Identification of kynurenine and quinolinic acid as promising serum biomarkers for drug-induced interstitial lung diseases.

BACKGROUND: Drug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need. METHODS: Biomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls. RESULTS: Serum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients. CONCLUSIONS: The serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.

Blood urea nitrogen-to-serum albumin ratio and A-DROP are useful in assessing the severity of Pneumocystis pneumonia in patients without human immunodeficiency virus infection.

INTRODUCTION: There is an increasing incidence of Pneumocystis pneumonia (PcP) among individuals without human immunodeficiency virus (HIV) infection (non-HIV PcP). However, prognostic factors for patients with non-HIV PcP have not been identified. Moreover, A-DROP (for classifying the severity of community-acquired pneumonia) or the blood urea nitrogen-to-serum albumin ratio (BUN/Alb), which is reported to be a predictor of mortality of community-acquired pneumonia, has not been established as an efficient prognostic factor in patients with non-HIV PcP. In this study, we analyzed the prognostic factors for non-HIV PcP and evaluated the prognostic ability of A-DROP and the BUN/Alb ratio. METHODS: This retrospective study involved a chart review of the medical records of 102 patients diagnosed with non-HIV PcP between January 2003 and May 2019 at five medical facilities. RESULTS: Overall, 102 patients were involved in this study. The 30-day mortality rate for non-HIV PcP was 20.5% in this study population. Compared with survivors, non-survivors had significantly lower serum albumin levels and significantly higher age, corticosteroid dosage at the PcP onset, alveolar-arterial oxygen gradient, A-DROP score, lactate dehydrogenase levels, blood urea nitrogen levels, and BUN/Alb ratio. Multivariate analysis showed that a high BUN/Alb ratio at treatment initiation was significantly associated with 30-day mortality risk. The receiver operating characteristic curves showed that A-DROP score had the highest prognostic ability in estimating 30-day mortality. CONCLUSIONS: In patients with non-HIV PcP, a high BUN/Alb ratio is an independent prognostic predictor of mortality risk, and A-DROP is useful for classifying the severity.

Isolated splenic Mycobacterium tuberculosis complex infection in an immunocompetent individual with FDG-PET positive mass.

Tuberculosis, caused by Mycobacterium tuberculosis complex, is a leading cause of mortality in the world, and 15% of the patients may present with extrapulmonary diseases, including splenic lesion. However, isolated splenic infection with M. tuberculosis complex is very rare. A 19-year-old otherwise healthy woman presented with left flank pain, revealing FDG-avid nodules in the spleen. She did not have pulmonary lesions. Histopathology of splenectomized sample showed granuloma, and subsequent PCR revealed amplification of IS6110, a genetic sequence exclusively detected in M. tuberculosis complex. A wide range of differential diagnosis of isolated splenic lesion should include M. tuberculosis infection regardless of pulmonary involvement. An elective splenectomy may be mandatory in timely manner.

The usefulness of a combination of age, body mass index, and blood urea nitrogen as prognostic factors in predicting oxygen requirements in patients with coronavirus disease 2019.

INTRODUCTION: Risk factors for seriously ill coronavirus disease 19 (COVID-19) patients have been reported in several studies. However, to date, few studies have reported simple risk assessment tools for distinguishing patients becoming severely ill after initial diagnosis. Hence, this study aimed to develop a simple clinical risk nomogram predicting oxygenation risk in patients with COVID-19 at the first triage. METHODS: This retrospective study involved a chart review of the medical records of 84 patients diagnosed with COVID-19 between February 2020 and March 2021 at ten medical facilities. The patients were divided into requiring no oxygen therapy (non-severe group) and requiring oxygen therapy (severe group). Patient characteristics were compared between the two groups. We utilized univariate logistic regression analysis to confirm determinants of high risks of requiring oxygen therapy in patients with moderate COVID-19. RESULTS: Thirty-five patients ware in severe group and forty-nine patients were in non-severe group. In comparison with patients in the non-severe group, patients in the severe group were significantly older with higher body mass index (BMI), and had a history of hypertension and diabetes. Serum blood urea nitrogen (BUN), lactic acid dehydrogenase (LDH), and C-reactive protein (CRP) levels were significantly higher in the severe group. Multivariate analysis showed that older age, higher BMI, and higher BUN levels were significantly associated with oxygen requirements. CONCLUSIONS: This study demonstrated that age, BMI, and BUN were independent risk factors in the moderate-to-severe COVID-19 group. Elderly patients with higher BMI and BUN require close monitoring and early treatment initiation.

Association of HLA-DRB1*04:05 allele with drug-induced interstitial lung disease in Japanese population.

Drug-induced interstitial lung disease (DILD) is a life-threatening adverse reaction. The Japanese population is more susceptible to DILD as compared with other populations, suggesting its pathogenesis could vary depending on ethnic genetic background. We conducted case-control studies to elucidate the association between DILD and HLA alleles in the Japanese. The 177 clinically diagnosed DILD patients and 3002 healthy controls for exploration and 55 DILD patients and 201 healthy controls for validation were genotyped for four HLA genes. HLA-DRB1*04:05 was significantly associated with DILD (corrected p = 0.014); this was also validated in the other set of patients/controls. Chemical drugs other than protein therapeutics showed this association (p = 1.7 × 10-4) . The Japanese population showed a higher HLA-DRB1*04:05 frequency than most other populations. In conclusion, HLA-DRB1*04:05 could be associated with DILD susceptibility in Japanese individuals, and its high general frequency may explain the high reported incidence of DILD in Japanese.

The utility of serum C-C chemokine ligand 1 in sarcoidosis: A comparison to IgG4-related disease.

We previously reported higher levels of C-C chemokine ligand (CCL) 1 in the bronchoalveolar lavage (BAL) fluid (BALF) of patients with sarcoidosis than in BALF of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD), indicating that CCL1 might act as a marker of disease activity in sarcoidosis. Notably, less invasive sampling sources are desirable, as BAL cannot always be performed due to its inherent risk. In this study, we sought to decipher the correlation between serum levels of CCL1 and clinical characteristics of sarcoidosis. Serum samples were obtained from 44 patients with clinically confirmed sarcoidosis, 14 patients with IgG4-RD, and 14 healthy controls. The clinical and radiological findings were retrospectively evaluated. Serum levels of CCL1 were measured using a sandwich enzyme-linked immunosorbent assay. Serum levels of other 17 cytokines and chemokines were measured using a MILLIPLEX® MAP KIT and Luminex® magnetic beads. Serum levels of CCL1 were significantly higher in patients with sarcoidosis than in patients with IgG4-RD and healthy controls. Serum CCL1 was positively correlated with the degree of hilar lymph node swelling on chest computed tomography and serum levels of soluble interleukin 2 receptor. Positive correlations were also observed between serum CCL1 and total cell counts, lymphocyte counts in BALF, and serum T helper 1 mediators such as IP-10 and TNF-α in patients with sarcoidosis. Serum CCL1 levels were significantly elevated in sarcoidosis and correlated with clinical parameters of the disease. In addition, serum and BALF levels of CCL1 were positively correlated in a statistically significant manner. Although further research in this field is necessary, CCL1 might have the potential to be a reliable serological marker of disease activity in sarcoidosis.

Prognosis of patients with acute exacerbation of combined pulmonary fibrosis and emphysema: a retrospective single-centre study.

BACKGROUND: Previous analyses of combined pulmonary fibrosis and emphysema (CPFE) cohorts have provided conflicting data on the survival of patients with CPFE. Therefore, the aim of this study was to investigate the clinical prognosis of acute exacerbations (AE) of CPFE. METHODS: We retrospectively reviewed the medical records of patients who had been treated at the Shinshu University Hospital (Matsumoto, Japan) between 2003 and 2017. We identified 21 patients with AE of CPFE and 41 patients with AE of idiopathic pulmonary fibrosis (IPF) and estimated their prognoses using the Kaplan-Meier method. RESULTS: Treatment content and respiratory management were not significantly different between the two groups before and after exacerbation. At the time of AE, the median serum Krebs von den Lungen-6 level was significantly lower in the CPFE group (Krebs von den Lungen-6: 966 U/µL; white blood cell count: 8810 /µL) than that in the IPF group (Krebs von den Lungen-6: 2130 U/µL, p < 0.001; white blood cells: 10809/µL, p = 0.0096). The baseline Gender-Age-Physiology scores were not significantly different between the two groups (CPFE, 4.5 points; IPF, 4.7 points; p = 0.58). Kaplan-Meier curves revealed that the survival time after AE for patients with CPFE was longer than that for patients with IPF (p < 0.001, log-rank test). CONCLUSIONS: Survival prognoses after AE were significantly better for patients with CPFE than that for those with IPF. Our findings may improve the medical treatment and respiratory management of patients with AE-CPFE.

Comparison of the chemokine profiles in the bronchoalveolar lavage fluid between IgG4-related respiratory disease and sarcoidosis: CC-chemokine ligand 1 might be involved in the pathogenesis of sarcoidosis.

BACKGROUND: We previously reported that the cytokine profiles in the bronchoalveolar lavage fluid (BALF) of IgG4-related respiratory disease (IgG4-RRD) more closely resemble the T-helper (Th) 2 response than sarcoidosis. The present study aimed to assess the chemokines in the BALF of IgG4-RRD and sarcoidosis in order to evaluate any possible associations between these chemokines and other markers. METHODS: We examined 12 chemokines using a MILLIPLEX® MAP Kit (Millipore, Darmstadt, Germany) in the same BALF samples of the same 44 patients (IgG4-RRD, n = 11; sarcoidosis, n = 33) in which we had previously evaluated the cytokines. RESULTS: The levels of CC-chemokine ligand (CCL)26 in the BALF of IgG4-RRD patients (median 24.5, range 3.1-401.1 pg/mL) were significantly higher than those in the BALF of sarcoidosis patients (median 3.1, range 3.1-155.6 pg/mL, p < 0.05). Interestingly, the BALF levels of CCL1 in the sarcoidosis patients (median 13.1, range 0.1-106.9 pg/mL) were significantly higher than those of the IgG4-RRD patients (median 9.8, range 0.1-14.7 pg/mL, p < 0.05). Furthermore, the CCL1 levels in the BALF were correlated with the total cell count (ρ = 0.539, p < 0.001), lymphocyte fraction (R = 0.406, P < 0.05), lymphocyte count (R = 0.686, P < 0.001), TNF-α level, (R = 0.748, P < 0.001), and IL-2 level (R = 0.757, P < 0.001) in the BALF of sarcoidosis patients. CONCLUSIONS: CCL1 might reflect disease activity and its involvement in the pathogenesis of sarcoidosis might be more closely related to Th1 than to Th2.

Virtual bronchoscopic navigation as an aid to CT-guided transbronchial biopsy improves the diagnostic yield for small peripheral pulmonary lesions.

BACKGROUND AND OBJECTIVE: Virtual bronchoscopic navigation (VBN) entails the provision of a virtual display of the bronchial routes that lead to small peripheral pulmonary lesions (PPL). It has been predicted that a combination of computed tomography (CT)-guided transbronchial biopsy (CT-TBB) with VBN might improve the diagnostic yield for small PPL. This study sought to investigate that prediction. METHODS: A total of 100 patients with small PPL (<20 mm) were enrolled for CT-TBB and randomly allocated to either a VBN+ or VBN- group (50 subjects per group). Group results were then compared in terms of diagnostic yield, whole procedure time, times at which the first CT scan and biopsy were taken and the number of lung biopsy specimens retrieved. RESULTS: The diagnostic yield for small PPL was significantly higher in the VBN+ group versus VBN- group (84% vs 58%, respectively (P = 0.013)), with no significant difference in (whole) examination time between groups (VBN+: 32:53 (32 min and 53 s) ± 12:01 vs VBN-: 33:06 ± 10:08 (P = NS)). However, the time periods between commencing the examination and either the first CT scan or first biopsy were significantly shorter for the VBN+ group, while the net biopsy time tended to be longer for this group with a significantly higher number of specimens collected (VBN+: 3.54 ± 1.07 specimens vs VBN-: 2.98 ± 1.06 specimens (P = 0.01)). CONCLUSION: Combining VBN with CT-TBB significantly improved the diagnostic yield for small PPL.

Bevacizumab-induced tracheoesophageal fistula in a patient suffering from lung cancer with bulky subcarinal lymph node: a case report.

A 66-year-old male with advanced non-small-cell lung cancer (NSCLC) who was previously treated with carboplatin, pemetrexed, and bevacizumab consequently suffered from severe coughing during deglutition. Chest computed tomography (CT) revealed a tracheoesophageal fistula (TEF) between the left main bronchus and esophagus through a subcarinal metastatic lymph node. Given the extreme swelling of the lymph node due to metastatic cancer, it was determined that the walls of the bronchus and esophagus had been injured simultaneously. Delayed and dysfunctional wound healing due to bevacizumab resulted in necrosis of the contact region leading to fistula formation. This case suggests that using bevacizumab for NSCLC in patients with bulky subcarinal lymphadenopathy may increase the risk for TEF.

A Four-Center Retrospective Study of the Efficacy and Toxicity of Low-Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Pneumonia in Patients without HIV Infection.

The dose of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of Pneumocystis pneumonia (PCP) in patients without human immunodeficiency virus (HIV) infection has not been verified. The aim of this study was to investigate the efficacy and toxicity of a low-dose TMP-SMX regimen in such patients. A retrospective study was conducted in four hospitals. We reviewed the medical records of patients with PCP but not HIV (non-HIV-PCP) who were treated with TMP-SMX between 2003 and 2016. The patients were divided into conventional-dose (TMP, 15 to 20 mg/kg/day) and low-dose (TMP, <15 mg/kg/day) groups after patients who received high-dose (TMP, >20 mg/kg/day) treatment were excluded. Grouping was done according to a correction dose, which was based on renal function. Eighty-two patients had non-HIV-PCP. The numbers of patients who received high-, conventional-, and low-dose treatments were 5, 36, and 41, respectively. Kaplan-Meier analysis for death associated with PCP showed no statistically significant difference in survival rates between the conventional- and low-dose groups. Ninety-day cause-specific mortality rates were 25.0% and 19.5% in the conventional-dose and low-dose groups (P = 0.76), respectively. Adverse events that were graded as ≥3 according to the Common Terminology Criteria for Adverse Events (version 4.0) (National Cancer Institute, 2010) were 41.7% and 17.1% in the conventional-dose and low-dose groups (P = 0.02), respectively. Moreover, vomiting (P = 0.03) and a decrease in platelet count (P = 0.03) occurred more frequently in the conventional-dose group. Treatment of non-HIV-PCP with low-dose or conventional-dose TMP-SMX produces comparable survival rates; however, the low-dose regimen is better tolerated and associated with fewer adverse effects.

Effect of multidrug therapy on the prognosis of Mycobacterium avium complex pulmonary disease.

Multidrug therapy for Mycobacterium avium complex pulmonary disease (MAC-PD) results in negative sputum cultures. However, the prognostic value of this treatment approach remains unclear. This study aimed to clarify whether multidrug therapy reduces the incidence of events related to MAC-PD and improves the mortality rate. Patients who met the diagnostic criteria for MAC-PD at our hospital between 2003 and 2019 were retrospectively evaluated using medical records. Events related to MAC-PD were defined as hospitalisation for haemoptysis or respiratory infection and the development of chronic respiratory failure. There were 90 and 108 patients in the multidrug and observation groups, respectively. The median observation period was 86 months. Intergroup differences in body mass index, proportion of patients with cavities, and erythrocyte sedimentation rate were not significant. However, the observation group was older with a higher mean age (multidrug group: 62 years, observation group: 69 years; P < 0.001) and had a higher proportion of male patients (multidrug group: 13/90 [14.4%], observation group: 35/108 [32.4%]; P < 0.01). Furthermore, intergroup differences in the incidence of events related to MAC-PD (multidrug group: 26.69/1000 person-years, observation group: 25.49/1000 person-years), MAC-PD-associated mortality rate (multidrug group: 12.13/1000 person-years, observation group: 12.74/1000 person-years), and total mortality (multidrug group: 24.26/1000 person-years, observation group: 29.50/1000 person-years) were not significant. Many patients relapse even after multidrug therapy, and our findings suggest that multidrug therapy has no effect in preventing the onset of respiratory events or prolonging life expectancy.

Antimicrobial and anti-inflammatory effects of clarithromycin on Mycobacterium avium complex replication in cultured human bronchial epithelial cells.

The Mycobacterium avium complex (MAC) invades cultured human bronchial cells, can replicate intracellularly, and facilitates the release of inflammatory cytokines and chemokines from cells. The purpose of this study was to examine the effects of clarithromycin (CAM) on MAC invasion, replication, and the release of cytokines and chemokines. A human bronchial epithelial cell line (BEAS-2B) monolayer grown on a tissue culture plate was infected with MAC. After 24 h, the cells were washed with Hanks' buffered salt solution, and extracellular bacteria were killed. The monolayer was further cultured for 5 days in medium containing CAM and subjected to a replication assay. The supernatants were assessed using a microchemotaxis assay and enzyme-linked immunosorbent assay (ELISA). mRNA expression was evaluated using a DNA array. The amount of intracellular MAC on day 5 of culture was significantly lower in the presence of CAM at the levels of 1× and 4× MIC. CAM inhibited the release of chemotactic activity and the production of interleukin (IL)-8 and macrophage chemotactic protein (MCP)-1. DNA array analysis of mRNA expression in BEAS-2B cells showed that CAM inhibited the expression of inflammatory cytokines and chemokines, involving IL-6, MCP-1, and IL-8 mRNA. MAC invaded and replicated in BEAS-2B cells and induced the production of chemotactic factors. In contrast, CAM may have bactericidal and bacteriostatic effects leading to the inhibition of inflammatory events.

Successful Rescue of Life-threatening Hemoptysis Caused by Pulmonary Tuberculosis Bridging with Extracorporeal Membrane Oxygenation.

Massive hemoptysis is a fatal complication associated with pulmonary tuberculosis (TB). It can lead to severe respiratory failure. Extracorporeal membrane oxygenation (ECMO) is a life-saving technology that is rarely indicated for bleeding disorders. We herein report a 26-year-old man who presented with severe respiratory failure caused by massive hemoptysis with pulmonary TB. Transcatheter artery embolization was successfully performed with venovenous ECMO support. The hemostatic procedure allowed concomitant anticoagulant use, and neither bleeding nor thrombotic complications occurred throughout the clinical course. Administering the appropriate hemostatic procedure with subsequent management, including anticoagulant therapy, supported ECMO application in a case of bleeding.

Obstructive Pneumonia Associated with Endobronchial Aspergilloma: Successful Treatment with Interventional Bronchoscopy and Antifungals.

Endobronchial aspergilloma is a rare disease. A 64-year-old man with severe diabetes mellitus developed a cough and fever and was referred to our hospital. He was diagnosed with obstructive pneumonia associated with endobronchial aspergilloma, underwent interventional bronchoscopy, and was treated with antifungals. While the optimal treatment has not been established, interventional bronchoscopy along with systemic antifungals may improve the outcome in such cases.

Tolerability of nintedanib in the elderly with idiopathic pulmonary fibrosis: A single-center retrospective study.

Idiopathic pulmonary fibrosis (IPF), a fibrosing interstitial lung disease, predominantly affects the elderly and is associated with a high mortality risk. Nintedanib, a tyrosine kinase inhibitor, significantly reduces IPF progression. However, data on the tolerability and efficacy of nintedanib in the elderly with IPF are limited. Therefore, this study aimed to examine the tolerability and efficacy of nintedanib in the elderly with IPF in a real-world setting. Medical records of 19 elderly IPF patients (≥ 75 years) and 46 non-elderly IPF patients (< 75 years) newly administered nintedanib were retrospectively analyzed. We compared the forced vital capacity (FVC) level, incidence and severity of adverse events, and continuation rates of nintedanib between the two groups. FVC and percent predicted diffusing capacity of the lung for carbon monoxide (DLco) were lower in the elderly IPF group at baseline. Although the elderly IPF patients had a significantly higher incidence of adverse events, such as diarrhea, nausea, and elevation of hepatic enzymes, the rate of discontinuation of nintedanib owing to adverse events was not different between the groups. The continuation rates of nintedanib treatment at 6 months and 1 year in the elderly IPF group were equivalent. Furthermore, there was a similar trend in the reduction of the annual FVC decline after nintedanib initiation between the groups. Our study demonstrated that nintedanib was tolerable in both the IPF patient groups in a real-world setting. Proper management of adverse events in the elderly with IPF would lead to a better clinical outcome.

Comparative analysis of humoral responses to BNT162b2 vaccine among patients with hematologic disorders and organ transplant recipients.

Vaccination against SARS-COV-2 is considered the most promising approach to curbing the pandemic. Patients with an immunocompromised state, such as those with hematological malignancies and organ transplantation recipients, are considered more susceptible to infection, but these at-risk patients were underrepresented in early clinical trials for vaccination. Although a growing body of studies suggests that the humoral response to COVID-19 vaccination in each of these at-risk groups of patients may be suboptimal in comparison to healthy controls, a clinical and strategic information for the further comparative analysis among these groups is not fully described. The humoral responses after two doses of BNT162b2 vaccination were evaluated in a total of 187 patients either with allogeneic hematopoietic transplantation, with renal transplantation, with anti-CD20 antibody therapy, or with anti-CD38 antibody therapy, and in 66 healthy controls. The early response at one to three months after vaccination was significantly inferior among patients with renal transplantation, patients with anti-CD20 antibody therapy, and patients with anti-CD38 antibody therapy in comparison to healthy control. But the patients with allogeneic hematopoietic transplantation showed early humoral response comparable to healthy control. The late response at 6 months after vaccination was still suboptimal among patients with renal transplantation and patients with anti-CD20 therapy. Among our patient group, renal transplant recipients had the lowest antibody titers after vaccination regardless of timing of vaccination. Patients who had received allogeneic hematopoietic transplantation attained a comparable serological response to the control group especially if they are vaccinated >300 days after transplantation, but the response was suboptimal if the vaccination was within 300 days after transplantation. Our results may provide policy makers with critical information for the further stratification of at-risk groups, helping contribute to a better allocation of resources, including additional booster vaccination.

Prognostic implication of IgG4 and IgG1-positive cell infiltration in the lung in patients with idiopathic interstitial pneumonia.

Immunoglobulin (Ig) G4-positive cells are rarely observed in the lungs of patients with idiopathic interstitial pneumonias (IIPs). IgG1 may be more pathogenic than IgG4, with IgG4 having both pathogenic and protective roles in IgG4-related disease (IgG4-RD). However, the role of both IgG1 and IgG4 in IIPs remains unclear. We hypothesized that patients with IgG4-positive interstitial pneumonia manifest different clinical characteristics than patients with IgG4-RD. Herein, we identified the correlation of the degree of infiltration of IgG1- and IgG4-positive cells with IIP prognosis, using a Japanese nationwide cloud-based database. We included eighty-eight patients diagnosed with IIPs after multidisciplinary discussion, from April 2009 to March 2014. IgG4-positive cell infiltration was identified in 12/88 patients with IIPs and 8/41 patients with idiopathic pulmonary fibrosis (IPF). Additionally, 31/88 patients with IIPs and 19/41 patients with IPF were diagnosed as having IgG1-positive cell infiltration. IgG4-positive IIPs tended to have a better prognosis. Conversely, overall survival in cases with IgG1-positive IPF was significantly worse. IIPs were prevalent with IgG1- or IgG4-positive cell infiltration. IgG1-positive cell infiltration in IPF significantly correlated with a worse prognosis. Overall, evaluating the degree of IgG1-positive cell infiltration may be prognostically useful in cases of IPF.

Identification and characterization of lysophosphatidylcholine 14:0 as a biomarker for drug-induced lung disease.

Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects' backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.