Collagen Vascular Disease-associated Interstitial Pneumonia Research Articles

＜Editors' Choice＞ Comparison of clinical features between patients with acute exacerbation of idiopathic interstitial pneumonia and collagen vascular disease-associated interstitial pneumonia.

Acute exacerbation (AE) of interstitial pneumonia (IP) shows poor prognosis, due to the typical histological pattern of diffuse alveolar damage superimposed upon lung fibrosis. The previous reports comparing clinical features between AE of idiopathic interstitial pneumonias (IIPs) and those of IPs with known etiology are limited. We retrospectively compared clinical parameters including age, sex, Charlson Comorbidity Index score (CCIS), blood biomarkers at diagnosis of AE, treatment, and 3-month mortality between patients with AE of IIPs and collagen vascular disease-associated interstitial pneumonia (CVD-IP). We assessed 85 patients, comprising 66 patients with AE of IIPs (78%) and 19 patients with AE of CVD-IP (22%). The least absolute shrinkage and selection operator regression selected CCIS (hazard ratio, 1.281; 95% confidence interval, 1.055-1.556; P = 0.012) and log serum lactate dehydrogenase (LDH) (hazard ratio, 6.267; 95% confidence interval, 2.172-18.085; P < 0.001) as significant predictors of 3-month mortality among these patients. Also, the adjusted survival curves using sex, CCIS, and serum LDH showed no significant differences between these two groups. In conclusion, among AE patients, CCIS and serum LDH level may be more important prognostic factors for 3-month mortality rather than two classification of IP subtypes: IIPs and CVD-IP.

Relief of dyspnea caused by Collagen Vascular Disease-Associated Interstitial Pneumonia through adjusting household behavior:

Relief of dyspnea caused by Collagen Vascular Disease-Associated Interstitial Pneumonia through adjusting household behavior:

Clinical features and outcome of acute exacerbation in connective tissue disease‐associated interstitial lung disease: A single‐center study from India

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is associated with high mortality, but there is limited clinical data on AE of interstitial lung disease (ILD) in connective tissue disease-associated ILD (CTD ILD). The present study was conducted to provide prevalence and clinical features of AE, as well as various risk factors associated with mortality among AE CTD ILD patients. Between May 2013 and April 2018, 15 patients who developed AE among 105 consecutive patients with CTD with chronic ILD were included. AE was defined using the criteria recently proposed by the IPF net, with slight modification for adaptation to CVD-IP6 (collagen vascular disease-associated interstitial pneumonia), and patients having CTD with AE met all the criteria. Fifteen patients with mean age of 45.8±13.9years developed AE; the most common subgroup (n=5, 33%) was systemic sclerosis. The mean duration (months) between diagnosis of ILD and AE was 56.5±38.0 with mean follow-up duration of 24±18.1months. The baseline arterial oxygen pressure (PaO2 ) was 81.7±8.1mmHg and mean forced vital capacity (%) was 57.9±8.9. Five patients requiring mechanical ventilation died. Patients with shorter duration (months) of disease between onset of ILD to AE had higher mortality, 40.4±45.1 vs 64.6±33.6. Those who had significantly lower baseline PaO2 (mean±SD), 72.6±3.4 vs 86.2±5.3mmHg (P=.002) had higher mortality. In our study, the majority of patients with AE CTD ILD had systemic sclerosis. Patients with lower baseline PaO2 and those requiring mechanical ventilation had higher mortality.

Successful Treatment of &lt;i&gt;Aspergillus&lt;/i&gt; Empyema Using Open Window Thoracostomy Salvage Treatment and the Local Administration of an Antifungal Agent

A 76-year-old woman received long-term immunosuppressive treatment for collagen vascular disease-associated interstitial pneumonia. The patient developed a cavitary mass lesion in the right lower lung field, and both nontuberculous mycobacteria and Aspergillus spp. were isolated after bronchial washing. The patient underwent a right lower lobectomy but developed Aspergillus empyema. Empyema due to Aspergillus spp. is a rare and life-threatening condition; however, the standard therapeutic strategies for treating Aspergillus empyema are not clear. We herein report a case of Aspergillus empyema that was successfully treated with a combination therapy which included open-window thoracostomy and the administration of antifungal agents (systemic micafungin and local amphotericin-B).

The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis

BackgroundIt is believed that Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are useful biomarkers for the diagnosis of various types of interstitial lung diseases, including hypersensitivity pneumonitis (HP). The clinical features of chronic HP are similar to those of idiopathic interstitial pneumonias, especially idiopathic pulmonary fibrosis (IPF). ObjectiveWe sought to clarify the usefulness of serum KL-6 and SP-D for the diagnosis and management of chronic HP. MethodsWe examined serum KL-6 and SP-D levels and retrospectively evaluated the clinical parameters of acute HP (n = 35), chronic HP (n = 57), IPF (n = 54), collagen vascular disease-associated interstitial pneumonia (CVD-IP) (n = 67), and sarcoidosis (n = 47). We analyzed the relations between the two biomarkers and clinical data in chronic HP. ResultsSerum KL-6 and SP-D levels in acute HP (2710 U/ml and 338 ng/ml, median) and chronic HP (1500 U/ml and 264 ng/ml, median) were significantly higher than in IPF, CVD-IP, and sarcoidosis. The area under the curve (AUC) values for serum KL-6 and SP-D between chronic HP and IPF were 0.771 and 0.729, respectively. Serum KL-6 levels in chronic HP were significantly higher during episodes of acute exacerbation than 1 month before acute exacerbation. The serum KL-6 levels had correlations with serum SP-D and the percentage of lymphocytes in bronchoalveolar lavage fluid. ConclusionsSerum KL-6 and SP-D levels are useful for the diagnosis and management of chronic HP.

Antigen avoidance tests for diagnosis of chronic hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis (HP) is induced by the inhalation of specific antigens. Patients with chronic HP may be able to improve their prognosis by avoiding these antigens. Chronic HP is often difficult to distinguish from idiopathic interstitial pneumonias (IIPs). This study was performed to find out how antigen avoidance tests contribute to the diagnosis of chronic HP. A retrospective analysis was conducted on 265 patients who underwent 2-week antigen avoidance tests between April 2002 and March 2012. The patients were classified into the following categories: acute HP, chronic HP, collagen vascular disease-associated interstitial pneumonia (CVD-IP), lung dominant connective tissue disease (LD-CTD), and IIPs. The following seven clinical parameters were evaluated: vital capacity, alveolar-arterial oxygen pressure difference, Krebs von den Lungen-6, surfactant protein-D, white blood cell count, C-reactive protein, and body temperature. These parameters were compared between the chronic HP group and a control group consisting of CVD-IP, LD-CTD, and IIPs. One-hundred and ninety-six patients with chronic HP and 43 control subjects were evaluated. All clinical parameters improved significantly in the chronic HP group but showed no significant changes in the control group. Four of the parameters changed significantly compared with the control group. Diagnostic criteria established using these data had a sensitivity of 51.0% and a specificity of 80.7%. It was difficult to diagnose chronic HP based solely on 2-week antigen avoidance tests; however, improved clinical parameters among patients supported the diagnosis of HP.

Identification of Helicobacter pylori VacA in human lung and its effects on lung cells

ObjectivePrior reports suggested that infection with Helicobacter pylori was associated with respiratory diseases; pathogenetic mechanisms however, were not defined. We tested the hypothesis that VacA, an exotoxin of H. pylori, a gastric pathogen, was aspirated into the lung and could stimulate secretion of inflammatory cytokines by lung epithelial cells. MethodsThe presence of VacA was determined by immunohistochemistry in surgical lung biopsy tissue samples from 72 patients with interstitial pneumonia. The effects of VacA on A549 human alveolar epithelial adenocarcinoma cells and normal human bronchial epithelial cells were determined. After incubation with VacA, the secretions of cytokines were measured by Multiplex Luminex® Assays. ResultsVacA was detected with anti-VacA antibodies in bronchial epithelial cells and alveolar epithelial cells from 10 of 72 patients with interstitial pneumonia. VacA was more prevalent in lungs of patients with collagen vascular disease-associated interstitial pneumonia than in those of patients with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia and cryptogenic organizing pneumonia. Incubation of A549 cells and normal human bronchial epithelial cells with VacA for 24 h was cytotoxic, and resulted in vacuolation. VacA induced interleukin-8 production by A549 cells and normal human bronchial epithelial cells and interleukin-6 production by A549 cells. Based on multiplex screening, interleukin-8 and interleukin-6 were the primary secretory products induced by VacA. ConclusionsH. pylori VacA is present in human lung and can induce interleukin-8 and interleukin-6 production by human lung cells. VacA could have a role in the pathogenesis of respiratory diseases by its cytotoxic effects and by inducing the secretion of interleukin-8 and interleukin-6 by targeted airway epithelial cells.

Seasonal variation of serum KL-6 concentrations is greater in patients with hypersensitivity pneumonitis.

BackgroundSerum KL-6 is a useful biomarker for the diagnosis of interstitial lung diseases (ILD). However, KL-6 has not been used to discriminate different types of ILD. Serum KL-6 concentrations can vary depending on antigen exposure levels in patients with hypersensitivity pneumonitis (HP); however, seasonal changes in serum KL-6 concentrations in ILD have not been determined. We hypothesized that seasonal variation of serum KL-6 is greater in HP than for the other ILD. The aim of this study was to determine seasonal variation of serum KL-6 concentrations in various ILD.MethodsSerum KL-6 concentrations in the summer season from June 1 to September 30 and the winter season from November 1 to February 28 were retrospectively analyzed in patients with idiopathic pulmonary fibrosis (IPF, n = 16), non-specific interstitial pneumonia (NSIP, n = 16), collagen vascular disease-associated interstitial pneumonia (CVD-IP, n = 33), house-related HP (House-HP, n = 9), bird-related HP (Bird-HP, n = 9), and combined pulmonary fibrosis and emphysema (CPFE, n = 13).ResultsBird-HP and House-HP showed greater seasonal serum KL-6 variation than the other ILD. Serum KL-6 concentrations in Bird-HP were significantly increased in the winter and KL-6 concentrations in House-HP were significantly increased in the summer. Serum KL-6 variation was significantly greater in acute HP than chronic HP. Receiver operating characteristic curve analysis revealed that greater seasonal variation in serum KL-6 concentrations is diagnostic for Bird-HP.ConclusionHP should be considered in ILD with greater seasonal changes in serum KL-6 concentrations.

Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases

Interstitial lung diseases (ILDs) are a diverse group of pulmonary disorders characterized by various patterns of inflammation and fibrosis in the interstitium of the lung. Because injury and/or regeneration of type II pneumocytes are prominent histological features of ILDs, substances derived from type II pneumocytes have been the focus of research investigating potential biomarkers for ILD. One important biomarker for ILD is the high-molecular-weight glycoprotein, Krebs von den Lungen-6 (KL-6). KL-6 is now classified as a human MUC1 mucin protein, and regenerating type II pneumocytes are the primary cellular source of KL-6/MUC1 in the affected lungs of patients with ILD. KL-6/MUC1 is detectable in the serum of patients with ILD, and extensive investigations performed primarily in Japan have revealed that serum KL-6/MUC1 is elevated in 70-100% of patients with various ILDs, including idiopathic interstitial pneumonias, collagen vascular disease-associated interstitial pneumonia, hypersensitivity pneumonia, radiation pneumonitis, drug-induced ILDs, acute respiratory distress syndrome, pulmonary sarcoidosis, and pulmonary alveolar proteinosis. The results from these various studies have supported the utility of KL-6/MUC1 as a serum biomarker for detecting these various ILDs. Moreover, KL-6/MUC1 serum levels have been demonstrated to be useful for evaluating disease activity and predicting the clinical outcomes of various ILD types. Based on these observations, we believe that KL-6/MUC1 is currently one of the best and most reliable serum biomarkers available for ILD management.

S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis

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. 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. 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. S100A9 in BALF might serve as a candidate biomarker to discriminate between IPF and other fibrotic interstitial pneumonias.

Lower-lobe shrinkage relative to total lung volume in collagen vascular diseases

It has been reported that the prognosis differs between patients who have collagen vascular diseaseassociated interstitial pneumonia (CVD-IP) and those with idiopathic IP (IIP). In this study, chest computed tomography (CT) findings were compared between patients with CVD-IP and IIP. A retrospective analysis was performed of 47 consecutive patients (23 with CVD-IP and 24 with IIP). The lower-lobe volume (LLV), total lung volume (TLV), and their ratio (LLV/TLV) were determined by volumetry using three-dimensional computed tomography (CT). There was no significant difference of the LLV/TLV ratio between the CVD-IP and IIP groups. However, the LLV/TLV ratio was <0.33 in 9/23 patients with CVD-IP versus 2/24 patients with IIP, and there was a significant difference in the percentage of patients with a ratio<0.33 between the CVD-IP and IIP groups (p = 0.01). The LLV/TLV ratio was not influenced by the severity of lung disease. Measuring the LLV/TLV ratio by threedimensional CT can help distinguish between CVD-IP and IIP at initial diagnosis, especially in patients with CVD-IP who have pulmonary involvement before other organ diseases and symptoms caused by CVD.

Acute exacerbation of interstitial pneumonia associated with collagen vascular diseases

BackgroundAcute exacerbation (AE) is currently established as a distinct condition with acute deterioration of respiratory status in idiopathic pulmonary fibrosis (IPF). Recently, several studies have reported that AE also occurred in interstitial pneumonias other than IPF, such as collagen vascular disease-associated interstitial pneumonia (CVD-IP). However, the incidence of AE in CVD-IP and its clinical characteristics remain to be fully determined. This study was conducted to elucidate cumulative incidence of AE in CVD-IP and its clinical features.MethodsWe reviewed 83 biopsy-proven CVD-IP patients, estimated cumulative incidence of AE, and examined its clinical characteristics.ResultsAmong 83 CVD-IP patients, six patients with a mean age of 65.7 years developed AE (overall incidence, 7.2%; 1-year incidence, 1.25%). Underlying CVDs included rheumatoid arthritis (RA) (n = 5; overall incidence, 20.0%) and primary Sjögren syndrome (n = 1; overall incidence, 5.9%). Patients with AE showed acute respiratory deterioration with severe hypoxemia (mean PaO2/FiO2 ratio, 131). Radiologically, ground-glass opacity was superimposed on the underlying reticular abnormalities. Preexisting histological patterns included three usual interstitial pneumonia (UIP) and two non-specific interstitial pneumonia (NSIP). Five (83.3%) of six patients died of respiratory failure despite intensive therapy. Univariate Cox's proportional hazards analysis showed that age and RA diagnosis were significantly associated with AE. Multivariate Cox's proportional hazards analysis indicated that age was an independent significant factor predicting AE.ConclusionsThese data suggest that AE can occur in CVD-IP, and this condition is closely similar to that of IPF with poor prognosis. AE is most common in RA, and associated with higher ages.

Immunohistochemical distribution of SP-D, compared with that of SP-A and KL-6, in interstitial pneumonias

The immunohistochemical distribution of SP-D was compared with that of SP-A and KL-6 using a monoclonal antibody in lung tissues of 15 cases of collagen vascular disease-associated interstitial pneumonia (CVD-IP), 4 cases of hypersensitivity pneumonitis (CHP), and 6 cases of other diseases to determine their differences in distribution. In this study, the main targets were alveolar epithelial cells, especially those in the regenerating stage, as well as lymph vessels and stroma. The cytoplasm of type II alveolar epithelial cells and Clara cells was positive for SP-D, with sharp margins; interestingly, however, during the process of regeneration large positive cells were intermingled with relatively small negative cells, even in the same row of cells. In sharp contrast, staining for SP-A and KL-6 was positive in the cytoplasm of all the regenerating alveolar epithelial cells, as well as Clara cells. Staining for KL-6 was usually positive in the surface of air spaces in linear fashion. Staining for SP-A was also positive in elastic fibers in vascular walls. In areas of destruction of pulmonary structures, loose stroma and the endothelial cells of lymph vessels as well as their contents were distinctly positive for SP-A and/or KL-6 but not SP-D. Judging from these results in pulmonary tissues of CVD-IP and HP, SP-D might be a marker for maturity of regenerating epithelial cells. Both SP-A and KL-6 were detected in intimate relationship to the stage of regeneration of alveolar epithelial cells and were expressed before SP-D. In addition, the lymph vessels play a very important role in transfer of KL-6 into the bloodstream.

Interstitial lung disease in rheumatoid arthritis: recent advances

Subsequent to the ATS/ERS consensus classification of idiopathic interstitial pneumonia, non-specific interstitial pneumonia pattern was the dominant pattern in many collagen vascular diseases, which may explain the better prognosis of interstitial pneumonia associated with collagen disease than idiopathic pulmonary fibrosis. Recent papers on rheumatoid arthritis suggest that this is not the same in all collagen diseases, and this paper will review previous data and discuss recent papers. In contrast to other collagen diseases, the usual interstitial pneumonia pattern seems to be more common, or at least as common in rheumatoid arthritis. This pathological observation was supported by high-resolution computed tomography findings. In addition to the usual interstitial pneumonia pattern, several types of small airway involvements were frequently observed in rheumatoid arthritis-associated interstitial pneumonia, the prognosis of which is also variable. Because the usual interstitial pneumonia pattern may be more frequent in rheumatoid arthritis and some data suggest a poor prognosis for rheumatoid arthritis-associated interstitial pneumonia, further studies are required on the prognosis of collagen vascular disease-associated interstitial pneumonia, especially in relation to the pathological pattern. Drug-related interstitial pneumonia should also be considered in rheumatoid arthritis patients on methotrexate or newer drugs such as leflunomide.

Exhaled Ethane: An In Vivo Biomarker of Lipid Peroxidation in Interstitial Lung Diseases

Oxidative stress plays a role in the pathogenesis and progression of interstitial lung disease (ILD). Exhaled ethane is a product of lipid peroxidation that has been proposed as a biomarker of oxidative stress in vivo. To determine whether the exhaled ethane level is elevated in patients with ILD and to compare it with other clinical parameters. Breath samples were collected from 34 patients with ILD, including 13 with idiopathic pulmonary fibrosis (IPF), 9 patients with cryptogenic organizing pneumonia, 6 patients with collagen vascular disease-associated interstitial pneumonia, and 6 patients with pulmonary sarcoidosis. Gas samples were obtained at hospital admission and after 3 weeks. After each expired sample was concentrated using a trap-and-purge procedure, the ethane level was analyzed by gas chromatography. Exhaled ethane levels were elevated in ILD patients (n = 34, mean +/- SD, 8.5 +/- 8.0 pmol/dL) compared with healthy volunteers (n = 16, 2.9 +/- 1.0 pmol/dL; p < 0.001). Serial measurements revealed that increase and decrease of ethane levels were largely consistent with the clinical course. Four patients with IPF who had persistently high ethane levels died or deteriorated, whereas those with ethane levels < 5.0 pmol/dL remained stable or improved. Exhaled ethane concentrations were positively correlated with levels of lactate dehydrogenase (Spearman rank correlation coefficient [rs], 0.28, p = 0.026) and C-reactive protein (rs, 0.38, p = 0.025) and were inversely correlated with Pa(O2) (rs, - 0.40, p = 0.0026). Patients showing increased uptake on (67)Ga scintigraphy demonstrated higher ethane levels (n = 19, 7.5 +/- 5.7 pmol/dL) compared with those who did not show increased uptake on scintigraphy (n = 10, 3.0 +/- 2.4 pmol/dL; p < 0.01). Exhaled ethane is elevated in patients with ILD and is correlated with the clinical outcome, suggesting that it provides useful information about ongoing oxidative stress, and thereby disease activity and severity in ILD.