How can autoantibodies predict the long-term outcome of patients with interstitial lung disease? Results from a retrospective cohort study.

OBJECTIVES: This study aimed to investigate whether positive serum autoantibodies (AAbs) have any impact on survival and time evolution of radiological findings and pulmonary function indices in patients with interstitial lung disease (ILD). PATIENTS AND METHODS: Ninety four patients with regular clinical, functional and high resolution computed tomography (HRCT) imaging follow-up for at least 12 consecutive months and complete testing for a panel of AAbs most commonly associated with ILD were enrolled in this retrospective two-center study. Eligible patients were divided into two groups based on the presence [ILD/AAb(+)] (n = 69) or absence [ILD/AAb(-)] (n = 25) of positive serum AAbs. All-cause mortality and longitudinal indicators of ILD progression such as a sustained decrease from baseline in absolute measurements of forced vital capacity (FVC) of ≥10% or single-breath diffusion capacity (DLCOSB) of ≥15% were the primary study endpoints. DLCOSB < 40% predicted on at least two consecutive measurements and progression of HRCT findings were our secondary endpoints. Kaplan-Meier (K-M) survival analysis and multivariate Cox proportional-hazards (PH) model were used to evaluate the prognostic significance of positive AAbs in the outcome of patients with ILD. RESULTS: ILD/AAb(+) patients were predominantly female (71% vs 32%), were significantly younger (54.8 ±â€¯14.6 vs 66.8 ±â€¯10.1 years), and had longer duration of follow-up (78.1 ±â€¯53.1 vs 41.6 ±â€¯26.7 months), compared with ILD/AAb(-) patients (p < .01 for each comparison). Baseline measurements of FVC (% pred.) and DLCOSB (% pred.) did not differ significantly between the two groups. At the end of follow-up, mortality rates and the percentage of patients with a sustained FVC decrease were lower in the ILD/AAb(+) group (p < .05 for each comparison). With the exception of DLCOSB < 40% pred., ILD/AAb(+) patients had a longer median time-to-event for each of the other studied outcomes (p < .01 for each K-M analysis). In addition, Cox PH models adjusted for age, smoking status, baseline pulmonary function tests and morphological pattern of ILD remained statistically significant in favor of the ILD/AAb(+) group (p < .05 for each comparison). CONCLUSIONS: AAb(+) patients with ILD seem to have a more favorable prognosis regarding all-cause mortality, long-term deterioration in lung function parameters and progression of HRCT findings than their AAb (-) counterparts.

Respiratory and lower limb muscle function in interstitial lung disease.

Growing evidence suggests that respiratory and limb muscle function may be impaired in patients with interstitial lung disease (ILD). Importantly, muscle dysfunction could promote dyspnoea, fatigue and functional limitation all of which are cardinal features of ILD. This article examines the risk factors for skeletal muscle dysfunction in ILD, reviews the current evidence on overall respiratory and limb muscle function and focuses on the occurrence and implications of skeletal muscle dysfunction in ILD. Research limitations and pathways to address the current knowledge gaps are highlighted.

Innate immunity alterations in idiopathic interstitial pneumonias and rheumatoid arthritis-associated interstitial lung diseases.

BACKGROUND: This is a prospective cohort study elucidating innate immunity in idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP) and RA-associated non specific interstitial pneumonia (RA-NSIP). METHODS: 23 IPF subjects, 9 COP subjects, 5 RA-UIP subjects, 8 RA-NSIP subjects were enrolled. 10 subjects were excluded. 19 healthy subjects served as controls. Blood and bronchoalveolar lavage (BAL) were obtained. Natural killer (NK) and NKT cells, NK cells apoptosis and the expression of triggering receptor expressed on myeloid cells type 1 (TREM-1) were assessed. Tumor necrosis factor-α (TNF-α) production was measured in cell cultures after stimulation with lipopolysaccharide endotoxin (LPS) and Pam3CysSK3, and in BAL. Surface expression of Toll-like receptors (TLR) 2 and 4 on peripheral blood monocytes (PBMC's) and circulating NK cells was also assessed. RESULTS: RA-NSIP had low blood NKs, marginally insignificant (p=0.07). These NKs poorly produced TNF-α after LPS stimulation. TLR's expression on NK cells was similar throughout disease groups and controls. PBMC's mainly from IPF patients exhibited low TNF-α production after LPS stimulation but not after Pam3CysSK3 stimulation, while TLR4 expression on PBMC's was found normal in all study groups. TLR2 expression on PBMC's was increased in IPF, but mainly in COP, RA-UIP and RA-NSIP (p=0.015). TREM-1 expression was significant on COP monocytes and on COP neutrophils versus controls. RA-NSIP monocytes also exhibited TREM-1 expression (p=0.07). Decreased TNF-α concentration in BAL was finally observed in IPF and RA-UIP. CONCLUSIONS: Innate immunity in the lungs and the peripheral circulation in IPF and RA-UIP are similar and more fibrotic than in RA-NSIP which is characterized by NK cell depletion and dysfunction. TREM-1 and TLR's likely affect patterns of inflammation in various interstitial lung diseases.

A prospective study on bacterial and atypical etiology of acute exacerbation in chronic obstructive pulmonary disease.

AIM: The bacterial and atypical etiology of acute exacerbations of chronic obstructive pulmonary disease was investigated and the diagnostic techniques used were compared among 92 hospitalized patients. MATERIALS & METHODS: Sputum specimens were investigated using culture and PCR, serological status evaluation was performed and the inflammatory profile was associated with the microbiological results. RESULTS & CONCLUSION: The majority of the patients (65.2%) had very severe airway obstruction. The most common bacteria were Haemophilus influenzae and Pseudomonas aeruginosa (23.9 and 14.1%, respectively). Acinetobacter baumannii- and P. aeruginosa-positive cultures were associated with prolonged hospitalization and severe airway obstruction (p = 0.03 and 0.031, respectively). Chlamydia pneumoniae or Mycoplasma pneumoniae infection was diagnosed in four and two patients, respectively. Discrepant results were detected between PCR and serology, especially regarding C. pneumoniae.

A case of tracheal hamartoma resected with loop electrocautery.

The authors report on the case of a 67-year-old man with longstanding breathlessness, which was eventually attributed to a fixed mass in the upper third of the trachea causing upper airway obstruction. The lesion was amenable to loop electrocautery resection via flexible bronchoscopy that led to prompt resolution of patient symptoms. Biopsy was consistent with tracheal hamartoma, an exceedingly rare benign tracheal tumor. All the cases of tracheal hamartomas in the literature to date, the application of electrocautery and other methods of interventional bronchoscopy for resection of selected tracheal tumors are discussed.

Decreased apoptotic rate of alveolar macrophages of patients with idiopathic pulmonary fibrosis.

Introduction. Increased apoptosis of epithelial cells and decreased apoptosis of myofibroblasts are involved in the pathogenesis of IPF. The apoptotic profile of alveolar macrophages (AMs) in IPF is unclear. Aim. To investigate whether AMs of patients with IPF exhibit a different apoptotic profile compared to normal subjects. Methods. We analyzed, by immunohistochemistry, the expression of the apoptotic markers fas, fas ligand , bcl-2, and bax in AM obtained from bronchoalveolar lavage fluid (BALF) of 20 newly diagnosed, treatment-naive IPF patients and of 16 controls. Apoptosis of AM was evaluated by Apoptag immunohistochemistry. IPF patients received either interferon-g and corticosteroids or azathioprine and corticosteroids for six months. Results. BALF AMs undergoing apoptosis were significantly less in IPF patients. No difference was found in the expression of fas or fas ligand, bcl-2 and bax between IPF and control group. No difference was found between the respiratory function parameters of the two treatment groups after six months. A positive correlation was found between the number of bcl-2 positive stained macrophages and DLCO after treatment. Conclusions. The decreased apoptotic rate of AM of patients with IPF is not associated with decreased expression of apoptosis mediators involved in the external or internal apoptotic pathway.

Prognostic value of C-reactive protein in parapneumonic effusions.

BACKGROUND AND OBJECTIVE: Parapneumonic effusions (PPE) that require drainage are referred to as complicated parapneumonic effusions (CPPE). Following resolution of these effusions, residual pleural thickening (RPT) may persist. We hypothesize that the concentrations of CRP in pleural fluid (CRP(pf)) and serum (CRP(ser)) can be used to identify CPPE and to predict RPT. METHODS: All patients with non-purulent PPE, who were admitted to two tertiary hospitals during a 30-month period, were enrolled in the study. Baseline CRP(pf) and CRP(ser) levels were compared between patients with complicated or uncomplicated PPE, as well as between patients with or without RPT of >10 mm, 6 months after discharge from hospital. Cut-off values for identification of CPPE and prediction of RPT were determined by receiver operating characteristic curve analysis. Logistic regression analysis was performed to assess the association between CRP levels and RPT. RESULTS: Fifty-four patients were included in the study. Patients with CPPE (n = 23) had significantly higher levels of both CRP(pf) and CRP(ser) than those with uncomplicated PPE. For identification of CPPE, a CRP(pf) level >78.5 mg/L and a CRP(ser) level >83 mg/L gave 84% and 47% sensitivity, with 65% and 87% specificity, respectively. Classical criteria (pleural fluid pH <7.20, LDH >1000 IU/L, glucose <600 mg/L) were superior for this purpose. A combination of classical biomarkers with CRP levels using an 'AND' or 'OR' rule improved the positive and negative predictive values, respectively. CRP(ser) was an independent predictor for development of RPT (adjusted OR 1.18). A CRP(ser) level >150 mg/L had 91% specificity and 61% sensitivity for prediction of RPT. CONCLUSIONS: This study demonstrated the value of CRP(ser) for prediction of RPT in patients with PPE. Moreover, when used in combination with classical biomarkers, CRP levels may be a useful adjunct for decision-making in relation to treatment of patients with non-purulent PPE.

Cryptogenic and secondary organizing pneumonia: clinical presentation, radiographic findings, treatment response, and prognosis.

BACKGROUND: Organizing pneumonia (OP) is a distinct clinical and pathologic entity. This condition can be cryptogenic (COP) or secondary to other known causes (secondary OP). In the present study, we reviewed the features associated with COP and secondary OP in patients from two teaching hospitals. METHODS: The medical records of 61 patients with biopsy-proven OP were retrospectively reviewed. Forty patients were diagnosed with COP and 21 patients with secondary OP. The clinical presentation, radiographic studies, pulmonary function tests (PFTs), laboratory data, BAL findings, treatment, and outcome were analyzed. RESULTS: The mean age at presentation was 60.46 ± 13.57 years. Malaise, cough, fever, dyspnea, bilateral alveolar infiltrates, and a restrictive pattern were the most common symptoms and findings. BAL lymphocytosis was observed in 43.8% of patients with OP. The relapse rate and mortality rate after 1 year of follow-up were 37.8% and 9.4%, respectively. The in-hospital mortality was 5.7%. The clinical presentation and radiographic findings did not differ significantly between patients with COP and secondary OP. A mixed PFT pattern (obstructive and restrictive physiology) and lower blood levels of serum sodium, serum potassium, platelets, albumin, protein, and pH were observed among patients with secondary OP. Higher blood levels of creatinine, bilirubin, Paco2, and BAL lymphocytes were also more common among patients with secondary OP. There were no differences in the relapse rate or mortality between patients with COP and secondary OP. The 1-year mortality correlated with an elevated erythrocyte sedimentation rate, low albumin, and low hemoglobin levels. CONCLUSIONS: The clinical and radiographic findings in patients with COP and secondary OP are similar and nonspecific. Although certain laboratory abnormalities are more common in secondary OP and can be associated with worse prognosis, they are likely due to the underlying disease. COP and secondary OP have similar treatment response, relapse rates, and mortality.

Acute exacerbations of interstitial lung diseases.

PURPOSE OF REVIEW: This review aims to highlight recent advances in pathogenesis, clinical presentation and treatment of interstitial lung diseases (ILDs). RECENT FINDINGS: Acute exacerbation is increasingly recognized as a major complication in the course of idiopathic pulmonary fibrosis. It is precipitated by a variety of intrinsic and extrinsic factors. Moreover, acute exacerbation is an apparently equally frequent event in hypersensitivity pneumonitis and collagen-vascular diseases associated ILDs, especially the rheumatoid pulmonary fibrosis. Treatment of acute exacerbations is unsatisfactory and prognosis extremely poor. SUMMARY: In a critically ill patient proper recognition of an acute exacerbation and of the underlying chronic ILD is warranted because treatment approach varies with the type of ILD. Advances in the understanding of the pathogenesis and treatment of this 'idiopathic' phenomenon are reviewed.

Organizing pneumonia.

Organizing pneumonia (OP) is a histologic term characterized by patchy filling of alveoli and bronchioles by loose plugs of connective tissue. OP may be an incidental finding in lung biopsy specimens or may be found nearby areas of lung involved by other diseases. On other occasions, OP may be the primary cause for pulmonary dysfunction and/or pulmonary symptoms. OP can be either idiopathic (cryptogenic organizing pneumonia, COP) or secondary to underlying disease (secondary organizing pneumonia, SOP). COP typically presents with a prodrome of symptoms of a respiratory illness followed by the insidious onset of dyspnea weeks to months later. The radiological findings typically reveal peripheral consolidation, although ground glass infiltrates or solitary nodules may be seen. The definitive diagnosis of OP requires histology. Open lung biopsy or video assisted thoracoscopy is usually required to obtain specimens large enough for the diagnosis to be made. In some cases, transbronchial biopsy specimens may be adequate for the diagnosis. The treatment of choice for OP includes corticosteroids plus treatment of the underlying disease in cases of SOP. Relapses occur frequently, usually when treatment is withdrawn or tapered. The prognosis is good in most of the cases of COP, whereas in SOP it is dependent on the underlying cause.

The impact on community acquired pneumonia empirical therapy of diagnostic bronchoscopic techniques.

The aim of the present study was to examine the modification of initial empirical treatment based on the microbiological results of bronchoscopic techniques after comparing the diagnostic yield of protected specimen brush (PSB) and bronchoalveolar lavage (BAL) in the immunocompetent patient with community acquired pneumonia (CAP) with results obtained from conventional sputum cultures. 88 patients with presumptive diagnosis of CAP necessitating hospitalization were prospectively studied. Fibreoptic bronchoscopy with quantitative PSB and BAL cultures for common pathogens, mycobacteria and fungi was performed. Conventional sputum cultures were also obtained. PSB and BAL quantitative cultures added 26.1% and 36.4%, respectively, more microbiological documentation for CAP compared to conventional sputum cultures (p < 0.0001). Gram staining was indicative of the pathogen mostly in cases where Streptococcus pneumoniae was isolated, which was also the most frequently isolated pathogen (19.3%), followed by Haemophilus influenzae (9%). M. tuberculosis was isolated in 6.8% of patients. Modification of treatment ensued in 27.3% of patients because of the application of the cultures of sputum and invasive technique. PSB and BAL added significant information to the aetiological diagnosis of hospitalized immunocompetent patients with CAP.

Terminal diffuse alveolar damage in relation to interstitial pneumonias. An autopsy study.

Acute exacerbations of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) are rare and typically terminal events, but their relationship to underlying patterns of idiopathic interstitial pneumonias is unknown. We reviewed autopsy material from patients who died of diffuse alveolar damage in the clinical setting of pulmonary fibrosis, both idiopathic and with background fibrosing alveolitis with connective tissue disorders (FA-CTDs), and compared them with cases of acute interstitial pneumonia. Of 15 patients with acute exacerbations of IPF/CFA (n = 12) or FA-CTD (n = 3), 12 had a background pattern of usual interstitial pneumonia and 3 had fibrotic nonspecific interstitial pneumonia. All cases of fibrotic nonspecific interstitial pneumonia were seen in association with FA-CTD. The cause of acute exacerbations is unknown, but our data suggest that toxic effects of oxygen and triggering infection are unlikely causes. In patients with CTDs, it remains uncertain whether the acute exacerbation is related to the fibrosis, the associated CTD, or a combination of these factors. Acute exacerbations of IPF/CFA may be a more common terminal event than previously thought.

Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome.

Fibrosing alveolitis associated with systemic sclerosis (FASSc) has a better prognosis than idiopathic pulmonary fibrosis. In view of recent reports that idiopathic nonspecific interstitial pneumonia (NSIP) has a better prognosis than idiopathic usual interstitial pneumonia (UIP), we classified histologic appearances of surgical lung biopsies performed in 80 patients with FASSc. NSIP (n = 62, 77.5%), subcategorized as cellular NSIP (n = 15) and fibrotic NSIP (n = 47) was much more prevalent than UIP (n = 6), end-stage lung disease (ESL, n = 6), or other patterns (n = 6). There were 25 deaths (NSIP 16/62, 26%; UIP/ESL 6/12, 50%). Five-year survival differed little between NSIP (91%) and UIP/ESL (82%); mortality was associated with lower initial carbon monoxide diffusing capacity (DL(CO)) and FVC levels (p = 0.004 and p = 0.007, respectively). Survival and serial FVC and DL(CO) trends did not differ between cellular and fibrotic NSIP. Increased mortality in NSIP was associated with lower initial DL(CO) levels (p = 0.04), higher BAL eosinophil levels (p = 0.03), and deterioration in DL(CO) levels during the next 3 years (p < 0.005). We conclude that NSIP is the histopathologic pattern in most patients with FASSc. However, outcome is linked more strongly to disease severity at presentation and serial DL(CO) trends than to histopathologic findings.