Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy.

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy's effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25-8.8). Median survival time was 9.9 months (95% CI 9.2-10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889-9.328; 60 days, HR: 2.351, 95% CI 1.104-5.009; 90 days, HR: 2.416, 95% CI 1.232-4.739; and 120 days, HR: 2.521, 95% CI 1.357-4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

Pulse versus non-pulse corticosteroid therapy in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Corticosteroids are commonly used for the treatment of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF); however, the optimal initial dose of corticosteroids remains uncertain due to a lack of sufficient evidence. We evaluated whether the administration of a pulse dose of corticosteroids resulted in improved survival outcomes compared with conventional non-pulse dose of corticosteroids. METHODS: We retrospectively analysed 238 patients with AE-IPF treated with corticosteroids at a tertiary referral hospital between January 2013 and December 2021. Based on whether a pulse dose of corticosteroids (methylprednisolone of ≥250 mg/day or equivalent) was administered within 7 days of hospitalization for AE-IPF, the patients were divided into the pulse and non-pulse regimen groups. The survival outcomes were compared between the two groups using multivariable regression and propensity score-matched analyses. RESULTS: Among the 238 patients, 59 patients received pulse dose of corticosteroids, whereas 179 patients received conventional non-pulse dose of corticosteroids. After adjusting for the confounding factors related to the baseline clinical and radiographic severity, compared with the conventional non-pulse regimen, the pulse regimen of corticosteroids did not reduce the risk of mortality at the 3-month (aHR 0.84, 95% CI 0.45-1.38) or 12-month (aHR 0.96, 95% CI 0.60-1.25) follow-ups. Propensity score-matched analysis revealed similar results. CONCLUSION: The survival outcomes of patients with AE-IPF who received a pulse dose of corticosteroids did not differ from those of patients who received conventional non-pulse dose of corticosteroids. Further prospective studies are required to establish the optimal initial dose of corticosteroids for the treatment of AE-IPF.

Carboplatin and weekly paclitaxel in combination with bevacizumab for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias: A feasibility study.

BACKGROUND: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We conducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. METHODS: Chemotherapy-naïve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle. RESULTS: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively. CONCLUSION: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008189.

Early corticosteroid dose tapering in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although corticosteroid therapy with dose tapering is the most commonly used treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), there is no consensus on the tapering regimen. This study aimed to investigate the association between early corticosteroid dose tapering and in-hospital mortality in patients with AE-IPF. METHODS: In this retrospective cohort study, we analyzed the data of a cohort from eight Japanese tertiary care hospitals and routinely collected administrative data from a cohort from 185 Japanese hospitals. Patients with AE-IPF were classified into the early and non-early tapering groups depending on whether the maintenance dose of corticosteroids was reduced within two weeks of admission. Propensity score analysis with inverse probability weighting (IPW) was performed to estimate the effect of early corticosteroid dose tapering. RESULTS: The multi-center cohort included 153 eligible patients, of whom 47 (31%) died, whereas the administrative cohort included 229 patients, of whom 51 (22%) died. Patients with early tapering tended to have a better prognosis than those without it (unadjusted hazard ratio [95% confidence interval] 0.41 [0.22-0.76] and 0.65 [0.36-1.18] in the multi-center and administrative cohorts, respectively). After IPW, the early tapering group had a better prognosis than the non-early tapering group (IPW-adjusted hazard ratio [95% confidence interval] 0.37 [0.14-0.99] and 0.27 [0.094-0.83] in the multi-center and administrative cohorts, respectively). CONCLUSION: Early corticosteroid dose tapering was associated with a favorable prognosis in patients with AE-IPF. Further studies are warranted to confirm the effects of early corticosteroid dose tapering in patients with AE-IPF.

Atezolizumab for Pretreated Non-Small Cell Lung Cancer with Idiopathic Interstitial Pneumonia: Final Analysis of Phase II AMBITIOUS Study.

BACKGROUND: Interstitial pneumonia (IP) is a poor prognostic comorbidity in patients with non-small cell lung cancer (NSCLC) and is also a risk factor for pneumonitis. The TORG1936/AMBITIOUS trial, the first known phase II study of atezolizumab in patients with NSCLC with comorbid IP, was terminated early because of the high incidence of severe pneumonitis. METHODS: This study included patients with idiopathic chronic fibrotic IP, with a predicted forced vital capacity (%FVC) of >70%, with or without honeycomb lung, who had previously been treated for NSCLC. The patients received atezolizumab every 3 weeks. The primary endpoint was the 1-year survival rate. RESULTS: A total of 17 patients were registered; the median %FVC was 85.4%, and 41.2% had honeycomb lungs. The 1-year survival rate was 53.3% (95% CI, 25.9-74.6). The median overall and progression-free survival times were 15.3 months (95% CI, 3.1-not reached) and 3.2 months (95% CI, 1.2-7.4), respectively. The incidence of pneumonitis was 29.4% for all grades, and 23.5% for grade ≥3. Tumor mutational burden and any of the detected somatic mutations were not associated with efficacy or risk of pneumonitis. CONCLUSION: Atezolizumab may be one of the treatment options for patients with NSCLC with comorbid IP, despite the high risk of developing pneumonitis. This clinical trial was retrospectively registered in the Japan Registry of Clinical Trials on August 26, 2019, (registry number: jRCTs031190084, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190084).

Safety of immune checkpoint inhibitors in non-small-cell lung cancer patients with idiopathic interstitial pneumonia: a matched case-control study.

PURPOSE: The immune checkpoint inhibitor nivolumab is commonly used for non-small-cell lung cancer treatment. Immune checkpoint inhibitors cause immune-related adverse events, including interstitial pneumonia. However, there are no studies on the risk factors for interstitial pneumonia exacerbation after immune checkpoint inhibitor administration in patients with a history of different types of interstitial pneumonia. Therefore, we aimed to investigate the risk factors for interstitial pneumonia exacerbation in patients with non-small-cell lung cancer and a history of interstitial pneumonia. We also aimed to explore differences in the risk of interstitial pneumonia exacerbation due to various types of interstitial pneumonia-idiopathic interstitial pneumonia, immune-related pneumonitis, and radiation pneumonitis. METHODS: Eleven patients with a history of interstitial pneumonia exacerbation following the administration of immune checkpoint inhibitor were included in the study. We performed 1:2 matching based on age and sex. Twenty-two patients whose interstitial pneumonia did not worsen after immune checkpoint inhibitor administration belonged to the control group. We calculated odds ratios for each factor in the patients and control subjects. RESULTS: The odds ratio of idiopathic interstitial pneumonia in the case group was 0.15 (95% confidence interval: 0.03-0.89) (p = 0.03). There were no significant differences in other factors, such as smoking history, pulmonary emphysema, and chronic obstructive pulmonary disease. CONCLUSION: The administration of immune checkpoint inhibitors in non-small-cell lung cancer patients with a history of idiopathic interstitial pneumonia might be a viable treatment option and have clinical benefits.

Comparison of clinical features and prognosis in patients with cryptogenic and secondary organizing pneumonia.

BACKGROUND: Organizing pneumonia (OP) can be diagnosed pathologically, and cryptogenic OP (COP) and secondary OP (SOP) have been classified by cause and particular underlying context. Because it is clinically difficult to differentiate between COP and SOP, this study investigated characteristics that could distinguish between COP and SOP. METHODS: The medical records of patients who underwent lung biopsy for a diagnosis of OP at a single tertiary hospital from January 2016 to December 2018 were retrospectively reviewed. RESULTS: Eighty-five patients had pathologically proven OP, including 16 diagnosed with COP and 69 diagnosed with SOP. The most common cause of SOP was infectious pneumonia, observed in 57 (82.6%) of the 69 patients, followed by cancer and radiation pneumonitis. The pathogens causing infectious pneumonia were identified in 45 (65.2%) patients. There were no differences in age, sex, and lung function between the COP and SOP groups. Median body mass index was significantly lower (P = 0.030), and median time from symptom onset to hospital admission significantly shorter (P = 0.006), in the SOP than in the COP group. Fever was more common in the SOP group (P = 0.024), and CURB 65, an index of pneumonia severity, tended to be higher in the SOP group (P = 0.017). Some laboratory results differed significantly between the two groups. Lymphocyte counts in bronchoalveolar lavage (BAL) fluid were significantly higher in the COP than in the SOP group (P = 0.012). Radiologic findings showed that effusion was more common in the SOP group (P = 0.036). There were no between-group differences in steroid use, 30 day and in-hospital mortality rates, and rates of OP outcomes and recurrences. Pneumonia recurrence rate was significantly higher in SOP patients who were than were not treated with steroids (P = 0.035). CONCLUSIONS: Infection is the main cause of SOP. Symptom onset is more rapid in patients with SOP than with COP. Some blood and BAL fluid test results differed significantly in the COP and SOP groups. Pleural effusion was more common in the SOP group but there were no differences in clinical course. Recurrence in patients with SOP was more common in those who were than were not treated with steroids.

Impact of bronchoalveolar lavage lymphocytosis on the effects of anti-inflammatory therapy in idiopathic non-specific interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, and unclassifiable idiopathic interstitial pneumonia.

BACKGROUND: Idiopathic non-specific interstitial pneumonia (iNSIP), idiopathic pleuroparenchymal fibroelastosis (iPPFE), and unclassifiable idiopathic interstitial pneumonia (IIP) are IIPs with chronic fibrotic phenotypes, and unlike idiopathic pulmonary fibrosis, they have often been treated with anti-inflammatory drugs, including corticosteroids and immunosuppressants. However, the impact of bronchoalveolar lavage (BAL) lymphocytosis on the effects of anti-inflammatory therapy has never been evaluated. This study aimed to elucidate whether BAL lymphocytosis can be used to predict the efficacy of anti-inflammatory drugs for iNSIP, iPPFE, and unclassifiable IIP. METHODS: Japanese patients diagnosed with iNSIP, iPPFE, and unclassifiable IIP by multidisciplinary discussion were identified using the nationwide registry. Eligible patients were stratified into four groups with and without BAL lymphocytosis and anti-inflammatory therapy to compare overall survival (OS) and changes in lung function. BAL lymphocytosis was defined as a lymphocyte differential count > 15%, and the cut-off was corroborated by survival classification and regression tree analysis. RESULTS: Overall, 186 patients (37 iNSIP, 16 iPPFE, and 133 unclassifiable IIP) were analyzed. Limited to patients treated with anti-inflammatory drugs (n = 123), patients with BAL lymphocytosis had a better prognosis [hazard ratio (HR), 0.26; 95% confidence interval (CI), 0.11-0.63; P = 0.003], higher slope of forced vital capacity (FVC) % predicted for 2 years, and longer OS (log-rank test, P = 0.012) than those without BAL lymphocytosis. On multivariate analysis, BAL lymphocytosis (HR 0.31; 95% CI 0.13-0.75; P = 0.009) was a prognostic factor for OS, along with age and FVC % predicted. Conversely, for patients managed without anti-inflammatory therapy (n = 63), the presence or absence of BAL lymphocytosis had no prognostic value. CONCLUSIONS: BAL lymphocytosis is associated with good outcomes in patients treated with anti-inflammatory drugs, but has no prognostic value when anti-inflammatory drugs are not used. BAL lymphocytosis may provide a predictive biomarker for identifying patients with iNSIP, iPPFE and unclassifiable IIP who are likely to benefit from anti-inflammatory drugs.

Advantages and disadvantages of corticosteroid use for acute exacerbation of interstitial pneumonia after pulmonary resection.

OBJECTIVES: Acute exacerbation of interstitial pneumonia (AE-IP) is the top cause of 30-day mortality in surgery for lung cancer patients. The general treatment for AE-IP is corticosteroid; however, there are some disadvantages of corticosteroid use after surgery. This study was conducted to report the clinical course of AE-IP after surgery and evaluate the effect of corticosteroid use. METHODS: This retrospective study was performed on 337 patients with interstitial pneumonia who underwent surgical resection for lung cancer at our institute between 2009 and 2018. AE-IP were observed in 14 patients (4.2%) and their management and clinical outcome were investigated. RESULTS: All patients received methylprednisolone pulse therapy. Six patients (42.9%) became convalescent after pulse therapy and eight (57.1%) died within 90 days after surgery due to lack of therapeutic efficacy. Oxygenation and ground-glass opacities of the survivors improved within 3 days after starting pulse therapy. Patients who responded to the first pulse also responded to the second pulse. Four patients developed complications including two with bronchopulmonary fistulas that may be related to steroid treatment. Even if the corticosteroid was effective, all AE-IP patients died within 1 year after surgery. CONCLUSIONS: Corticosteroid therapy is effective for AE-IP after surgery; however, it may lead to severe complications after surgery.

The significance of multidisciplinary classifications based on transbronchial pathology in possible idiopathic interstitial pneumonias.

Surgical lung biopsy is regarded as the golden standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). Here, we attempted to show the diagnostic accuracy of multidisciplinary classifications based on transbronchial pathology including transbronchial lung cryobiopsy (TBLC) , bronchoalveolar lavage fluid (BALF) and endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA).Patients with suspected interstitial lung diseases admitted from June 1, 2016 to December 31, 2018 were involved. Patients with known causes of interstitial lung diseases and typical idiopathic pulmonary fibrosis diagnosed through clinical, radiological information were excluded. Patients with atypical idiopathic pulmonary fibrosis and possible IIPs accepted transbronchial pathological evaluation. Initial multidisciplinary diagnosis (MDD) classifications were made depending on clinical, radiological and transbronchial pathological information by a multidisciplinary team (MDT). The final MDD classifications were confirmed by subsequent therapeutic effects. All patients were followed up for at least 6 months.A total of 70 patients were finally involved. The samples of lung parenchyma extracted through TBLC were enough for confirmation of pathological diagnoses in 68.6% (48/70) cases. Samples of 6 cases were extracted by EBUS-TBNA. Bacteriological diagnoses were positive in 1 case by BALF. Pathological diagnoses of 77.1% (54/70) cases were achieved through TBLC, EBUS-TBNA and BALF. During the follow up study, the pulmonary lesions of 60% patients were improved, 11.43% were relapsed when glucocorticoid was reduced to small dose or withdrawal, 14.29% were leveled off and 8.57% were progressed. The diagnoses of 4 patients with progressed clinical feature were revised. As a result, 94.3% initial MDD classifications based on transbronchial pathology were consistent with the final MDD, and the difference of diagnostic yield wasn't significant between initial and final MDD (Z = -1.414, P = .157).Classifications of IIPs based on transbronchial pathology were useful and quite agreed with final MDD.

A case report of fungal infection associated acute fibrinous and organizing pneumonitis.

BACKGROUND: Acute fibrinous and organizing pneumonitis (AFOP) is an uncommon variant of acute lung injury, characterized by intra-alveolar fibrin and organizing pneumonia. Proposed etiologies include connective tissue diseases, infections, occupational exposure, drug reactions, and autoimmune disease. Here we present a rare case of fungal infection associated AFOP in patient with diabetes mellitus (DM) and review the relevant literature. CASE PRESENTATION: A 67-year-old man complained of cough, fever, dyspnea and hemoptysis. Patient experienced a rapidly progressive course exhibit diffuse predominant consolidation, ground glass opacities, and multifocal parenchymal abnormalities on chest computed tomography (CT). Antibacterial, antifungal, and antiviral treatments were ineffective. A CT-guided percutaneous lung biopsy was performed. Histologically, the predominant findings were as follows: alveolar spaces filled with fibrin and organizing loose connective tissues involving 70% of the observed region, pulmonary interstitial fibrosis, and small abscesses and epithelioid cell granuloma in the focal area. Result of periodic acid-silver methenamine stain was positive. The fungal pathogen from the sputum culture was identified as P. citrinum repeatedly over 3 times. Patient was diagnosed with DM during hospitalization. Corticosteroids combined with an antifungal therapy were effective. Follow-up for 4 months showed complete radiological resolution. CONCLUSIONS: As this common "contaminant" can behave as a pathogen in the immunocompromised host, both clinicians and microbiologists should consider the presence of a serious and potentially fatal fungal infection on isolation of P. citrinum. Based on this case, it could be speculated that AFOP may be associated with fungal infection including P. citrinum.

A case report of acute fibrinous and organizing pneumonia.

RATIONALE: Acute fibrinous and organizing pneumonia (AFOP) is a newly evolving rare non-infectious lung pathology, characterized by intra-alveolar fibrin balls on histology. It is usually difficult to be diagnosed and mistaken for other lung diseases. PATIENT CONCERNS: In this article, an interesting case about a male patient with a 15-day history of high-grade fever, chills, and no productive cough was presented. He was misdiagnosed as the lung infection early, but exhibited no response to the antibiotic therapy. DIAGNOSIS: The diagnosis of AFOP was determined by the lung biopsy and pathology. INTERVENTIONS: With the diagnosis of AFOP, all antibiotics were discontinued, and 40 mg methylprednisolone daily was given intravenously. OUTCOMES: The patient responded well to the treatment with steroids. LESSONS: AFOP is a rare lung disease characterized by bilateral basilar infiltrates and histological findings of organizing pneumonia and intra-alveolar fibrin in the form of "fibrin balls". Lung biopsy and histopathology were the most important diagnostic methods for the AFOP. Glucocorticoid was an effective drug for the treatment. Subacute patients of AFOP have excellent prognosis with corticosteroids.

Comparison of anti-aminoacyl-tRNA synthetase antibody-related and idiopathic non-specific interstitial pneumonia.

BACKGROUND AND PURPOSE: Patients with anti-aminoacyl-tRNA synthetase (ARS) antibodies frequently experience complications of interstitial pneumonia (ARS-IP), and the computed tomography (CT) of ARS-IP frequently shows nonspecific interstitial pneumonia (NSIP) pattern. The CT pattern of ARS-IP might be different from that of idiopathic IP. However, the clinical differences in patients with ARS-IP and idiopathic IP showing the similar CT patterns have not yet been well studied. The objective of this study was to evaluate the clinical differences between patients with ARS-NSIP and idiopathic NSIP (I-NSIP). METHODS: Two groups of 34 patients each, with ARS-NSIP and I-NSIP, who visited Hiroshima University Hospital between January 2005 and December 2017, were enrolled. Clinical features and outcomes were retrospectively compared between the two groups. RESULTS: The ARS-NSIP group included more female patients and significantly younger patients than the I-NSIP group. The percentage of lymphocytes in bronchoalveolar lavage fluid (BALF) was significantly higher, and the CD4/CD8 ratio in BALF was significantly lower in the ARS-NSIP group compared with the I-NSIP group. The proportion of patients with traction bronchiectasis detected by CT was significantly higher in I-NSIP compared with ARS-NSIP. The number of patients who received corticosteroid and/or immunosuppressant therapy was significantly larger in the ARS-NSIP group than in the I-NSIP group. In addition, the patients in the I-NSIP group who underwent the immunosuppressive therapy demonstrated shorter survival than those who underwent no treatment; this tendency was not observed in the ARS-NSIP group. The 10-year survival rate of patients in the ARS-NSIP group was significantly higher than that of patients in the I-NSIP group (91.8% vs. 43.0%; log-rank, p = 0.012). The multivariate survival analysis revealed that positive anti-ARS antibody was an independent favorable prognostic factor in the patients with NSIP (OR, [95% CI]:0.12 [0.02-0.55], p = 0.013). CONCLUSIONS: Patients with ARS-NSIP had a significantly better prognosis than those with I-NSIP; this may be associated with the sensitivity to immunosuppressive therapies, and the different findings of BALF and HRCT between the two groups.

Rituximab in connective tissue disease-associated interstitial lung disease.

INTRODUCTION/OBJECTIVES: To evaluate rituximab (RTX) effectiveness and safety in patients with interstitial lung disease (ILD) related to connective tissue diseases (CTD). METHODS: Retrospective multicenter cohort study, including patients with CTD-ILD, followed in six Portuguese rheumatology departments until November 2018. ILD diagnosis was based on high-resolution CT (HRCT) and/or lung biopsy. Results of HRCT, pulmonary function tests, and 6-min walking test before and after RTX were compared using the Wilcoxon matched pair test. Safety, including adverse events during treatment and reasons for RTX discontinuation, was also analyzed. RESULTS: A total of 49 patients were included, with rheumatoid arthritis being the commonest CTD (61.2%). The median interval between CTD onset and ILD diagnosis was 4 years (IQR 1-9.5) and median ILD duration at first RTX administration was 1 year (IQR 0-4). The median RTX treatment duration until the last follow-up was 3 years (IQR 1-6). Usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) were the commonest patterns, occurring in 20 and 18 patients, respectively. One year after RTX first administration, there was a stabilization in carbon monoxide diffusing capacity (DLCO; mean + 5.4%, p = 0.12) and improvement in forced vital capacity (FVC; mean + 4.3%, p = 0.03), particularly in patients with NSIP. Patients with UIP had less promising results, but at 1 year, pulmonary function tests remained stable (DLCO + 2.5%, p = 0.77; FVC + 4.2%, p = 0.16). Infection was the main reason for RTX discontinuation and led to two deaths. CONCLUSIONS: RTX seems to be a promising treatment for CTD-ILD patients, particularly when NSIP pattern is present. Key points • The use of rituximab in patients with interstitial lung disease related to connective tissue disease is associated with long-standing disease stability in a wide range of systemic rheumatic diseases. • Efficacy results were particularly impressive in patients with non-specific interstitial pneumonia pattern, although in a subgroup of patients with usual interstitial pneumonia pattern, disease progression was also hold with this treatment. • In a large number of patients, rituximab was used in monotherapy and as first-line treatment.

Association of serum high-mobility group box protein 1 level with outcomes of acute exacerbation of idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia.

BACKGROUND AND OBJECTIVE: High-mobility group box 1 (HMGB1) protein is important in acute lung injury. However, the role of HMGB-1 in acute exacerbation of fibrosing interstitial pneumonia (AE-FIP) has not been adequately studied. METHODS: We prospectively measured serum HMGB1 level from disease onset to day 7 in 36 patients with AE-FIP6 patients had missing data because of early death (within 7 days). We then examined the association of HMGB1 level and outcome, and the associations of rhTM with HMGB1 level and outcome in 19 patients who were treated with rhTM (rhTM group) and 11 patients who were not (control group). RESULTS: Data from 36 AE-FIP patients (mean age, 73.5±6.7years) were analyzed. Serum HMGB1 level was significantly higher in patients with AE-FIP than in those with stable idiopathic pulmonary fibrosis (16.4±13.5 vs 5.7±2.6 ng/ml, respectively; p = 0.003). HMGB1 was significantly lower on day 7 than at AE-FIP onset in survivors (6.5±4.8 vs 14.7±12.9 ng/ml, respectively; p = 0.02) but not in nonsurvivors (14.6±10.5 vs 9.2±4.8 ng/ml, respectively; p = 0.08). Although HMGB1 level at day 7 was significantly lower after rhTM treatment than at AE-FIP onset (8.4±6.1 vs 15.2±12.5 ng/ml, respectively; p = 0.02), it did not significantly decrease in patients receiving treatments other than rhTM (11.3±11.3 vs 8.3±5.3 ng/ml, respectively; p = 0.37). Three-month survival was 60.0% in the rhTM group and 36.4% in the control group (p = 0.449). In multivariate analysis, a decrease in HMGB1 was a significant independent predictor of 3-month survival (Odds ratio, 12.4; p = 0.007). CONCLUSION: rhTM lowers serum HMGB1 level and may improve survival after AE-FIP. HMGB1 may be a promising therapeutic target for AE-FIP.

Clinical features, risk factors, and outcomes of patients with interstitial pneumonia with autoimmune features: a population-based study.

To investigate the clinical features, risk factors and outcomes of patients with interstitial pneumonia with autoimmune features (IPAF). A total of 1429 patients with idiopathic interstitial pneumonia (IIP) and undifferentiated connective tissue disease-associated interstitial lung disease (UCTD-ILD) were screened to identify patients who met IPAF criteria. Clinical, serological, and morphological features of patients with IPAF were characterized. Outcomes between patients with IPAF, UCTD-ILD, and IIP who were divided into idiopathic pulmonary fibrosis (IPF) and non-IPF groups were compared using survival as an endpoint. Patients with IPAF were much common in young female and had lower percentage of ever smoking and a significantly shorter survival than those with non-IPAF (P < 0.001). Subgroup analysis revealed that IPAF cohort survival was worse than that in non-IPF (P < 0.001), but better than that in IPF (P < 0.001). In IPAF cohort, the most common systemic symptom and serological abnormality were Raynaud's phenomenon (12.9%) and ANA ≥ 1:320 (49.2%); the most frequent high-resolution computed tomography (HRCT) pattern was nonspecific interstitial pneumonia (NSIP) (61.6%). Multivariate analysis indicated that several factors including age, smoking history, organizing pneumonia (OP) pattern in HRCT, and anti-RNP positivity were independently associated with significantly worse survival. IPAF had the distinct clinical features and outcomes compared with other groups of ILD. Additional studies should be needed to explore the underlying autoimmune mechanism and to determine risk stratification in future clinical research.

Successful Treatment of Rapidly Progressive Unclassifiable Idiopathic Interstitial Pneumonia with Anti-melanoma Differentiation-associated Gene-5 Antibody by Intensive Immunosuppressive Therapy.

We describe a case of a woman who presented with a persistent cough, general fatigue, and a fever. Interstitial lung disease was rapidly progressive and resistant to high-dose steroid therapy. She tested positive for the presence of anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, although she had no skin manifestations of dermatomyositis. She was eventually diagnosed with unclassifiable idiopathic interstitial pneumonia and was successfully treated with intensive immunosuppressive therapy including intravenous cyclophosphamide. To our knowledge, this is the first report of anti-MDA-5 antibody in a patient with idiopathic interstitial pneumonia.

Interstitial pneumonia with autoimmune features (IPAF) and radiological findings suggestive of lymphocytic interstitial pneumonia (LIP) - case report.

Interstitial pneumonia with autoimmune features (IPAF) is a term to describe individuals with both interstitial lung disease (ILD) and combinations of other clinical, serologic, and/or pulmonary morphologic features, which presumably originate from an underlying systemic autoimmune condition, but do not meet current rheumatologic criteria for a defined connective tissue disease (CTD). Predominantly, interstitial pneumonia arises in the course of an established CTD, but it is not so rare for the ILD to be the first, and possibly the one and only manifestation of a latent CTD. Lymphocytic Interstitial Pneumonia (LIP) is an uncommon disease, characterized by infiltration of the interstitium and alveolar spaces of the lung by lymphocytes, plasma cells and other lymphoreticular elements. The cause of LIP is still unknown but it could be also a manifestation of CTD. Clinically, it is highly variable, from spontaneous resolution to progressive respiratory failure and death despite glucocorticoid treatment. Since there are no recent standards for the management of LIP, the disease is treated empirically. We report a case of a HIV-negative 54-year-old woman, who was suspected of LIP according to clinical features and radiological findings. Positive laboratory results were highly suggestive of underlying autoimmune process, but did not fulfil the criteria of any particular CTD. Because of severe general condition of the patient, immunosuppressive treatment was started immediately, without further invasive diagnostics including lung biopsy, which is required for a definitive diagnosis. We present two-year observation of the patient with all our doubts concerning clinical proceedings.

Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy?

Advances in the treatment of idiopathic interstitial pneumonia (IIP) represent an urgent, unmet medical need for patients with this category of diffuse parenchymal lung disease. IIPs involve varying combinations of fibrosis and inflammation of unknown cause and may be associated with pulmonary hypertension (PH). When it occurs, PH is associated with higher oxygen needs, greater functional impairment, and increased mortality. However, whether or when PH is a maladaptive versus adaptive phenomenon remains to be determined. Despite their differing prognoses, it does appear that the IIPs may follow a similar course once PH supervenes. Therefore, it may be worthwhile to explore studies of PH medications in IIP as a group rather than as individual entities. Such a broad approach eliminates the need to nuance specific diagnoses and thereby facilitates study recruitment and broadens the applicability of the results.

Cutaneous Pseudallescheria boydii/Scedosporium apiospermum Complex (Molecular type: Scedosporium apiospermum [Clade 4]) Infection: A Case Report and Literature Review of Cases from Japan.

We report a case of subcutaneous Pseudallescheria boydii/Scedosporium apiospermum complex infection occurring in a 77-year-old Japanese female farmer suffering from interstitial pneumonia. Seven months prior to the current presentation, she noticed nodes on her right forearm after pulling up weeds, and the nodes grew larger. Two soft dome-shaped, protruded nodes ( 15 mm and 30 mm in size ) had fused together on the extensor surface of the right forearm. Yellowish-white, rice-grain-sized pustules clustered on the surface. Histopathological examination of the skin specimen showed large and small abscesses surrounded by epithelioid granuloma; separate branching hyphae within the granulation tissue were stained with PAS. No grains were observed. Fungal culture yielded fast-growing, grayish-white, fluffy colonies which were identified as Scedosporium apiospermum (Clade 4) using sequence analysis of the ß-tubulin gene. We also reviewed 28 previously reported Japanese cases of P. boydii or S. apiospermum infection presenting with skin manifestations.