Human Vγ9Vδ2 T cells exhibit antifungal activity against Aspergillus fumigatus and other filamentous fungi.

Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus (Af293) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae, and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus, indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus. The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus. Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis. IMPORTANCE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.

Lung Involvement in Adult T-Cell Lymphoma Diagnosed Using Bronchoscopic Cryobiopsy: A Case Report and Review of the Literature.

The diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. Moreover, pulmonary involvement in adult T-cell lymphoma (ATL) is often difficult to diagnose, especially in cases without characteristic flower cells. Here, we present the case of a 78-year-old man, in whom pathological examination of the transbronchial lung biopsy (TBLB) specimen did not reveal malignant findings; therefore, transbronchial lung cryobiopsy (TBLC) in combination with endobronchial ultrasonography (EBUS) was used to diagnose ATL based on the pathological findings. A literature review identified 18 cases of pulmonary lymphomas diagnosed using TBLC. Among the 19 cases, including our own, 16 cases were of B-cell lymphoma (84.2%), and the present case is the first case of ATL diagnosed using TBLC. Eighty percent of the cases underwent a biopsy (more than two samples) of the middle or lower lobe and were diagnosed without major complications. EBUS was used with TBLC in three cases to identify the location of the pulmonary lesions. In the present case, EBUS was also useful for avoiding vascular biopsy. Although large-scale prospective studies are required to establish precise guidelines for diagnosing pulmonary lymphomas using TBLC, our case report and review contributes to a deeper understanding of the diagnosis of rare diseases.

Pulmonary Langerhans cell histiocytosis diagnosed using transbronchial lung cryobiopsy: A case report.

A 63-year-old Japanese woman with multiple cysts in both lungs on chest computed tomography (CT) was referred to our hospital after a thorough examination, including a transbronchial lung biopsy (TBLB), failed to provide a diagnosis. Based on the findings on chest CT and pathological examination of the bronchoalveolar lavage fluid and transbronchial lung cryobiopsy (TBLC) specimen, the patient was diagnosed with pulmonary Langerhans cell histiocytosis (PLCH). TBLC may replace TBLB as the main diagnostic technique for PLCH, although further studies are required to determine the usefulness of TBLC for the diagnosis of PLCH.

HSP47: A Therapeutic Target in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by a progressive decline in lung function and poor prognosis. The deposition of the extracellular matrix (ECM) by myofibroblasts contributes to the stiffening of lung tissue and impaired oxygen exchange in IPF. Type I collagen is the major ECM component and predominant collagen protein deposited in chronic fibrosis, suggesting that type I collagen could be a target of drugs for fibrosis treatment. Heat shock protein 47 (HSP47), encoded by the serpin peptidase inhibitor clade H, member 1 gene, is a stress-inducible collagen-binding protein. It is an endoplasmic reticulum-resident molecular chaperone essential for the correct folding of procollagen. HSP47 expression is increased in cellular and animal models of pulmonary fibrosis and correlates with pathological manifestations in human interstitial lung diseases. Various factors affect HSP47 expression directly or indirectly in pulmonary fibrosis models. Overall, understanding the relationship between HSP47 expression and pulmonary fibrosis may contribute to the development of novel therapeutic strategies.

Disseminated Mycobacterium genavense Infection Mimicking Sarcoidosis: A Case Report and Review of Literature on Japanese Patients.

Sarcoidosis is a systemic inflammatory disease characterized by noncaseating epithelioid cell granulomas. However, certain infections can exhibit similar histological findings. We present a case of a 69-year-old man who was initially diagnosed with sarcoidosis and later was confirmed, through 16S rRNA sequencing, to have disseminated Mycobacterium genavense infection. Acid-fast bacteria were detected in the bone marrow biopsy using Ziehl-Neelsen staining, but routine clinical tests did not provide a definitive diagnosis. The patient tested negative for HIV, anti-interferon-gamma antibodies, and genetic immunodeficiency disorders. He was treated with multiple drugs, including aminoglycosides and macrolides, but showed no improvement in fever and pancytopenia. However, these clinical signs responded favorably to steroid therapy. We reviewed 17 Japanese cases of M. genavense infection. All cases were in males; 7/17 (41%) were HIV-negative; and 12/17 (71%) had a decreased CD4 count. Genetic analysis confirmed M. genavense isolation, and macrolides were used universally. Mycobacterium genavense infection is challenging to identify and mimics other systemic inflammatory diseases such as sarcoidosis. There are no standard treatment protocols. Our case report and Japanese case review contribute to understanding this rare disease.

Evaluation of the Effectiveness and Use of Anti-Methicillin-Resistant Staphylococcus aureus Agents for Aspiration Pneumonia in Older Patients Using a Nationwide Japanese Administrative Database.

Studies indicated potential harm from empirical broad-spectrum therapy. A recent study of hospitalizations for community-acquired pneumonia suggested that empirical anti-methicillin-resistant Staphylococcus aureus (MRSA) therapy was associated with an increased risk of death and other complications. However, limited evidence supports empirical anti-MRSA therapy for older patients with aspiration pneumonia. In a nationwide Japanese database, patients aged ≥65 years on admission with aspiration pneumonia were analyzed. Patients were divided based on presence of respiratory failure and further sub-categorized based on their condition within 3 days of hospital admission, either receiving a combination of anti-MRSA agents and other antibiotics, or not using MRSA agents. An inverse probability weighting method with estimated propensity scores was used. Out of 81,306 eligible patients, 55,098 had respiratory failure, and 26,208 did not. In the group with and without respiratory failure, 0.93% and 0.42% of the patients, respectively, received anti-MRSA agents. In patients with respiratory failure, in-hospital mortality (31.38% vs. 19.03%, p < 0.001), 30-day mortality, and 90-day mortality were significantly higher, and oxygen administration length was significantly longer in the anti-MRSA agent combination group. Anti-MRSA agent combination use did not improve the outcomes in older patients with aspiration pneumonia and respiratory failure, and should be carefully and comprehensively considered.

Impact of Administering Intravenous Azithromycin within 7 Days of Hospitalization for Influenza Virus Pneumonia: A Propensity Score Analysis Using a Nationwide Administrative Database.

The potential antimicrobial and anti-inflammatory effectiveness of azithromycin against severe influenza is yet unclear. We retrospectively investigated the effect of intravenous azithromycin administration within 7 days of hospitalization in patients with influenza virus pneumonia and respiratory failure. Using Japan's national administrative database, we enrolled and classified 5066 patients with influenza virus pneumonia into severe, moderate, and mild groups based on their respiratory status within 7 days of hospitalization. The primary endpoints were total, 30-day, and 90-day mortality rates. The secondary endpoints were the duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. The inverse probability of the treatment weighting method with estimated propensity scores was used to minimize data collection bias. Use of intravenous azithromycin was proportional to the severity of respiratory failure (mild: 1.0%, moderate: 3.1%, severe: 14.8%). In the severe group, the 30-day mortality rate was significantly lower with azithromycin (26.49% vs. 36.65%, p = 0.038). In the moderate group, the mean duration of invasive mechanical ventilation after day 8 was shorter with azithromycin; there were no significant differences in other endpoints between the severe and moderate groups. These results suggest that intravenous azithromycin has favorable effects in patients with influenza virus pneumonia using mechanical ventilation or oxygen.

Pulmonary Nodular Lymphoid Hyperplasia Evaluated with Bronchoalveolar Lavage Fluid Findings: A Case Report and Review of the Literature on Japanese Patients.

Pulmonary nodular lymphoid hyperplasia (PNLH) is a very rare disease, and it is difficult to diagnose PNLH and distinguish it from mucosa-associated lymphoid tissue (MALT) lymphoma. In addition, information on bronchoalveolar lavage fluid (BALF) analyses is lacking. We herein report a 36-year-old Japanese woman diagnosed with PLNH by a surgical biopsy and analysis of BALF. The BALF showed an increase in B-cell marker-positive lymphocytes, normal patterns of B-cell clonality, mucosa-associated lymphoid tissue 1 gene, and immunoglobulin heavy chain at 14q32 translocations. We also reviewed Japanese cases of PNLH described in Japanese or English to explore the characteristics of such cases.

Pulmonary and Intestinal Involvement in a Patient with Myeloperoxidase-specific Antineutrophil Cytoplasmic Antibody-positive Hermansky-Pudlak Syndrome.

A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.

Two Distinct Mechanisms Underlying γδ T Cell-Mediated Regulation of Collagen Type I in Lung Fibroblasts.

Idiopathic pulmonary fibrosis is a chronic intractable lung disease, leading to respiratory failure and death. Although anti-fibrotic agents delay disease progression, they are not considered curative treatments, and alternative modalities have attracted attention. We examined the effect of human γδ T cells on collagen type I in lung fibroblasts. Collagen type I was markedly reduced in a γδ T cell number-dependent manner following treatment with γδ T cells expanded with tetrakis-pivaloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2. Collagen type I levels remained unchanged on addition of γδ T cells to the culture system through a trans-well culture membrane, suggesting that cell-cell contact is essential for reducing its levels in lung fibroblasts. Re-stimulating γδ T cells with (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) reduced collagen type I levels without cell-cell contact, indicating the existence of HMBPP-induced soluble anti-fibrotic factors in γδ T cells. Adding anti-interferon-γ (IFN-γ)-neutralizing mAb restored collagen type I levels, demonstrating that human γδ T cell-derived IFN-γ reduces collagen type I levels. Conversely, interleukin-18 augmented γδ T cell-induced suppression of collagen type I. Therefore, human γδ T cells reduce collagen levels in lung fibroblasts via two distinct mechanisms; adoptive γδ T cell transfer is potentially a new therapeutic candidate.

Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review.

Primary ciliary dyskinesia (PCD) is a genetic and congenital disease associated with an abnormal ciliary ultrastructure and function and is estimated to affect 1 in 15,000-20,000 individuals. A PCD diagnosis can be achieved by genotyping. Here, we performed whole-exome analysis for the diagnosis of PCD and described the detailed clinical characteristics of the case. A 39-year-old Japanese woman with sinusitis and bronchiectasis without situs inversus had had upper and lower respiratory symptoms since childhood and had received long-term macrolide therapy without an accurate diagnosis. A moderate deterioration of cilia function was observed by high-speed video microscopy analysis; additionally, the number of cells with moving cilia was fewer than that in patients without PCD. Electron microscopy revealed no apparent structural abnormalities. We performed whole-exome analysis and identified novel biallelic variants of SPEF2 in the homozygous state (c.1860_1861insCT). We confirmed the absence of SPEF2 protein expression in the cilia of the nasal mucosa using fluorescent immunostaining. Accordingly, she was diagnosed as having PCD with the SPEF2 variant. The present case suggests that the deterioration of cilia function is moderate, the number of respiratory cells with moving cilia might be reduced, and the respiratory condition could be severe in patients with PCD with the SPEF2 variant.

HLA-B54 is an independent risk factor for pneumonia in Japanese patients with interstitial lung disease: A multicenter retrospective cohort study.

PURPOSE: Pneumonia is a major cause of respiratory-related hospitalization and an important prognostic factor in patients with chronic interstitial lung disease (ILD). However, the relationship between the incidence of pneumonia and human leukocyte antigen (HLA) serotype has not been fully elucidated. Therefore, this study aimed to determine if there is a relationship between HLA serotype and the incidence of pneumonia in Japanese patients with ILD. METHODS: The medical records of patients with ILD treated at any of three centers in Japan were reviewed to determine their HLA-A and HLA-B serotypes. The characteristics of patients with and without pneumonia were compared. Cox regression analysis was performed to identify risk factors for pneumonia and death in these patients. RESULTS: One hundred and forty-four patients with ILD (pneumonia group, n = 27; non-pneumonia group, n = 117) and complete HLA serology data available were included. HLA-B54 positivity was significantly more common in the pneumonia group than in the non-pneumonia group (37.0% vs. 15.4%, p = 0.010). HLA-B54 positivity was also a significant risk factor for pneumonia (hazard ratio [HR] 4.166, 95% confidence interval [CI] 1.862-9.320, p = 0.001) and death (HR 4.050, 95% CI 1.581-10.374, p = 0.004) in patients with ILD. Furthermore, HLA-B54 positivity was a significant risk factor for pneumonia (HR 3.964, 95% CI 1.392-11.090, p = 0.010) and death (HR 8.131, 95% CI 1.763-37.494, p = 0.007) in patients with idiopathic pulmonary fibrosis. CONCLUSION: HLA-B54 positivity was a significant risk factor for pneumonia and death in patients with ILD, including those with idiopathic pulmonary fibrosis.

Screening of Inhibitors Targeting Heat Shock Protein 47 Involved in the Development of Idiopathic Pulmonary Fibrosis.

Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is causally related to fibrotic diseases, including idiopathic pulmonary fibrosis. The identification of Compounds that interfere with the HSP47-collagen interaction is essential for the development of relevant therapeutics. Herein, we prepared human HSP47 as a soluble fusion protein expressed in E. coli and established an assay system for HSP47 inhibitor screening. We screened a natural and synthetic Compound library established at Nagasaki University. Among 1023 Compounds, 13 exhibited inhibitory activity against human HSP47, of which three inhibited its function in a dose-dependent manner. Epigallocatechin-3-O-gallate, one of these three Compounds, is a typical polyphenol Compound derived from tea leaves. Structurally related Compounds were synthesized and examined for their activity, revealing a hydroxyl group at A-ring position 5 as important for its activity. The present findings provide valuable insight for the development of natural product-derived therapeutics for fibrotic diseases, including idiopathic pulmonary fibrosis.

Duration of antifungal therapy for septic pulmonary embolism caused by Candida albicans from a central venous catheter: A case report.

The treatment duration for candidemia with septic pulmonary embolism should be determined based on the clearance of fungus from the bloodstream and improvement of symptoms. The remaining lung nodules may not necessarily indicate persistent infection.

Impact of Corticosteroid Administration within 7 Days of the Hospitalization for Influenza Pneumonia with Respiratory Failure: A Propensity Score Analysis Using a Nationwide Administrative Database.

Influenza pneumonia, which causes acute respiratory distress syndrome and multiple organ failure, has no established management protocol. Recently, corticosteroid therapy was used to treat coronavirus disease 2019 with respiratory failure; however, its effectiveness as a treatment for influenza pneumonia remains controversial. To investigate the impact of corticosteroid therapy for the early phase of severe influenza pneumonia, we compared influenza pneumonia patients with respiratory failure treated with or without corticosteroids within 7 days after hospital admission using a Japanese nationwide administrative database. The primary endpoint was the mortality rate. The secondary endpoints were duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. The inverse probability weighting method with estimated propensity scores was used to minimize the data collection bias. We included 3519 patients with influenza pneumonia with respiratory failure. Of these, 875 were treated with corticosteroids. There was no significant difference between the groups regarding 30-day and 90-day mortality, duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. However, the in-hospital mortality rate was higher in the corticosteroid group. The use of systematic corticosteroid therapy in patients with influenza pneumonia was associated with a higher in-hospital mortality rate.

Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer.

BACKGROUND: Heat shock protein 47 (HSP47), a collagen-binding protein, has a specific role in the intracellular processing of procollagen production. HSP47 expression is associated with cancer growth and metastasis in several types of cancers. However, none of the studies have assessed whether HSP47 expression is associated with the risk of postoperative recurrence of lung cancer until now. Therefore, we aimed to assess this association. METHODS: The study population consisted of a cohort of consecutive patients who underwent surgery for lung cancer at Nagasaki University Hospital, Nagasaki, Japan, from January 2009 to December 2010. Patient characteristics, survival and disease-free survival (DFS), and laboratory findings were compared between patients who tested positive and negative for HSP47 expression in lung cancer cells and between those who showed high and low numbers of HSP47-positive fibroblasts in cancer stroma. RESULTS: A total of 133 patients underwent surgery for lung cancer. Sixty-seven patients (50.4%) had HSP47-positive cancer cells, and 91 patients (68.4%) had a higher number of HSP47-positive fibroblasts. The patients with a high number of HSP47-positive fibroblasts had a shorter DFS than those with a low number of HSP47-positive fibroblasts. Multivariate analysis identified only the presence of a high number of HSP47-positive fibroblasts as an independent risk factor for recurrence of lung cancer after surgery (odds ratio, 4.371; 95% confidence interval, 1.054-29.83; P = 0.042). CONCLUSION: The present study demonstrated that the presence of a high number of HSP47-positive fibroblasts in the cancer stroma was a risk factor for recurrence of lung cancer after surgery.

Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells.

Increasing attention has been paid to human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) in the field of cancer immunotherapy. We have previously demonstrated that a novel bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA), efficiently expands peripheral blood Vγ2Vδ2 T cells to purities up to 95-99% in 10-11 days. In the present study, we first examined the effect of PTA on farnesyl diphosphate synthase (FDPS) using liquid chromatography mass spectrometry (LC-MS) to analyze the mechanism underlying the PTA-mediated expansion of Vγ2Vδ2 T cells. We find that the prodrug induced the accumulation of both isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), direct upstream metabolites of FDPS. This indicates that not only IPP but also DMAPP plays an important role in PTA-mediated stimulation of Vγ2Vδ2 T cells. We next analyzed TCR-independent cytotoxicity of Vγ2Vδ2 T cells. When human lung cancer cell lines were challenged by Vγ2Vδ2 T cells, no detectable cytotoxicity was observed in 40 min. The lung cancer cell lines were, however, significantly killed by Vγ2Vδ2 T cells after 4-16 h in an effector-to-target ratio-dependent manner, demonstrating that Vγ2Vδ2 T cell-based cell therapy required a large number of cells and longer time when tumor cells were not sensitized. By contrast, pulsing tumor cell lines with 10-30 nM of PTA induced significant lysis of tumor cells by Vγ2Vδ2 T cells even in 40 min. Similar levels of cytotoxicity were elicited by ZOL at concentrations of 100-300 µM, which were much higher than blood levels of ZOL after infusion (1-2 µM), suggesting that standard 4 mg infusion of ZOL was not enough to sensitize lung cancer cells in clinical settings. In addition, Vγ2Vδ2 T cells secreted interferon-γ (IFN-γ) when challenged by lung cancer cell lines pulsed with PTA in a dose-dependent manner. Taken together, PTA could be utilized for both expansion of Vγ2Vδ2 T cells ex vivo and sensitization of tumor cells in vivo in Vγ2Vδ2 T cell-based cancer immunotherapy. For use in patients, further studies on drug delivery are essential because of the hydrophobic nature of the prodrug.

Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro.

Excessive extracellular matrix deposition, in particular collagen, is an important cause of lung fibrosis. Heat shock protein 47 (HSP47), a collagen-binding protein, plays an important role in the intracellular processing of procollagen. A small molecule that blocks the collagen chaperone function of HSP47 has been reported as an HSP47 inhibitor. The aim of this study was to assess the effect of the HSP47 inhibitor on collagen synthesis and other fibrotic process in vitro. We evaluated collagen expression by western blot, and determined cell viability and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch test, respectively, in human and mouse lung fibroblasts. Treatment of lung fibroblasts with HSP47 siRNA decreased collagen type I expression. Similarly, the HSP47 inhibitor decreased collagen type I expression in transforming growth factor beta 1 (TGF-ß1)-treated lung fibroblasts in a dose-dependent manner. The inhibitor also decreased the viability and cell migration ability of TGF-ß1-treated lung fibroblasts. Overall, we demonstrated that HSP47 is a potential therapeutic target for pulmonary fibrosis. The small molecule HSP47 inhibitor may mediate antifibrotic effects by suppressing the overexpression of collagen, and inhibiting the viability and migration of fibroblasts. Further research is needed to clarify the therapeutic potential of this HSP47 inhibitor for pulmonary fibrosis.

Serum Soluble Interleukin-2 Receptor Is a Biomarker for Pneumocystis jirovecii Pneumonia among Patients with Rheumatoid Arthritis under Methotrexate Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation and may manifest as interstitial pneumonia (IP). Methotrexate (MTX) is one of the main therapeutic drugs used for RA, but MTX could cause severe side effects, including Pneumocystis jirovecii pneumonia (PCP) and IP. Owing to similar symptoms, it is sometimes difficult to discriminate MTX therapy-associated PCP (MTX-PCP) and MTX therapy-associated IP (MTX-IP). Soluble interleukin-2 receptor (sIL-2R) is considered a marker of T-cell activation, and serum sIL-2R levels are elevated in RA and PCP. This led us to hypothesize that serum sIL-2R is a potential biomarker for discriminating MTX-PCP and MTX-IP. Accordingly, we carried out a retrospective analysis of 20 MITX-PCP cases, 30 MTX-IP cases, and as controls, 16 patients with RA-associated IP (RA-IP) and 13 patients with PCP without MTX treatment (PCP group). C-reactive protein and alveolar-arterial oxygen differences were higher in the MTX-PCP group than those in the RA-IP and MTX-IP groups. Importantly, serum levels of sIL-2R in MTX-PCP were significantly higher than those in other three groups. Based on the receiver operating characteristic curve, the cut-off level of sIL-2R resulting in the highest diagnostic accuracy for MTX-PCP was 1,311.5 U/mL, discriminating between MTX-PCP and other groups with 91.7% sensitivity and 78.6% specificity. Thus, patients with MTX-PCP show a higher degree of systemic inflammation, severe hypoxemia, and increased sIL-2R levels compared with those in MTX-IP cases. In conclusion, serum sIL-2R could be a biomarker for PCP diagnosis among patients with RA under MTX therapy.

Postoperative acute exacerbation of interstitial pneumonia in pulmonary and non-pulmonary surgery: a retrospective study.

BACKGROUND: Acute exacerbation of interstitial pneumonia (AE-IP) is a serious complication of pulmonary surgery in patients with IP. However, little is known about AE-IP after non-pulmonary surgery. The aim of this study was to determine the frequency of AE-IP after non-pulmonary surgery and identify its risk factors. METHODS: One hundred and fifty-one patients with IP who underwent pulmonary surgery and 291 who underwent non-pulmonary surgery were retrospectively investigated. RESULTS: AE-IP developed in 5 (3.3%) of the 151 patients in the pulmonary surgery group and 4 (1.4%) of the 291 in the non-pulmonary surgery group; the difference was not statistically significant. A logistic regression model showed that serum C-reactive protein (CRP) was a predictor of AE-IP in the non-pulmonary surgery group (odds ratio 1.187, 95% confidence interval 1.073-1.344, P = 0.002). CONCLUSIONS: This is the first study to compare the frequency of AE-IP after pulmonary surgery with that after non-pulmonary surgery performed under the same conditions. The results suggest that the frequency of AE-IP after non-pulmonary surgery is similar to that after pulmonary surgery. A high preoperative C-reactive protein level is a potential risk factor for AE-IP after non-pulmonary surgery.