Takeshi Kawasaki

Mesalazine is a recognised cause of drug‐induced eosinophilic pneumonia. The condition usually occurs after 2–6 months of therapy, and onset within the first week is rare. A 29‐year‐old woman with bronchial asthma and newly diagnosed ulcerative colitis was initiated on oral mesalazine. On Day 7, she developed a persistent cough. Three weeks later, imaging revealed a right upper‐lobe pulmonary infiltrate, promoting referral for evaluation. Bronchoalveolar lavage and transbronchial cryobiopsy demonstrated marked eosinophilic infiltration, confirming eosinophilic pneumonia. Discontinuation of mesalazine led to rapid clinical and radiographic improvement. Clinical course and exclusion of alternative aetiologies identified mesalazine as the causative drug. This case demonstrates that mesalazine can induce eosinophilic pneumonia within 7 days of initiation.

Background: While immune checkpoint inhibitor (ICI)-related pneumonitis (CIP) may relapse during or after steroid treatment, clinical factors associated with CIP relapse are unclear. This study explored risk factors potentially associated with CIP relapse. Methods: This single-center retrospective study included 1099 patients who received ICIs at our institution between April 2015 and March 2022. Among them, 39 patients who developed CIP and were treated with systemic steroids and tapered to prednisolone (PSL) ≤ 20 mg/day were analyzed. Patients were classified into relapse and non-relapse groups based on whether CIP recurred during or after steroid treatment. Patient characteristics, clinical features at onset, and treatment strategies were compared between the two groups. Results: Thirteen patients (33.3%) experienced relapse. Compared with the non-relapse group, the relapse group had a significantly higher proportion of non-smokers (30.8 vs. 3.3%, p = 0.035), a greater frequency of Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 pneumonitis (92.3 vs. 53.8%, p = 0.029), and lower serum KL-6 levels (288 vs. 704 U/mL, p = 0.014). The relapse group also had a shorter duration of steroid therapy at the initial dose, ≥0.5 mg/kg/day, ≥15 mg/day, and ≥20 mg/day (p < 0.05) and lower cumulative steroid doses (1140 vs. 1902 mg, p = 0.015). Relapse tended to occur in patients with relatively mild pneumonitis who received lower steroid doses and shorter treatment durations. Conclusions: Non-smoking status, CTCAE Grade 2 pneumonitis, lower serum KL-6 levels, shorter duration of steroid therapy, and lower cumulative steroid dose were potentially associated with CIP relapse. Adequate steroid dosing and tapering may help prevent relapse.

Background: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Pulmonary sarcoidosis with extrapulmonary lesions (EPL) confers poor prognoses. The transcriptomic features of peripheral blood mononuclear cells (PBMCs) could be crucial in sarcoidosis pathogenesis. However, the gene expression characteristics associated with EPL development remain unknown. Methods: Bulk PBMCs were collected from 26 healthy controls and 14 patients with pulmonary sarcoidosis stratified into those with (n = 9) or without (n = 5) EPL. None of the participants were receiving immunosuppressive agents. PBMC transcriptomic analysis was conducted using RNA sequencing. Results: Principal component analysis (PCA) revealed a clear distinction between pulmonary sarcoidosis and healthy control groups, with 227 differentially expressed genes (88 upregulated, 139 downregulated), including upregulated (CLEC7A, GBP5, JAK2, IL15, IL1B, CXCL8, and CXCL10) and downregulated (TNFRSF13C, CD40LG, CD28, and ID3) genes in pulmonary sarcoidosis group. Enrichment analysis revealed upregulated immunological pathways related to granuloma formation in pulmonary sarcoidosis PBMCs, including T helper 17 and tumor necrosis factor-alpha signaling pathways, IL-1B, IL-6, and IL-17 production, and response to external stimuli. Furthermore, patients with and without EPL showed 206 differentially expressed genes (131 upregulated, 75 downregulated), including upregulated (IFNG and IFNLR1) and downregulated (SOCS3, MMP9, and CXCL10) genes. Gene ontology (GO) analysis revealed that interleukin 6 (IL-6) and IL-23 production were upregulated in patients with EPL. Conclusions: These findings elucidate the mechanisms underlying granuloma formation in sarcoidosis and demonstrate the differential transcriptomic features of PBMCs in patients with and without EPL. The upregulation of IFNG and IFNLR1 may be related to EPL development and could serve as potential therapeutic targets for sarcoidosis.

Background: Bronchoalveolar lavage fluid (BALF) analysis is essential for the accurate diagnosis and management of interstitial lung diseases (ILDs). Despite established guidelines, variability in sample handling may affect diagnostic accuracy. This study aimed to evaluate how different storage conditions impact BALF cell counts and differentials to guide optimal sample handling practices. Methods: Forty patients who underwent BAL at Chiba University Hospital from June to December 2024 were included. BALF samples were allocated into five groups based on processing conditions: immediate analysis within 1 h, storage at either at 4 °C or room temperature (RT) for 6 h, or storage at 4 °C or RT for 24 h. Total cell counts (TCC) and differential counts were measured and compared among conditions. Results: TCC remained stable over 24 h at both 4 °C (p = 0.86) and RT (p = 0.90). Similarly, the percentages of eosinophils, lymphocytes, and macrophages did not significantly change at either temperature (all p > 0.05). Notably, neutrophil percentages showed a significant decline over time under both storage conditions—at 4 °C (p = 0.02) and at room temperature (p < 0.01). Post hoc tests revealed a notable decreasing trend at 6 h and significant reductions by 24 h at 4 °C (p = 0.09 and p = 0.02, respectively), and significant decreases at both 6 and 24 h at RT (p = 0.01, <0.01). Conclusions: Among the various cell types in BALF, neutrophil proportions are particularly susceptible to storage conditions, showing a significant decline over time—especially at room temperature—while other cell types remain stable for up to 24 h. Therefore, prompt processing or appropriate refrigeration of BALF is essential to ensure reliable cytological analysis and accurate clinical interpretation.

Mycobacterium goodii, a rapidly growing non‐tuberculous mycobacterium, rarely causes pulmonary diseases. A patient was admitted to our hospital with a fever and cough. Chest radiography revealed consolidation in the right middle lung. As he had previously been treated for organizing pneumonia (OP), he was diagnosed with OP recurrence and administered systemic corticosteroids. Although initial improvement was observed, the pulmonary consolidations worsened. Transbronchial lung cryobiopsy revealed an OP pattern. M. goodii was identified in sputum acid‐fast bacilli cultures. The patient was diagnosed with M. goodii pulmonary disease and secondary OP. Although intravenous imipenem‐cilastatin, amikacin, and ciprofloxacin led to initial improvement in pulmonary consolidations, the consolidations re‐worsened. Systemic corticosteroids were initiated, resulting in improvement in the consolidations. The dose of systemic corticosteroids was tapered; oral antimycobacterial therapy was continued. M. goodii can cause pulmonary disease and induce OP; antimycobacterial therapy and systemic corticosteroids can be effective.

In hypoxic pulmonary hypertension (PH), pulmonary vascular remodeling is characterized by the emergence of activated adventitial fibroblasts, leading to medial smooth muscle hyperplasia. Previous studies have suggested that CD26/dipeptidyl peptidase-4 (DPP4) plays a crucial role in the pathobiological processes in lung diseases. However, its role in pulmonary fibroblasts in hypoxic PH remains unknown. Therefore, we aimed to clarify the mechanistic role of CD26/DPP4 in lung fibroblasts in hypoxic PH. Dpp4 knockout (Dpp4 KO) and wild-type (WT) mice were exposed to hypoxia for 4 weeks. The degree of PH severity and medial wall thickness was augmented in Dpp4 KO mice compared with that in WT mice, suggesting that CD26/DPP4 plays a suppressive role in the development of hypoxic PH. Transcriptome analysis of human lung fibroblasts cultured under hypoxic conditions revealed that TGFB2, TGFB3, and TGFA were all upregulated as differentially expressed genes after DPP4 knockdown with small interfering RNA treatment. These results suggest that CD26/DPP4 plays a suppressive role in TGFβ signal-regulated fibroblast activation under hypoxic conditions. Therefore, CD26/DPP4 may be a potential therapeutic target in patients with PH associated with chronic hypoxia.

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell–cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between “patients with IPF and healthy controls” and “before and after anti-fibrotic treatment” were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-β/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/Dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells. In LPS-induced lung injury, inflammatory responses (bronchoalveolar lavage fluid (BALF) neutrophil numbers and several pro-inflammatory cytokine levels) were attenuated in Dpp4 knockout (Dpp4 KO) mice. However, multiple assays of alveolar capillary permeability were similar between the Dpp4 KO and wild-type mice. TNF-α and IL-6 production was suppressed in alveolar macrophages isolated from Dpp4 KO mice. In contrast, in cultured mouse lung microvascular endothelial cells (MLMVECs), reduction in CD26/DPP4 expression by siRNA resulted in greater ICAM-1 and IL-6 expression after LPS stimulation. Moreover, the LPS-induced vascular monolayer permeability in vitro was higher in MLMVECs treated with Dpp4 siRNA, suggesting that CD26/DPP4 plays a protective role in endothelial barrier function. In summary, this study demonstrated that genetic deficiency of Dpp4 attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential functional roles of CD26/DPP4 expression in resident cellular components of the lung. CD26/DPP4 may be a potential therapeutic target for ARDS and warrants further exploration to precisely identify the multiple functional effects of CD26/DPP4 in ARDS pathophysiology.