Prognostic value of myositis-specific antibodies in patients with idiopathic interstitial pneumonia.

BACKGROUND: Patients with idiopathic interstitial pneumonia (IIP) often exhibit positivity for myositis-specific antibodies (MSA). However, the significance of this finding remains unclear. In this study, we investigated the association of MSA with the prognosis and risk of acute exacerbation in patients with IIP. METHODS: We retrospectively reviewed the medical records of patients with IIP and examined the effect of each MSA subtype on survival and acute exacerbation. RESULTS: Of 240 patients with IIP, 48 (20%) exhibited positivity for MSA. The MSA subtypes included: PL-7 (antithreonyl; n = 16, 6.7%); signal recognition particle (n = 13, 5.4%); PL-12 (antialanyl; n = 9, 3.8%); Mi-2 (n = 8, 3.3%); OJ (anti-isoleucyl; n = 7, 2.9%). During the 382 days (382 ± 281 days) of observation, 32 (13%) patients expired, and 27 (11%) experienced an acute exacerbation. Cox proportional hazards regression analysis demonstrated that age at the initial visit (hazard ratio [HR]: 1.072; 95% confidence interval [CI]: 1.017-1.131; P = 0.01), PL-7 (HR: 4.785; 95% CI: 1.528-14.925; P = 0.007), and PL-12 (HR: 3.922; 95% CI: 1.198-12.82; P = 0.024) were independent predictors of survival time. PL-7 (HR: 3.268; 95% CI: 1.064-10; P = 0.039) and PL-12 (HR: 5.747; 95% CI: 1.894-7.544; P = 0.002) were independent predictors of time from first visit to acute exacerbation. CONCLUSION: Detecting MSA in patients with interstitial lung disease may be useful in predicting prognosis and providing a rationale for intensive treatment.

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.

The role of interleukin-6 as a prognostic biomarker for predicting acute exacerbation in interstitial lung diseases.

BACKGROUND: Interstitial lung diseases (ILDs) are chronic, parenchymal lung diseases with a variable clinical course and a poor prognosis. Within various clinical courses, acute exacerbation (AE) is a devastating condition with significant morbidity and high mortality. The aim of this study was to investigate the role of interleukin-6 (IL-6) to predict AE and prognosis in patients with ILD. METHODS: Eighty-three patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea, were included and their clinical data were retrospectively analyzed. RESULTS: The median follow-up period was 20 months. The mean age was 68.1 years and 65.1% of the patients were men with 60.2% of patients being ever-smokers. Among ILDs, idiopathic pulmonary fibrosis was the most common disease (68.7%), followed by connective tissue disease-associated ILD (14.5%), cryptogenic organizing pneumonia (9.6%), and nonspecific interstitial pneumonia (6.0%). The serum levels of IL-6 were measured at diagnosis with ILD and sequentially at follow-up visits. During the follow-ups, 15 (18.1%) patients experienced an acute exacerbation (AE) of ILD and among them, four (26.7%) patients died. In the multivariable analysis, high levels of IL-6 (OR 1.014, 95% CI: 1.001-1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. In the receiver operating characteristic curve analysis, the area under the curve was 0.815 (p < 0.001) and the optimal cut-off value of serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. In the multivariable Cox analysis, a high level of serum IL-6 (HR 1.007, 95% CI: 1.001-1.014, p = 0.018) was only an independent risk factor for mortality in ILD patients. CONCLUSIONS: In our study, a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD.

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.

Cluster analysis-based clinical phenotypes of idiopathic interstitial pneumonias: associations with acute exacerbation and overall survival.

BACKGROUND: The precise classification of idiopathic interstitial pneumonia (IIP) is essential for selecting treatment as well as estimating clinical outcomes; however, this is sometimes difficult in clinical practice. Therefore, cluster analysis was used to identify the clinical phenotypes of IIPs, and its usefulness for predicting clinical outcomes was evaluated. METHODS: Cluster analysis was performed using clinical features including patients' demographics; histories; pulmonary function test data; and laboratory, physical and radiological findings. RESULTS: In 337 patients with IIPs, four clusters were identified: Cluster I, in which > 80% of the patients had autoimmune features; Cluster II, which had the lowest rate of smoking, the lowest percent predicted forced vital capacity (%FVC) and the lowest body mass index (BMI); Cluster III, which had the highest rate of smoking, the highest rate of dust exposure, the second lowest %FVC and normal BMI; and Cluster IV, which exhibited maintenance of %FVC and normal BMI. Cluster IV had significantly longer overall survival than Clusters II and III. Clusters I and III had significantly longer overall survival than Cluster II. Clusters II and III had a significantly higher cumulative incidence of acute exacerbation than Cluster IV. CONCLUSION: Cluster analysis using clinical features identified four clinical phenotypes of IIPs, which may be useful for predicting the risk of acute exacerbation and overall survival.

Correlation between preoperative 18F-FDG PET/CT findings and postoperative short-term prognosis in lung cancer patients with idiopathic interstitial pneumonia after lung resection.

BACKGROUND: The present study aimed to investigate the correlation between preoperative 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET/CT findings and short-term survival in lung cancer patients with idiopathic interstitial pneumonia (IIP). METHODS: We retrospectively reviewed the data of 425 patients who underwent lung resection for non-small cell lung cancer without preoperative radiation therapy between November 2012 and October 2017. The maximum SUV (SUVmax) in the IIP area except the lung cancer site was measured in each patient. RESULTS: Thirty-one of the 425 patients (7.3%) showed findings of IIP in chest CT. Five of the 31 patients (16.1%) developed acute exacerbation (AE) after lung resection (AE+ group). Twenty-six of the 31 patients (83.9%) did not develop AE (AE- group). In the AE+ group, 18F-FDG SUVmax in the IIP area was significantly higher (1.9 ± 0.6 vs. 2.7 ± 0.7, p = 0.02) compared with that in the AE- group. The receiver operating characteristic analysis identified an SUVmax threshold score of 2.55 (p = 0.02) for AE. There was no 90-day mortality in the patients with SUVmax < 2.55 (n = 25). On the other hand, the 90-day mortality rate in patients with SUVmax ≥ 2.55 (n = 6) was 33.3% (2 patients). CONCLUSIONS: 18F-FDG PET/CT may predict AE after lung resection and could be related to short-term survival in lung cancer patients with IIP. Further investigations are needed to improve the prognosis in patients with high SUVmax in the IIP area.

Clinical significance of minor salivary gland biopsy in patients with idiopathic interstitial pneumonia.

BACKGROUND: Significant overlap may occur between idiopathic interstitial pneumonia (IIP) and connective tissue diseases (CTDs) that do not meet the established classification criteria for any known CTDs (i.e., occult CTD). Performing minor salivary gland biopsy (MSGB) to detect occult primary Sjogren's syndrome (pSS) in IIP patients is not well studied. METHODS: Consecutive IIP patients underwent MSGB to determine the prevalence of positive MSGB findings. Furthermore, we characterised the clinical, physiological and serological profiles of the MSGB-positive patients. Cox regression models were used to identify independent predictors of survival. RESULTS: The data of 155 patients with IIP were available for analysis. Sixty patients (38.7%) had positive MSGB findings. Of them, the mean age was 63.3 years, 51.6% were women, usual interstitial pneumonia (UIP) was the predominant pattern (63.3%), and seronegative antibodies (61.6%) were likely. Patients with positive MSGB findings had significantly greater survival than those with negative MSGB findings (p = 0.041). After stratifying the MSGB cohort based on the presence of a UIP pattern, no significant difference in survival was noted between those with positive MSGB-UIP pattern and those with a negative MSGB-UIP pattern (p = 0.231). Multivariate analysis on all UIP patients showed that higher forced vital capacity (p = 0.010) and smoking status (p = 0.035) were independently associated with survival. CONCLUSIONS: A substantial number of IIP patients had underlying occult CTD, highlighting the importance of performing MSGB to identify the salivary component of pSS when evaluating patients with interstitial lung disease of undetermined aetiology.

Disease course and prognosis of pleuroparenchymal fibroelastosis compared with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a rare interstitial lung disease characterized by unique radiological and pathological findings. However, pathological evaluations are available only in a limited number of patients. Therefore, several clinical diagnostic criteria have been proposed. Nevertheless, the applicability of these criteria has not yet been validated. Moreover, the clinical course of iPPFE and its prognosis have not yet been completely elucidated. METHODS: The present study assessed previously proposed clinical diagnostic criteria by comparing the clinical features between pathologically diagnosed iPPFE (p-iPPFE) and clinically diagnosed iPPFE (c-iPPFE). Subsequently, the clinical features of iPPFE were characterized and compared with those of idiopathic pulmonary fibrosis (IPF, n = 323). RESULTS: Clinical characteristics of c-iPPFE (n = 27) and p-iPPFE (n = 35) were similar. No significant difference was observed in terms of prognosis between c-iPPFE and p-iPPFE. The number of patients with iPPFE (both c-iPPFE and p-iPPFE) who developed lung cancer was significantly lower than that of patients with IPF. However, acute exacerbation (AE) showed similar incidence in patients with iPPFE and IPF. Survival of patients with iPPFE was significantly worse than that of patients with IPF (5-year survival rate: 38.5% vs. 63.5%, p < 0.0001), and the most common cause of death was chronic respiratory failure (73.8%), followed by AE (14.3%). Male gender was the only poor prognostic factor of iPPFE. CONCLUSION: The present study demonstrated efficiency of clinical diagnosis and also revealed clinically important characteristics of iPPFE that should be considered for management of iPPFE.

Acute exacerbation of unclassifiable idiopathic interstitial pneumonia: comparison with idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is well known as a life-threatening condition during its clinical course. However, the clinical features and prognosis in AE of unclassifiable idiopathic interstitial pneumonia (AE-UCIIP) remain to be elucidated. The aim of this study was to clarify the clinical features and prognosis of AE-UCIIP compared with those of AE-IPF. METHODS: In 187 patients with UCIIP or IPF, 64 patients with AE-UCIIP or AE-IPF, who were diagnosed and treated at our hospital, were retrospectively evaluated. RESULTS: A total of 24 patients with AE-UCIIP were significantly older (p = 0.011), included more women (p < 0.001) and never-smokers (p < 0.001), and showed fewer lung lesions on high-resolution computed tomography (p = 0.006) than 40 patients with AE-IPF. Incidence of AE-UCIIP was 10.29%/year and was significantly higher than in AE-IPF (Gray's test, p = 0.008). Prognosis of AE-UCIIP was as poor as that of AE-IPF (log-rank, p = 0.681). Percent-predicted forced vital capacity (%FVC) [hazard ratio (HR) 0.934, p = 0.045], and GAP stage within 12 months before AE (HR 3.530, p = 0.023), and partial pressure arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio at AE (HR 0.998, p = 0.016) were significant prognostic factors. Finally, commencement of long-duration (⩾12 h) direct hemoperfusion with a polymyxin B-immobilised fibre column (PMX-DHP) within 2 days after admission significantly improved survival (log-rank, p = 0.038) and was a significant prognostic factor (HR 0.175, p = 0.0039) in AE-UCIIP. Long-duration PMX-DHP showed favourable treatment effects even in the combined group of patients with AE-UCIIP or AE-IPF (log-rank p = 0.002; HR 0.328, p = 0.006). CONCLUSIONS: Patients with AE-UCIIP were older and included more women and never-smokers than those with AE-IPF. Prognosis of AE-UCIIP was as poor as that of AE-IPF. The reviews of this paper are available via the supplemental material section.

Efficacy of recombinant thrombomodulin for poor prognostic cases of acute exacerbation in idiopathic interstitial pneumonia: secondary analysis of the SETUP trial.

BACKGROUND: Acute exacerbation (AE) in idiopathic pulmonary fibrosis and other idiopathic interstitial pneumonias (IIPs) are poor prognostic events although they are usually treated with conventional therapy with corticosteroids and immunosuppressants. Previously, we demonstrated the safety and efficacy of recombinant human soluble thrombomodulin (rhTM) for AE-IIP in the SETUP trial. Here, we aimed to clarify the efficacy of rhTM for poor-prognosis cases of AE-IIP. METHODS: In this study, we included 85 patients, in whom fibrin degradation product (FDP)/d-dimer was evaluated at AE, from the 100 patients in the SETUP trial. The AE-IIP patients in the rhTM arm (n=39) were diagnosed using the Japanese criteria from 2014 to 2016 and treated with intravenous rhTM for 6 days in addition to the conventional therapy. The AE-IIP patients in the control arm (n=46) were treated with the conventional therapy without rhTM between 2011 and 2013. The subjects were classified into higher and lower FDP/d-dimer groups based on the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation scoring system. A multivariate Cox proportional hazard regression analysis with stepwise selection was performed to reveal the prognostic factors of AE-IIP. RESULTS: We developed a prognostic scoring system using two significant prognostic factors, higher FDP/d-dimer at AE and prednisolone therapy before AE, with 3 and 2 points assigned for each parameter, respectively. The prognostic scores ranged from 0 to 5. Survival of AE-IIP patients with a prognostic score=0 was significantly better than that of patients with score ≥2. Survival was improved with the rhTM therapy (p<0.05) in the poor prognostic cases (score ≥2), but not in the good prognostic cases (score=0). CONCLUSIONS: Treatment with rhTM might improve survival in AE-IIP cases with poor prognoses.Trial registration numberUMIN000014969, date: 28 August 2014.

[The clinical features and prognosis of interstitial lung disease patients with positive anti-neutrophil cytoplasmic antibody].

Objective: To investigate the clinical features and prognosis of interstitial lung disease patients with positive anti-neutrophil cytoplasmic antibody. Methods: The patients with interstitial lung disease who visited Peking Union Medical College Hospital from March 2006 to March 2016 were divided into three groups: interstitial lung disease with ANCA-positive(ANCA-ILD), connective tissue disease associated interstitial lung disease and interstitial pneumonia with autoimmune features (CTD-ILD/IPAF) and idiopathic interstitial pneumonia (IIP). The three groups were analyzed in terms of clinical manifestations, serology, lung function, imaging, survival and recurrence. Results: Two hundred and seventy four patients were enrolled and 38 (14%) were ANCA-positive of whom 16 were male and 22 were female. The age of 38 ANCA-positive patients was (59±10) years and the follow-up time was (52±31) months. Seven among the 38 ANCA-positive patients died and the death rate is 18.42%. The ANCA-positive patients with interstitial lung disease have higher onset age (ANCA-ILD:59±10,CTD-ILD/IPAF:52±10,IIP:53±11,H=19.29, P<0.001), lower hemoglobin (ANCA-ILD: 129±21, CTD-ILD/IPAF: 138±15, IIP: 140±19, H=8.17, P=0.017), higher erythrocyte sedimentation rate (ANCA-ILD:45±35, CTD-ILD/IPAF:26±24,IIP:19±22,H=19.73, P<0.001), lower lung function improvement rate after treatment (ANCA-ILD:31%,CTD-ILD/IPAF:59%,IIP: 39%,χ(2)=11.74,P=0.003), lower absorption rate of CT lesion (ANCA-ILD:61%,CTD-ILD/IPAF:82%,IIP:67%, χ(2)=9.23,P=0.010) and higher death rate(ANCA-ILD:18%,CTD-ILD/IPAF:6%,IIP:12%, χ(2)=7.16,P=0.028). Conclusions: There are significant differences in clinical characteristics between ANCA-positive patients and other types of pulmonary interstitial disease. And both the treatment effect and the prognosis is poor for the ANCA-positive patients.

Lobe-specific outcomes of surgery for lung cancer patients with idiopathic interstitial pneumonias.

OBJECTIVE: Idiopathic interstitial pneumonias (IIPs) are predominantly encountered in the lower lobe, and frequently with concomitant emphysema that is predominantly in the upper lobe. However, the impact of the resection site on surgical outcomes of lung cancer with IIPs remains unclear. This study was conducted to evaluate the surgical outcome between patients undergoing upper or lower lobe resection. METHODS: This retrospective study was performed on 1972 patients who underwent surgical resection for lung cancer at our institute between 2009 and 2018. Review of CT findings revealed that 337 (14.1%) patients had IIPs. Morbidity, mortality, and postoperative pulmonary function test (PFT) were compared between patients who underwent upper or lower lobectomy and stratified by presence or absence of emphysema (CPFE and non-CPFE). RESULTS: Surgical mortality and morbidity were not statistically different between the two groups regardless of CPFE. The difference between actual and predicted postoperative PFTs was statistically larger in the upper lobectomy compared to the lower lobectomy among the non-CPFE patients. (FVC: p = 0.019, FEV1.0: p = 0.001, %DLCO: p = 0.090) CONCLUSIONS: Site of the resected lobe in lung cancer is not a prognostic factor of surgical mortality and morbidity in patients with IIPs. However, the impact of upper lobectomy on postoperative respiratory function reduction is larger than lower lobectomy in non-CPFE patients.

Impact of radiological honeycombing in rheumatoid arthritis-associated interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is the most common and important pulmonary manifestation of rheumatoid arthritis (RA). A radiological honeycomb pattern has been described in diverse forms of ILD that can impact survival. However, the clinical course and sequential radiological changes in the formation of the honeycomb pattern in patients with RA-ILD is not fully understood. METHODS: We evaluated the sequential changes in computed tomography findings in 40 patients with chronic forms of RA-ILD without the honeycomb pattern at initial diagnosis. We classified the patients into the Non-honeycomb group and Honeycomb group, and then analyzed the characteristics and prognosis of the two groups. The term "honeycomb formation" indicated a positive finding of honeycombing on any available follow-up CT. RESULTS: Our RA-ILD cohort included patients with probable usual interstitial pneumonia (UIP) (35%), nonspecific interstitial pneumonia (NSIP) (20%), and mixed NSIP/UIP (45%). Among all RA-ILD patients, 16 (40%) showed honeycomb formation on follow-up CT (median time between initial and last follow-up CT was 4.7 years). Patient characteristics and prognosis were not significantly different between the Non-honeycomb and Honeycomb groups. However, Kaplan-Meier survival curve for the time from the date of honeycomb formation to death showed a poor median survival time of 3.2 years. CONCLUSIONS: A certain number of patients with RA-ILD developed a honeycomb pattern during long-term follow-up, regardless of whether they had UIP or NSIP. Prognosis in the patients with characteristics of both progressive ILD and honeycomb formation could be poor. Although radiological findings over the disease course and clinical disease behavior in RA-ILD are heterogenous, clinicians should be alert to the possibility of progressive disease and poor prognosis in patients with RA-ILD who form a honeycomb pattern during follow-up observation.

Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias.

BACKGROUND: Few studies have examined the relationship between echocardiographic indices of right ventricular (RV) function and the severity of pulmonary disease, or their prognostic impact. We evaluated the RV function in patients with interstitial pneumonia and its prognostic impact at each stage of disease severity. METHOD: A total of 176 patients with idiopathic interstitial pneumonias (IIPs) were retrospectively enrolled and we evaluated RV function by transthoracic echocardiography. The severity of IIPs was graded according to the Goh score. The primary outcome was all-cause death. RESULTS: There were 55 patients in mild group (31%), 66 in moderate group (38%), and 55 in severe group (31%). Regarding RV function, RV free wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) deteriorated with increasing severity of IIPs, but fractional area change (FAC) decreased significantly only in severe group. There were 64 all-cause deaths during the follow-up period (median 908 days). In moderate group, TAPSE [hazard ratio (HR): 0.85, 95% confidence interval (CI): 0.74-0.97, p=0.017], FAC (HR: 0.89, 95% CI: 0.83-0.96, p=0.001), and mean pulmonary artery pressure (PAP)/cardiac output (HR: 1.50, 95% CI: 1.08-2.09, p=0.015) were independent predictors of all-cause death, even after adjusting for age and log brain natriuretic peptide (BNP). On the other hand, not RV function or PAP but male sex and BNP level were associated with mortality in severe group. CONCLUSIONS: Among patients with IIPs, RV longitudinal function deteriorated with increasing severity of IIPs. Echocardiographic indices of RV function were independently associated with mortality in moderate-stage IIPs.

Prognostic differences among patients with idiopathic interstitial pneumonias with acute exacerbation of varying pathogenesis: a retrospective study.

BACKGROUND: Acute exacerbation of chronic fibrosing idiopathic interstitial pneumonias (AE-IIPs) is associated with a high mortality rate. In 2016, an international working group proposed a revised diagnostic criteria for AE-IIPs, suggesting that it be classified as idiopathic or triggered. Many factors are known to trigger AE-IIPs, including surgery, infection, and drugs. However, it is unknown which AE-IIPs triggers have a worse prognosis. We aimed to investigate the prognosis of patients with various clinical types of AE-IIPs, particularly infection-triggered, non-infection triggered, and idiopathic AE-IIPs. METHODS: We retrospectively collected data from 128 chronic fibrosing IIPs (CF-IIPs) patients who were hospitalized by respiratory failure between April 2009 and March 2019 at Juntendo University Hospital. Among these patients, we evaluated 79 patients who developed AE-IIPs and 21 who developed pneumonia superimposed on CF-IIPs. Patients with AE-IIPs were classified into three types: idiopathic, infection-triggered, and non-infection-triggered AE-IIPs. We analyzed differences in patient characteristics, examination findings; level of serum markers, results of pulmonary function, and radiological findings, prior treatment for baseline CF-IIPs, and prognosis. We then evaluated the risk factor for early death (death within 30 days from the onset of AE-IIPs) associated with AE-IIPs. RESULTS: Among the patients who developed AE-IIPs, 34 were characterized as having idiopathic, 25 were characterized as having infection-triggered, and 20 were categorized as having non-infection-triggered AE-IIPs. Survival time for pneumonia superimposed on IIPs was significantly longer than that for any AE-IIPs. Survival time for bacterial pneumonia superimposed on CF-IIPs was significantly longer than that for AE-IIPs (for each idiopathic and all triggered IIPs). Thereafter, survival time for infection-triggered was significantly longer than for idiopathic or non-infection-triggered AE-IIPs. The mortality rate was significantly lower in infection-triggered AE-IIPs than in other types of AE-IIPs. Furthermore, the incidence of infection-triggered AE-IIPs in winter was significantly higher than that in other seasons. Moreover, the clinical AE-IIPs types and radiological findings at AE-IIP onset were significant risk factors for AE-IIPs-induced early death. CONCLUSIONS: Our findings suggest that patients with infection-triggered AE-IIPs can expect a better prognosis than can patients with other clinical types of AE-IIPs.

Demographic and clinical predictors of progression and mortality in connective tissue disease-associated interstitial lung disease: a retrospective cohort study.

BACKGROUND: Connective tissue disease-associated interstitial lung disease (CTD-ILD) is associated with reduced quality of life and poor prognosis. Prior studies have not identified a consistent combination of variables that accurately predict prognosis in CTD-ILD. The objective of this study was to identify baseline demographic and clinical characteristics that are associated with progression and mortality in CTD-ILD. METHODS: Patients were retrospectively identified from an adult CTD-ILD clinic. The predictive significance of baseline variables on serial forced vital capacity (FVC), diffusion capacity (DLCO), and six-minute walk distance (6MWD) was assessed using linear mixed effects models, and Cox regression analysis was performed to assess impact on mortality. RESULTS: 359 patients were included in the study. Median follow-up time was 4.0 (IQR 1.5-7.6) years. On both unadjusted and multivariable analysis, male sex and South Asian ethnicity were associated with decline in FVC. Male sex, positive smoking history, and diagnosis of systemic sclerosis (SSc) vs. other CTD were associated with decline in DLCO. Male sex and usual interstitial pneumonia (UIP) pattern predicted decline in 6MWD. There were 85 (23.7%) deaths. Male sex, older age, First Nations ethnicity, and a diagnosis of systemic sclerosis vs. rheumatoid arthritis were predictors of mortality on unadjusted and multivariable analysis. CONCLUSION: Male sex, older age, smoking, South Asian or First Nations ethnicity, and UIP pattern predicted decline in lung function and/or mortality in CTD-ILD. Further longitudinal studies may add to current clinical prediction models for prognostication in CTD-ILD.

The utility of the Japanese Association for Acute Medicine DIC scoring system for predicting survival in acute exacerbation of fibrosing idiopathic interstitial pneumonia.

BACKGROUND: Although evidence of a disseminated intravascular coagulation (DIC)-like reaction has been identified in the lung parenchyma of patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF), an association between DIC and IPF outcome has not been elucidated. Therefore, we retrospectively investigated the association between the Japanese Association for Acute Medicine (JAAM)-DIC score and mortality in patients with acute exacerbation of fibrosing idiopathic interstitial pneumonia (AE-fIIP). METHODS: Between January 2008 and December 2016, consecutive patients with chronic fIIP who were admitted for the first time for AE-fIIP were recruited into the study. Associations between clinical data and JAAM-DIC score at the time of admission and mortality were examined. RESULTS: During the study period, a total of 91 patients with fIIP (73.0±8.4 y.o.) were hospitalized for AE-fIIP for the first time. The 30-day and hospital mortality were 8.7% and 17.5%, respectively. A multivariate analysis showed that the JAAM-DIC score on admission was an independent predictor of 30-day mortality (odds ratio [OR] 2.57, 95% confidential interval [CI] 1.50-4.40, P = 0.0006). The APACHE II score (OR 1.29, 95% CI 1.01-1.63, P = 0.03) and the JAAM-DIC score (OR 3.47, 95% CI 1.73-6.94, P = 0.0004) were independent predictors of hospital mortality. CONCLUSIONS: The JAAM-DIC scoring system can predict survival in patients with AE-fIIP. The role of DIC in the pathogenesis of AE-fIIP merits further investigation.

Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f-IPF).

BACKGROUND: The aim of this study was to analyze the relative frequency, clinical characteristics, disease onset and progression in f-IPF vs. sporadic IPF (s-IPF). METHODS: Familial IPF index patients and their family members were recruited into the European IPF registry/biobank (eurIPFreg) at the Universities of Giessen and Marburg (UGMLC). Initially, we employed wide range criteria of f-IPF (e.g. relatives who presumably died of some kind of parenchymal lung disease). After narrowing down the search to occurrence of idiopathic interstitial pneumonia (IIP) in at least one first grade relative, 28 index patients were finally identified, prospectively interviewed and examined. Their family members were phenotyped with establishment of pedigree charts. RESULTS: Within the 28 IPF families, overall 79 patients with f-IPF were identified. In the same observation period, 286 f-IIP and s-IIP patients were recruited into the eurIPFreg at our UGMLC sites, corresponding to a familial versus s-IPF of 9.8%. The both groups showed no difference in demographics (61 vs. 79% males), smoking history, and exposure to any environmental triggers known to cause lung fibrosis. The f-IPF group differed by an earlier age at the onset of the disease (55.4 vs. 63.2 years; p < 0.001). On average, the f-IPF patients presented a significantly milder extent of functional impairment at the time point of inclusion vs. the s-IPF group (FVC 75% pred. vs. FVC 62% pred., p = 0.011). In contrast, the decline in FVC was found to be faster in the f-IPF vs. the s-IPF group (4.94% decline in 6 months in f-IPF vs. 2.48% in s-IPF, p = 0.12). The average age of death in f-IPF group was 67 years vs. 71.8 years in s-IPF group (p = 0.059). The f-IIP group displayed diverse inheritance patterns, mostly autosomal-dominant with variable penetrance. In the f-IPF, the younger generations showed a tendency for earlier manifestation of IPF vs. the older generation (58 vs. 66 years, p = 0.013). CONCLUSIONS: The 28 f-IPF index patients presented an earlier onset and more aggressive natural course of the disease. The disease seems to affect consecutive generations at a younger age. TRIAL REGISTRATION: Nr. NCT02951416 http://www.www.clinicaltrials.gov.

Nationwide cloud-based integrated database of idiopathic interstitial pneumonias for multidisciplinary discussion.

Multidisciplinary discussion (MDD) requiring close communication between specialists (clinicians, radiologists and pathologists) is the gold standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). However, MDD by specialists is not always feasible because they are often separated by time and location. An online database would facilitate data sharing and MDD. Our aims were to develop a nationwide cloud-based integrated database containing clinical, radiological and pathological data of patients with IIPs along with a web-based MDD system, and to validate the diagnostic utility of web-based MDD in IIPs.Clinical data, high-resolution computed tomography images and lung biopsy slides from patients with IIPs were digitised and uploaded to separate servers to develop a cloud-based integrated database. Web-based MDD was performed using the database and video-conferencing to reach a diagnosis.Clinical, radiological and pathological data of 524 patients in 39 institutions were collected, uploaded and incorporated into the cloud-based integrated database. Subsequently, web-based MDDs with a pulmonologist, radiologist and pathologist using the database and video-conferencing were successfully performed for the 465 cases with adequate data. Overall, the web-based MDD changed the institutional diagnosis in 219 cases (47%). Notably, the MDD diagnosis yielded better prognostic separation among the IIPs than did the institutional diagnosis.This is the first study of developing a nationwide cloud-based integrated database containing clinical, radiological and pathological data for web-based MDD in patients with IIPs. The database and the web-based MDD system that we built made MDD more feasible in practice, potentially increasing accurate diagnosis of IIPs.

Recombinant thrombomodulin for acute exacerbation in idiopathic interstitial pneumonias.

BACKGROUND AND OBJECTIVE: Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) or other idiopathic interstitial pneumonias (IIP) is a poor prognostic event despite conventional therapy with corticosteroids and/or immunosuppressants. We aimed to evaluate the efficacy and safety of recombinant human soluble thrombomodulin (rhTM) for AE-IIP. METHODS: For this prospective single-arm open-label multicentre cohort study, we retrospectively registered 61 cases of AE-IIP treated with conventional therapy between 2011 and 2013 (control arm), and prospectively enrolled 39 cases of AE-IIP treated with conventional therapy and rhTM (380 U/kg/day for 6 days) between 2014 and 2016 (rhTM arm). To reduce potential confounding in treatment comparisons, an adjusted mortality analysis for 90-day survival was conducted with weighted Cox proportional hazards regression models using inverse probability of treatment weighting. Weights were derived from propensity scores estimated using a multivariable logistic regression analysis including potential confounders. RESULTS: The 90-day survival rates of AE-IIP patients treated with/without rhTM were 66.7% (26/39) and 47.5% (29/61), respectively. After adjusting for imbalances, rhTM therapy was significantly associated with reduced mortality (adjusted hazard ratio (HR): 0.453; 95% CI: 0.237-0.864; P = 0.0163). The frequencies of adverse events with/without rhTM were 17.9% (7/39) and 19.7% (12/61), which were similar in both arms (P = 1.0). Two bleeding-related adverse events occurred in the rhTM arm. CONCLUSION: Safety and efficacy were observed for rhTM treatment of AE-IIP. A future randomized controlled trial is required to draw final conclusions.