), and serologies. Clinical and bacteriologic factors associated with hospital mortality were studied by univariate regression analysis (p < 0.05)., Results: Ninety-eight of 164 patients (60%) admitted with the diagnosis of AIE underwent valvular surgery. The duration between the beginning of AIE and surgery was 23 +/- 16 (mean +/- standard deviation) days. Only 45 patients had a previous history of valvular disease. Seventy-two patients presented with aortic and 41 with mitral valve AIE. Fifty suffered from embolic events. Streptococcus species were responsible in 64 cases (23 were Streptococcus bovis) and Staphylococcus species in 24 cases. Death occurred postoperatively in 19 patients. The factors associated with fatal outcome were preoperative hemodynamic instability, age, Parsonnet and Simplified Acute Physiology Score II scores, diabetes mellitus, preexisting valvulopathy, antiarrhythmic treatment, hypoalbuminemia, renal dysfunction, duration of extracorporeal circulation, and red cell allogeneic transfusions. The type of bacteria did not influence mortality. The mean intensive care unit and hospital stays were 10 and 39 days, respectively. Eleven patients suffered from neurologic sequelae; 2 years later, 2 of them presented with severe deficit and 1 had died., Conclusions: AIE necessitating cardiac surgery should be considered as a severe and resource-consuming disease.

Rheumatoid arthritis (RA)-associated constrictive bronchiolitis is a severe condition with no established efficient treatment. A 55-year-old woman with seropositive RA developed rapidly progressive constrictive bronchiolitis confirmed by lung biopsy. Her clinical condition worsened despite steroids and azathioprine. Treatment with etanercept-a tumor necrosis factor (TNF)-alpha inhibitor-combined with methotrexate, resulted in a marked improvement of both her clinical condition and pulmonary function tests. Treatment with TNF-alpha inhibitors and methotrexate may be proposed in RA-associated constrictive bronchiolitis, a severe condition hitherto not amenable to improvement.

The pathological features of Whipple endocarditis, which is caused by Tropheryma whipplei, were histologically evaluated in cardiac valves from 5 patients. We used quantitative image analysis to compare the valvular fibrosis, calcifications, vegetations, inflammation, and vascularization due to Whipple endocarditis with those due to non-Whipple endocarditis and degenerative valves. We also studied the presence of T. whipplei in valves by immunohistochemical analysis, culture, and polymerase chain reaction (PCR). In histologic analysis, Whipple endocarditis was characterized by significant fibrosis, a lack of calcifications, slight inflammation and vascularization, and vegetations of intermediate size. Inflammatory infiltrates consisted mainly of foamy macrophages and lymphocytes. We found that the detection of T. whipplei in cardiac valves, by immunohistochemical analysis, was correlated with the detection of the bacterium by culture and PCR. We report, for the first time, the immunodetection of T. whipplei in a surgically removed arterial embolus. Pathological and immunohistologic analyses may contribute to the diagnosis of Whipple endocarditis.

We report two cases of a rare presentation of pulmonary sclerosing hemangioma as an endobronchial polyp resulting in clinical symptoms of bronchial obstruction. We describe the histological and cytological description of this entity based on material obtained during bronchoscopic examination. In both cases, bronchoscopy revealed a polypoid mass protruding into the left lower lobar bronchus, with a smooth and hemorrhagic surface, reminiscent of a carcinoid tumor. On bronchial washing in case 1, numerous small round cells were seen with uniform nuclei and inconspicuous nucleoli, arranged in clusters with a pavement-type pattern and papillary configuration. The presence of a few reactive pneumocytes gives a dual cell proliferation, in a background of numerous foamy macrophages. Although the four architectural patterns of sclerosing hemangioma were present in the resected tumors, the papillary and solid patterns predominated in the endobronchial component of the tumors and these were seen on the bronchial biopsies. Recognition of the papillary pattern, the typical round cells coexpressing thyroid transcription factor-1 and epithelial membrane antigen without cytokeratin immunoreactivity, are helpful clues for the diagnosis on bronchial biopsy. Finally, hopefully awareness by clinicians and pathologists that sclerosing hemangioma can present as an endobronchial mass will facilitate diagnosis when this rare event occurs.

Objective: We investigated whether ischemic preconditioning (PC) may modify mitochondrial permeability transition (MPT) pore opening., Methods: In protocol 1, New Zealand White rabbits underwent either no intervention (sham group) or 10 min of ischemia followed by 5 min of reperfusion, preceded (PC) or not (C; control) by one episode of 5 min of ischemia and 5 min of reperfusion. Rabbits were pretreated by either saline or the MPT pore inhibitor cyclosporin A (CsA), or its non-immunosuppressive derivative Cs29 (10 mg/kg, IV bolus). Hearts were harvested and mitochondria isolated for further assessment of Ca(2+)-induced MPT using a Ca(2+)-sensitive micro-electrode. In protocol 2, C and PC hearts underwent 30 min of ischemia and 4 h of reperfusion. They were pretreated either by saline, CsA or Cs29, as in protocol 1. Infarct size was assessed by triphenyltetrazolium, and apoptosis by TUNEL staining., Results: In protocol 1, the Ca(2+) overload required to induce MPT pore opening was significantly higher in PC than in C hearts. CsA and Cs29 significantly increased the Ca(2+) overload required for MPT pore opening. In protocol 2, mean infarct size averaged 25% of the risk region in CsA/Cs29 treated hearts versus 15% in PC and 55% in controls (P<0.05 vs. C, P=ns vs. PC). Cardiomyocyte apoptosis was significantly reduced by PC and cyclosporin treatment with a mean apoptotic index of less than 2% in either group versus more than 11% in controls., Conclusion: This suggests that delayed opening of MPT pore may play a major role in ischemic PC.

This study investigated interstitial pneumonia associated with amyopathic dermatomyositis, dermatomyositis and polymyositis, paying particular attention to muscular and/or cutaneous manifestations and their chronology relative to lung involvement. Patients included four males and 13 females, aged 51.7+/-10.8 yrs, who had surgical lung biopsy. Diagnoses included dermatomyositis (10 patients), polymyositis (four patients) and amyopathic dermatomyositis (three patients). Solitary respiratory manifestations preceded the onset of any skin or muscle disease in four cases (24%). Reticular and ground glass opacities were the most frequent computed tomography (CT) findings. Pathological review showed nonspecific interstitial pneumonia (eleven, 65%; cellular, two; cellular and fibrotic, five; fibrotic, four), usual interstitial pneumonia (two), organising pneumonia (two), lymphocytic interstitial pneumonia (one), and unclassifiable interstitial pneumonia (one). Nonspecific interstitial pneumonia was the most common histological pattern of interstitial pneumonia in patients with amyopathic dermatomyositis (three of three) and in patients with respiratory symptoms as the initial clinical manifestation of the connective tissue disease (three of four). Survival at 5 yrs was 50%. This study shows the clinician should remain alert to potential muscular or cutaneous manifestations whenever a pathological diagnosis of nonspecific interstitial pneumonia is made.

We used broad-range eubacterial PCR amplification followed by direct sequencing to identify microbial pathogens in heart valve material from 29 patients with histologically confirmed infective endocarditis and 23 patients free of infective endocarditis. Microorganisms cultured by conventional techniques matched those identified by PCR in 21 cases. PCR alone identified the causative agent in three cases (Streptococcus bovis, Staphylococcus cohnii, and Coxiella burnetii), allowing better patient management. PCR corrected the initial bacteriological diagnosis in three cases (Streptococcus bovis, Streptococcus mutans, and Bartonella henselae). Among the 29 cases of histologically confirmed infective endocarditis, PCR findings were positive in 27 cases and were consistent with the bacterial morphology seen at Gram staining (26 cases) or with the results obtained by immunohistologic analysis with an anti-C. burnetii monoclonal antibody (one case). In two other cases of histologically confirmed infective endocarditis, PCR remained negative in a blood culture-negative case for which no bacteria were seen at histological analysis and in one case with visualization of cocci and blood cultures positive for Enterococcus faecalis. Ten clinical diagnoses of possible infective endocarditis were ruled out by histopathological analysis of the valves and subsequently by PCR. PCR was negative in 13 of the 14 patients in whom infective endocarditis was rejected on clinical grounds; the other patient was found to have Coxiella burnetii infective endocarditis on the basis of PCR and histopathological analysis and was subsequently included in the group of 29 definite cases. In total, PCR contributed to the diagnosis and management of infective endocarditis in 6 of 29 (20%) cases.

Four cases of lymphomatoid granulomatosis are reported, three of them involving the lung. Histological features included a true angiocentric and angiodestructive polymorphic cellular proliferation. This included histiocytes, plasma cells, many reactive T-cells and rare large, atypical cells which were of the B phenotype. Epstein-Barr virus was detected in the atypical cells by in situ hybridization in three cases, with expression of both latent membrane proteins (LMP)-1 and Epstein-Barr nuclear antigen-2 in two cases and expression of only LMP-1 in the third case. Expression of both of these proteins suggests a defect in the T-cell-mediated immunity and that Epstein-Barr virus is not only a silent passenger but may also be involved in the pathogenesis of the disease. This could have implications for therapy.

Background: Solid papillary carcinoma of the breast was recently described. This tumor display distinctive clinical and morphologic features. It is an intraductal papillary carcinoma frequently associated with mucinous carcinoma and infiltrating ductal carcinoma not otherwise specified., Case: Fine needle aspiration cytology (FNAC) of a solid papillary carcinoma of the right breast in an 82-year-old female, demonstrated a cellular specimen of discohesive, small, uniform and ovoid tumor cells, with occasional loose cluster. The cytoplasm was abundant and finely granular. The nuclei were round, without marked atypia. The nucleoli were inconspicuous. SCant mucinous material was present. The diagnosis was confirmed histologically and immunohistochemically., Conclusion: The cytologic aspects of solid papillary carcinoma of the breast suggest a carcinoma with endocrine differentiation and a weak mucinous component.