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Summary Background Kinder et al. proposed a broader definition of undifferentiated connective tissue disease (UCTD) and reported that the entity of nonspecific interstitial pneumonia (NSIP) is a lung manifestation of this more broadly defined UCTD. However, a retrospective study did not support their findings and its clinical significance remains unclear. Methods We prospectively evaluated the significance of this broadly defined UCTD in idiopathic interstitial pneumonias (IIPs) in consecutive patients with surgical lung biopsy. Patients were evaluated with a symptoms check list and underwent comprehensive serologic testing as screening for UCTD. Clinical characteristics, high-resolution CT images, lung biopsy specimens, serial FVC change, and survival were analyzed. Results Among 76 patients with IIPs, 24 patients (32%) fulfilled the UCTD criteria. Diagnosis of 24 patients with UCTD was usual interstitial pneumonia in 12 (50%), NSIP in 7 (29%), and unclassifiable interstitial lung disease (ILD) in 5 (21%). The diagnosis of 52 patients who did not have UCTD was idiopathic pulmonary fibrosis in 27 (52%), NSIP in 11 (21%), unclassifiable ILD in 13 (25%) and cryptogenic organizing pneumonia in 1 (2%). One-year and two-year FVC changes showed no significant difference between UCTD and non-UCTD, however, significant differences in FVC change were observed among histopathological diagnoses both in UCTD and in non-UCTD. In multivariate survival analysis, %FVC and histopathological UIP pattern were independent predictors for survival but UCTD diagnosis was not. Conclusions A diagnosis of UCTD was not useful in discriminating NSIP or in predicting disease progression and prognosis in our cohort of IIPs. Histopathological UIP pattern was an independent predictor for mortality irrespective of a diagnosis of UCTD.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia. The pathogenicity of IPF has been widely investigated but still remains to be clarified. Efferocytosis, the specialized recognition and ingestion of apoptotic cells by phagocytes, is essential for the resolution of inflammation in the lungs and repair of injured tissues. Impaired efferocytosis contributes to the pathogenesis of chronic lung diseases such as emphysema and cystic fibrosis. We hypothesized that efferocytosis would also be reduced in alveolar macrophages isolated from subjects with IPF. Methods: Efferocytosis, was evaluated using Wright-Giemsa stained cell preparations isolated from the bronchoalveolar lavage (BAL) fluid of patients with IPF (n = 5), nonspecific interstitial pneumonitis (n = 6), cryptogenic organizing pneumonia (n = 4) and eosinophilic pneumonia (EP) (n = 5). Results: Uningested apoptotic cells were significantly higher in BAL fluid from patients with IPF compared to other forms of interstitial lung disease. Macrophages isolated from patients with eosinophilic pneumonia had significantly fewer phagocytic ingestions than macrophages from the other three groups. Conclusion: Efferocytosis by alveolar macrophages was significantly lower in subjects with IPF compared to subjects with other interstitial pneumonia. Dysregulated efferocytosis may contribute to the pathogenesis of IPF., Respiratory Medicine, 106(12), pp.1800-1803; 2012

Summary Background Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, and the prognosis remains poor. On the other hand, other fibrotic interstitial pneumonias such as idiopathic nonspecific interstitial pneumonia (I-NSIP) and collagen vascular disease-associated interstitial pneumonia (CVD-IP) resemble IPF, but they respond to therapy and the prognosis is better. We searched for biomarkers to distinguish IPF from other fibrotic interstitial pneumonias and investigated whether S100A9 could be useful for discriminating types of fibrotic interstitial pneumonia based on our preliminary proteomic findings. Methods We measured S100A9 levels in serum and bronchoalveolar lavage fluid (BALF) from 28 patients with IPF, 15 with I-NSIP, 20 with cryptogenic organizing pneumonia (COP), 35 with CVD-IP and 23 healthy individuals (controls) using enzyme-linked immunosorbent assays. S100A9 in the lung was also immunohistochemically localized. Results S100A9 levels in BALF, but not in serum, were significantly elevated in patients with IPF compared with I-NSIP, COP, CVD-IP and healthy individuals. S100A9 immunoreactivity was localized mainly in macrophages and neutrophils in lung specimens from patients with IPF. The results of receiver operating characteristic (ROC) curve analysis showed that BALF S100A9 levels had sufficient specificity and sensitivity to distinguish IPF from I-NSIP and CVD-IP. Conclusion S100A9 in BALF might serve as a candidate biomarker to discriminate between IPF and other fibrotic interstitial pneumonias.

SummaryBackgroundTNF receptors (TNFR1 and TNFR2) and Fas belong to the system of apoptosis-signalling receptor molecules and may play a role in the pathogenesis of interstitial lung disease. Patients with cryptogenic organizing pneumonia (COP) usually respond well to corticosteroids, in contrast to those with idiopathic pulmonary fibrosis (IPF). This may be due to the different pathogenesis.MethodsThe expression of TNFR1, TNFR2 and Fas on bronchoalveolar lavage (BAL) macrophages and lymphocytes was analysed in 9 patients with COP, 10 with IPF and 12 controls. The production of soluble TNFR1, 2 and TNF-α by alveolar macrophages was measured by ELISA.ResultsTNFR1 and Fas expression on alveolar macrophages was significantly higher in COP than in controls and IPF. The expression of TNFR2 on alveolar macrophages was also increased in COP compared to controls. The expression of TNFR2 and Fas on lymphocytes was significantly higher in COP than in IPF and controls. In addition, the expression of TNFR1, TNFR2 and Fas on BAL cells correlated positively with BAL lymphocytes (p

SummaryBackgroundsEpithelial cell apoptosis plays an important role in the pathogenesis of idiopathic interstitial pneumonia (IIP).MethodsSerum levels of caspase-cleaved cytokeratin-18 (M30) were measured in 55 patients with IIP and 34 healthy controls using enzyme-linked immunosorbent assays. The IIP cases included usual interstitial pneumonia (UIP; n = 30), nonspecific interstitial pneumonia (NSIP; n = 15), and cryptogenic organizing pneumonia (COP; n = 10). The radiological scoring was performed based on high-resolution computed tomography (HRCT) findings.ResultsPatients with IIP had higher serum M30 levels than did the control group (178.6 ± 91.5 vs. 113.7 ± 46.8 U/L, p

Summary Background Cryptogenic organizing pneumonia (COP) is a rare disease, and its diagnosis requires histological confirmation. The objective of our study was to describe the findings of the thoracic high-resolution computed tomography (HR-CT) and bronchoalveolar lavage (BAL) in patients with confirmed COP and evaluate the complementary diagnostic use of BAL and thoracic HR-CT. Methods Patients recorded in the registry of interstitial pulmonary diseases between 1991 and 2008 were located and the COP patients selected. Results We identified 21 patients with histological confirmation of COP. The median age was 58.0 ± 15.9 years, and 61.9% of patients were female. The most frequent thoracic HR-CT profile was patchy infiltrate (71.4%), followed by parenchymatous consolidation (42.9%). The most frequent BAL profile was mixed alveolitis (62%) with lymphocyte predominance, a CD4/CD8 index of 0.4 and foamy macrophages. The effectiveness of transbronchial biopsy was 66.6%. The diagnostic utility of Poletti’s BAL criteria gives us a specificity of 88.8%, although the sensitivity obtained was low. The specificity of certain HR-CT profiles is 99%. In addition, we observed a complementary use of the HR-CT and the BAL. Conclusions The imaging findings and BAL could be useful for patients with appropriate clinical presentation and for those whose transbronchial biopsy is negative or for whom a confirmatory biopsy cannot be performed.

Defensins are endogenous antibiotics and regulators of inflammation, immunity and wound repair. Their concentrations are substantially increased in bronchoalveolar lavage fluid (BALF) of patients with infectious lung diseases. alpha-defensin (HAD) levels are also elevated in patients with idiopathic pulmonary fibrosis (IPF) and correlated with the decline in pulmonary function tests, suggesting the association of defensins with the pathogenesis of interstitial lung diseases. The aim of this study was to determine the profile of defensins in interstitial lung diseases. Serum and BALF levels of HAD and beta-defensin 1 and 2 (HBD-1, and -2) were measured by radioimmunoassay in 63 patients with interstitial lung diseases, including idiopathic pulmonary alveolar proteinosis (PAP), IPF, nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) and pulmonary sarcoidosis, and in 9 healthy volunteers as controls. Levels of HAD in BALF of patients with PAP were significantly higher than those in controls and patients with COP and sarcoidosis. Serum levels of HAD in all groups were significantly higher than those in controls. Levels of HBD-1 and -2 in BALF of patients with PAP were extremely high in all subjects. Serum levels of HBD-1 were higher in all patient groups, with the exception of those with PAP, and those of HBD-2 were also higher in patients with IPF and sarcoidosis, compared with controls. BALF of PAP patients, but not IPF patients and controls, expressed antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. Our findings suggest different kinetics of HAD and HBD-1 and -2 in serum and BALF of interstitial lung diseases and that these antimicrobial peptides in the airway lumen may contribute to prevention of bacterial airway infections in PAP.

Summary Background Organizing pneumonia (OP) is a distinct histopathologic lesion that occurs in a variety of clinical contexts. There have been occasional reports of OP occurring in patients with hematologic malignancies. Study objectives To examine the association of OP with hematologic malignancies and to assess the clinical course of affected patients. Design A retrospective review of our institutional experience of unexplained OP developing in patients with hematologic malignancies. Setting Tertiary care, referral medical center. Patients We identified 6 patients with a verified histopathologic diagnosis of OP and antecedent or concomitant diagnosis of a hematologic malignancy from the Mayo Clinic database (1995–2003). Clinical, radiologic, and outcome data were abstracted from records. Results Underlying hematologic disorders included lymphoma (2), acute leukemia (2), cutaneous T-cell lymphoma (1), and myelodysplastic syndrome (1). OP was diagnosed by surgical lung biopsy in 4 and bronchoscopic biopsy in 2. Four of the 6 patients had previously been exposed to chemotherapeutic agents, two had not. Three of the 6 patients had bone marrow transplantation prior to development of OP. Five patients were treated with prednisone and all experienced symptomatic improvement with documented radiologic resolution in 4. One patient experienced symptomatic and radiologic resolution with observation alone. Three patients ultimately died from complications of their underlying hematologic disorder and 1 patient died of unknown causes. Two patients were alive without respiratory complaints more than 1 year after lung biopsy. Conclusions OP occurs in patients with underlying hematologic malignancies who may or may not have been treated with chemotherapy and responds favorably to corticosteroid therapy.

Bronchiolitis obliterans with organizing pneumonia (BOOP) is an infrequently encountered clinical condition that can mimic a number of other pathologic lung processes. The presentation of this treatable condition in cancer patients has not been described in any large series. We conducted a retrospective study of patients with BOOP at Memorial Sloan–Kettering Cancer Center, New York, NY, U.S.A. from January 1992 to December 1999. The type and treatment of primary cancer, clinical and radiographic features of initial BOOP presentation, and outcome following therapy were recorded. Forty-three patients with an underlying diagnosis of cancer were found on lung biopsy to have BOOP as an isolated entity. BOOP was encountered in patients with a variety of clinical presentations, and many types of malignancies. The symptom patterns were non-specific, as were the physiological abnormalities. The only clear relationship between the underlying malignancy and the diagnosis of BOOP at presentation was in the chest radiographic findings. Patients with solid organ tumors were more likely to have nodular or mass like radiographic abnormalities (81%) than to have diffuse infiltrates (19%). We observed the opposite pattern in patients with hematologic malignancies (22% vs .67%). The vast majority of patients recovered from this condition. In conclusion, For cancer patients, BOOP represents a treatable cause of lung disease with protean manifestations. BOOP can mimic pulmonary malignancy and pulmonary infection. In cancer patients, the evaluation of new pulmonary symptoms accompanied by radiographic changes should include a consideration of this diagnosis.

Summary Introduction Few data are available on the epidemiology of interstitial lung diseases (ILDs), especially after the current classification of idiopathic interstitial pneumonias. The aim of this study is to provide data on the epidemiology of ILDs in Greece, under the ATS/ERS international consensus. Methods Departments of Pneumonology were contacted and asked to complete a questionnaire for every case of ILD that was alive on 2004 as well as for every new case from 1st January 2004 to 31st December 2004. Questions on the patients' demographic data, the exact diagnosis and the procedures used to establish the diagnosis were included. Centers covering about 60% of the Greek population have been analyzed. Results A total of 967 cases have been registered. The estimated prevalence of ILDs is 17.3 cases per 100,000 inhabitants. The estimated annual incidence of ILDs is 4.63 new cases per 100,000 inhabitants. The most frequent disease is sarcoidosis (34.1%), followed in decreasing order by idiopathic pulmonary fibrosis (19.5%), ILD associated with collagen vascular diseases (12.4%), cryptogenic organizing pneumonia (5.3%), histiocytosis (3.8%), and hypersensitivity pneumonitis (2.6%). Unclassified ILD or not otherwise specified accounted for the 8.5% of prevalent cases. Conclusions These data suggest that sarcoidosis and idiopathic pulmonary fibrosis are the most frequent ILDs in our population. In comparison with the few previous reports, interesting dissimilarities have been observed.

A patient receiving carbamazepine and imipramine presented with severe bronchiolitis obliterans organizing pneumonia (BOOP). He developed progressive respiratory failure in spite of high-dose steroid treatment. Cyclophosphamide was given as adjunctive therapy, and a rapid improvement was seen. The authors suggest that an early therapeutic trial of cyclophosphamide should be considered in patients with BOOP who fail to respond to steroids.

Noninfectious or unusual infectious diseases may present with clinical, radiological and laboratorial characteristics of community-acquired pneumonia (CAP). Usually their presence is only suspected after treatment failure, leading to inappropriate interventions, unnecessary costs and risks related to the untreated potentially life-threatening disease. The present study aimed to assess the noninfectious or unusual infectious diseases that may be misdiagnosed as CAP that progresses with treatment failure.Sixteen hospitalized patients with presumptive diagnosis of CAP and treatment failure were described. The most prevalent symptoms were fever and cough. Radiological pattern of air-space disease was observed in 10 (62%) patients. The diagnosis was established by autopsy (12%) or invasive procedures (88%), as follows: open lung biopsy (nine), flexible fiberoptic bronchoscopy (two), transthoracic fine needle aspiration (two) and bone marrow aspiration (one). Eight patients had noninfectious diseases: pulmonary embolism, cryptogenic organizing pneumonia, Wegener's granulomatosis, hypersensitivity pneumonitis, bronchocentric granulomatosis, neoplastic disease and acute leukemia. The unusual infectious diseases were: tuberculosis, cryptococcosis, actinomycosis, histoplasmosis and paracoccidioidomycosis.Patients with noninfectious or unusual infectious diseases may present with symptoms and radiological findings that mimic CAP. These diseases should always be suspected in patients who do not respond to initial empirical antimicrobial treatment, especially young patients or those without comorbidity.

A 50-year-old Chinese lady presented with subacute onset of dyspnoea, bilateral infiltrates on chest X-ray and type I respiratory failure. There were minor symptoms of arthralgia and myalgia. Subsequent investigations confirmed that she had organizing pneumonia, polymyositis and serum anti-Jo-1 antibody. Treatment with corticosteroids resulted in prompt improvement of the respiratory condition and myositis.

Pneumonitis is a serious adverse effect of amiodarone therapy, which is related to the average daily dose. A case of pneumonitis is described which developed after exposure to a low dose of amiodarone. This challenges the concept that low dose amiodarone therapy is safe.

The purpose of this study was to describe the clinical features at onset and outcome and the diagnostic approach in subjects with bronchiolitis obliterans-organizing pneumonia (BOOP). Over a 7-year period we observed 78 cases of biopsy-proven bronchiolitis obliterans-organizing pneumonia, in which well documented clinical and radiographic data were available. The final diagnosis of BOOP was validated when patients presented: (i) negative microbiological analysis on BAL fluid; (ii) a well documented improvement either spontaneous, or after steroid treatment or (iii) cases with progressive respiratory failure and increasing radiographic shadows, an open lung biopsy or autopsy that excluded other entities. There were 42 males and 36 females; the mean age was 61±12 years (range 12–85 years). Forty-two (54%) patients were current smokers, 25 (32%) had never smoked and 11 (14%) were ex-smokers. The clinical pattern at presentation of BOOP was more frequently similar to classical acute or sub-acute infectious pneumonia. Fever (63%), dyspnoea (58%) and dry cough (53%) were the typical symptoms on admission. A flu-like syndrome preceeding BOOP was observed in 21 cases (27%). Inspiratory crackles (78%) were the most typical finding at physical examination. However, 13% of the patients were asymptomatic and an abnormal chest X-ray film was the reason for seeking medical attention. Radiographically the most frequent pattern of BOOP was a unilateral consolidation (44%) with lower field predominance. A migratory behaviour was present in 22% of the cases. High-resolution computed tomographic (HR-CT) scan when performed, was more sensitive in detecting ground glass infiltrates, sub-pleural or peri-bronchovascular distribution or the presence of nodules or cavitation.Most patients (68%) were classified as having idiopathic BOOP. However, the same clinical-roentgenological pattern was observed in patients after radiotherapy for ductal breast carcinoma (6%), in collagen-vascular diseases (6%), related to drugs (9%), to infections serologically documented (4%), and to graft vs. host disease (4%).Four patients (all of whom had idiopathic BOOP) presented a rapid progressive respiratory failure needing mechanical ventilation. In another two cases respiratory failure appeared after a long period during which patients experienced exertional dyspnoea and low grade fever.BAL profile was characterized by lymphocytosis with a reduction of the CD4/CD8 ratio, associated with a slight increase of neutrophils and eosinophils and scattered mast cells. However in two cases we had an increased CD4/CD8 ratio and in one case the presence of a significant 12% of polyclonal B cells. In a few cases atypical (cytokeratin-positive cells) epithelial cells were detected: these cells were constantly present in the BAL fluid of patients with rapidly progressive respiratory failure.From the diagnostic point of view this series documents that transbronchial lung biopsy (coupled with BAL) can be the first diagnostic step. However, therapy can be started on the basis of BAL data (when a characteristic morphological and phenotypical profile is evident) in cases in which the clinical presentation is suggestive and a biopsy cannot be made. Most patients showed a rapid and good response to steroid therapy. However, three patients died (4%) in spite of steroid therapy (two cases) and steroid and cyclophosphamide therapy (one case).In conclusion, although clinical findings, chest X-ray film and CT Scan findings usually suggest the diagnosis a definite confirmation requires transbronchial lung biopsy and BAL and, less frequently, open lung biopsy.

SummaryAcute fibrinous and organizing pneumonia (AFOP) has recently been identified as an unusual variant of acute lung injury. We describe a man with rapidly progressive lung disease who had AFOP detected via surgical lung biopsy. The patient acutely decompensated while in the hospital and required mechanical ventilation as well as a prolonged ICU stay. He responded poorly to initial treatment and progressively worsened, but he subsequently responded very well to combined therapy with mycophenolate mofetil and methylprednisolone. The combination of corticosteroids and mycophenolate may provide a safe and effective treatment strategy for severe forms of this newly defined pulmonary syndrome.