Pneumocystis jirovecii pneumonia mortality risk associated with preceding long-term steroid use for the underlying disease: A multicenter, retrospective cohort study.

OBJECTIVE: Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality. METHODS: Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome. RESULTS: Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not. CONCLUSION: A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population.

Switching to Dupilumab from Other Biologics without a Treatment Interval in Patients with Severe Asthma: A Multi-Center Retrospective Study.

BACKGROUND: Dupilumab is a fully humanized monoclonal antibody that blocks interleukin-4 and interleukin-13 signals. Several large clinical trials have demonstrated the efficacy of dupilumab in patients with severe asthma. However, few studies have examined a switch to dupilumab from other biologics. METHODS: This retrospective, multi-center observational study was conducted by the Okayama Respiratory Disease Study Group. Consecutive patients with severe asthma who were switched to dupilumab from other biologics without a treatment interval between May 2019 and September 2021 were enrolled. Patients with a treatment interval of more than twice the standard dosing interval for the previous biologic prior to dupilumab administration were excluded. RESULTS: The median patient age of the 27 patients enrolled in this study was 57 years (IQR, 45-68 years). Eosinophilic chronic rhinosinusitis (ECRS)/chronic rhinosinusitis with nasal polyp (CRSwNP) was confirmed in 23 patients. Previous biologics consisted of omalizumab (n = 3), mepolizumab (n = 3), and benralizumab (n = 21). Dupilumab significantly improved FEV1 (median improvement: +145 mL) and the asthma control test score (median improvement: +2). The overall response rate in patients receiving dupilumab for asthma as determined using the Global Evaluations of Treatment Effectiveness (GETE) was 77.8%. There were no significant differences in the baseline characteristics of the GETE-improved group vs. the non-GETE-improved group. ECRS/CRSwNP improved in 20 of the 23 patients (87.0%). Overall, 8 of the 27 patients (29.6%) developed transient hypereosinophilia (>1500/µL), but all were asymptomatic and able to continue dupilumab therapy. CONCLUSIONS: Dupilumab was highly effective for the treatment of severe asthma and ECRS/CRSwNP, even in patients switched from other biologics without a treatment interval.

A single-center, person-month-based analysis of the risk of developing Pneumocystis pneumonia (PCP) in immunosuppressed non-HIV patients: Preventive effects of trimethoprim-sulfamethoxazole.

OBJECTIVE: We performed a retrospective study to evaluate the risk factors for acquiring Pneumocystis pneumonia (PCP) by pharmacologically immunosuppressed HIV-negative patients. METHODS: Patients who received corticosteroids, immunosuppressive agents, anticancer agents, and radiotherapy with or without trimethoprim-sulfamethoxazole (TMP-SMX) at Himeji Medical Center between 2010 and 2021 were evaluated. Drugs and doses of the treatments for each patient were divided by month into person-month units. Each person-month datum includes information on the administered drug (or radiotherapy), average doses, and whether the patient had PCP during the corresponding month. ROC curves with person-month data were generated for each treatment, and AUCs >0.7 were identified as possessing positive classification utility. The risks for PCP according to gender, age (grouped by median) and each treatment were examined by univariate analysis, followed by multivariate analysis to identify independent factors. RESULTS: Of a total of 17,733 patients (214,676 person-months), 32 developed PCP. The cut-off values by ROC analysis were 13.7 mg/day for corticosteroid (prednisolone equivalent), 0.92 mg/day (6.45 mg/week) for methotrexate (MTX), and 34.3 mg/day for TMP-SMX. The cut-off values for other treatments could not be estimated. The above three drugs and male sex were significant variables in univariate analysis and were all confirmed as independent factors by multivariate analysis. CONCLUSION: The results suggest that a monthly average dose of ≥13.7 mg/day of prednisolone, ≥0.92 mg/day of MTX and male sex are significant independent risk factors for PCP, and that prophylaxis with ≥34.3 mg/day of TMP-SMX is to be recommended.

Precut technique using an injection needle: A retrospective study on a new ancillary procedure for pleural biopsy.

The effectiveness of thoracoscopic biopsy as a diagnostic method for pleural diseases has been reported; however, obtaining a sufficient specimen size is sometimes difficult. Therefore, an ancillary technique, the precut technique using an injection needle, was devised to address this problem. This study aimed to evaluate the effectiveness and safety of the novel precut technique in patients with undiagnosed pleural effusion. This retrospective study included 22 patients who underwent pleural biopsy using the precut technique to examine exudative pleural effusion of unknown etiology. Thoracoscopy was performed under local anesthesia. The biopsy procedure was performed as follows: a needle was inserted into the pleura around the lesion using a semiflexible thoracoscope; the needle was positioned to make an incision in the pleura while injecting 1% lidocaine with epinephrine and lifting the pleura from the fascia; 2 or 3 precut incision lines were arranged in a triangle; and the specimen was obtained from the parietal pleura using forceps or a cryoprobe. Patient data including age, number of biopsies, biopsy specimen size, pathological and final diagnosis, and postoperative complications were examined. All patients were male with an average age of 74 years. Pleural effusion was found on the right and left sides in 16 and 6 patients, respectively. The average major axis of the biopsy specimens was 18 mm (range, 10-30 mm), which was sufficient to establish a pathological diagnosis. Only 1 patient experienced minor temporal bleeding as a complication. The precut technique enabled the procurement of specimens sufficient in size for pleural biopsy.

Identification of the amino acid residues involved in the species-dependent differences in the pyridoxine transport function of SLC19A3.

Recent studies have shown that human solute carrier SLC19A3 (hSLC19A3) can transport pyridoxine (vitamin B6) in addition to thiamine (vitamin B1), its originally identified substrate, whereas rat and mouse orthologs of hSLC19A3 can transport thiamine but not pyridoxine. This finding implies that some amino acid residues required for pyridoxine transport, but not for thiamine transport, are specific to hSLC19A3. Here, we sought to identify these residues to help clarify the unique operational mechanism of SLC19A3 through analyses comparing hSLC19A3 and mouse Slc19a3 (mSlc19a3). For our analyses, hSLC19A3 mutants were prepared by replacing selected amino acid residues with their counterparts in mSlc19a3, and mSlc19a3 mutants were prepared by substituting selected residues with their hSLC19A3 counterparts. We assessed pyridoxine and thiamine transport by these mutants in transiently transfected human embryonic kidney 293 cells. Our analyses indicated that the hSLC19A3-specific amino acid residues of Gln86, Gly87, Ile91, Thr93, Trp94, Ser168, and Asn173 are critical for pyridoxine transport. These seven amino acid residues were found to be mostly conserved in the SLC19A3 orthologs that can transport pyridoxine but not in orthologs that are unable to transport pyridoxine. In addition, these residues were also found to be conserved in several SLC19A2 orthologs, including rat, mouse, and human orthologs, which were all found to effectively transport both pyridoxine and thiamine, exhibiting no species-dependent differences. Together, these findings provide a molecular basis for the unique functional characteristics of SLC19A3 and also of SLC19A2.

Toward Easy and Rapid Bronchial Occlusion With an Endobronchial Watanabe Spigot: A New Technique Using a Guide Sheath and Curette.

BACKGROUND: Bronchial occlusion using an endobronchial Watanabe spigot (EWS) is reportedly effective for intractable bronchopleural fistula. Here, we describe a rapid and easy method for bronchial occlusion using a guide sheath (GS) and curette. METHODS: Thirty consecutive patients who underwent bronchial occlusion under mild sedation between October 2014 and February 2018 were enrolled. The devices used were a flexible bronchoscope (BF-1T260 or BF-1TQ290), GS (SG-201C; with 30 mm of the proximal end cutaway), and a CC-4CR-1 curette (all supplied by Olympus Ltd). The curette was inserted into the GS with the tip of the curette exposed outside the GS. The curette and GS were inserted into the bronchoscope. The EWS attached to the curette tip was inserted into the target bronchus and left in position by pulling the curette back through the GS while pushing the EWS with the GS under the bronchoscopic view. The success rate and procedure time were recorded. RESULTS: Bronchial occlusion with an EWS was performed on 143 target bronchi (2 to 9 bronchi/patient). The bronchial occlusion success rate was 98.6%. The median procedure time for bronchial occlusion per EWS on video recordings of the 10 most recent procedures was 110 (range, 40 to 521) seconds. The target bronchial occlusion success rate was 100%. This method enabled easy insertion of the EWS, even in the sharply branching upper lobe bronchus. No complications were observed. CONCLUSION: Bronchial occlusion using a GS and curette is a rapid and easy technique even in a sharply branching target bronchus.

Clinical features of chronic summer-type hypersensitivity pneumonitis and proposition of diagnostic criteria.

BACKGROUND: Trichosporon asahii (T. asahii) causes chronic summer-type hypersensitivity pneumonitis (C-SHP); however, little is known about the clinical features of this condition. We aimed to elucidate the clinical features of C-SHP and propose practical diagnostic criteria for C-SHP based on the presence of serum anti-T. asahii antibody (TaAb). METHODS: Patients diagnosed with C-SHP and idiopathic pulmonary fibrosis (IPF) between January 2010 and May 2017 were reviewed retrospectively. Clinical findings were compared between the two groups. Criteria for C-SHP were proposed on the basis of significant characteristics and applied to the development and validation cohorts. RESULTS: Thirty-one patients with C-SHP and 26 with TaAb-negative IPF were identified. C-SHP patients were more likely to live in wooden houses; their serum Krebs von den Lungen-6 (KL-6) and serum surfactant protein-D (SP-D) levels were higher than those of IPF patients. C-SHP patients were more likely to have subpleural consolidation, micronodules, and extensive ground-glass opacification on high-resolution computed tomography (HRCT). The following 3 items were considered to have diagnostic value: I) TaAb positivity; II) an HRCT pattern consistent with chronic hypersensitivity pneumonitis, including mosaic attenuation or micronodules; and III) elevated serum biomarker levels (KL-6 > 1500 U/mL or SP-D > 250 ng/mL). We defined cases satisfying I) and II) as "probable C-SHP" and those satisfying all 3 criteria as "confident clinical diagnosis of C-SHP". The areas under the receiver-operating curve were 0.965 and 0.993 in the development and validation cohorts, respectively, which suggested that these criteria had good discriminative ability in clinical evaluations. CONCLUSIONS: Clinical features could be useful for distinguishing C-SHP from IPF and other etiologies of ILDs.

Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents.

OBJECTIVES: To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD. METHODS: Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development. RESULTS: Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapy-free patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy. CONCLUSIONS: Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.

Anti-C1q antibodies are associated with systemic lupus erythematosus global activity but not specifically with nephritis: a controlled study of 126 consecutive patients.

OBJECTIVE: Several studies have shown that anti-C1q antibodies correlate with the occurrence and activity of nephritis in systemic lupus erythematosus (SLE). However, the significance of anti-C1q antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti-C1q antibodies and clinical and serologic parameters of SLE. METHODS: An enzyme-linked immunosorbent assay kit was used to measure anti-C1q antibodies in the sera of 126 consecutive patients with active SLE who were admitted to our university hospital from 2007 through 2009. Sera obtained from patients with high titers of anti-C1q antibodies at the initial evaluation (n = 20) were reevaluated following treatment. Control sera were obtained from patients with other autoimmune diseases and from normal healthy control subjects (n = 20 in each group). Associations between anti-C1q antibodies and clinical and serologic parameters of SLE were statistically analyzed. RESULTS: Anti-C1q antibodies were detected in the sera of 79 of 126 patients with SLE. The prevalence and titers of anti-C1q antibodies were significantly (P < 0.0001) higher in SLE patients than in patients with rheumatoid arthritis, patients with systemic sclerosis, and normal healthy control subjects. The prevalence and titers of anti-C1q antibodies were not significantly associated with active lupus nephritis (P = 0.462 and P = 0.366, respectively). Anti-C1q antibody titers were significantly correlated with SLE Disease Activity Index 2000 scores and the levels of anti-double-stranded DNA antibodies, C3, C4, CH50, and C1q (P < 0.0001 for all comparisons). Moreover, anti-C1q antibody titers significantly decreased as clinical disease was ameliorated following treatment (P = 0.00097). CONCLUSION: These findings indicate that anti-C1q antibodies are associated with SLE global activity but not specifically with active lupus nephritis.

Inflammatory cytokine-induced expression of vasohibin-1 by rheumatoid synovial fibroblasts.

Angiogenesis is an essential event in the development of synovial inflammation in rheumatoid arthritis (RA). The aim of the current study was to investigate the expression of vasohibin-1, a novel endothelium-derived vascular endothelial growth factor (VEGF)-inducible angiogenesis inhibitor, in the RA synovium, and to test the effect of inflammatory cytokines on the expression of vasohibin-1 by RA synovial fibroblasts (RASFs). Synovial tissue samples were obtained at surgery from patients with osteoarthritis (OA) and RA, and subjected to immunohistochemistry to investigate the expression and distribution of vasohibin-1 relevant to the degree of synovial inflammation. In an in vitro analysis, RASFs were used to examine the expression of vasohibin-1 and VEGF mRNA by real-time PCR after stimulation with VEGF or inflammatory cytokines under normoxic or hypoxic conditions. The immunohistochemical results showed that vasohibin-1 was expressed in synovial lining cells, endothelial cells, and synovial fibroblasts. In synovial tissue, there was a significant correlation between the expression of vasohibin-1 and histological inflammation score (p=0.002, r=0.842). In vitro, stimulation with VEGF induced the expression of vasohibin-1 mRNA in RASFs under normoxic conditions, and stimulation with cytokines induced vasohibin-1 mRNA expression under a hypoxic condition. These results suggest that vasohibin-1 was expressed in RA synovial tissue and might be regulated by inflammatory cytokines.