ARAF Amplification in Small-Cell Lung Cancer-Transformed Tumors Following Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors.

BACKGROUND/OBJECTIVES: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. METHODS: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). RESULTS: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC. CONCLUSIONS: ARAF amplification was identified in 5-8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.

Combined use of serum ferritin and KL-6 levels as biomarkers for predicting COVID-19 severity.

OBJECTIVES: To assess the value of serum ferritin and Krebs von den Lungen-6 (KL-6) levels for predicting severe COVID-19 (death or requirement for invasive mechanical ventilation [IMV]/high-flow oxygen). METHODS: Data were analyzed on 2495 patients with COVID-19 from February 2020 to November 2022 using data from a nationwide COVID-19 database. RESULTS: Patients with high KL-6 and low ferritin levels were older with more comorbidities and higher mortality rates, whereas those with high ferritin and low KL-6 levels were younger, predominantly male, and more likely to need IMV. A high level of both markers was strongly associated with critical outcomes (adjusted odds ratio: 13.6, 95% confidence interval: 8.58-21.5). The combination of both markers had higher predictive value than either marker alone (area under the curve: 0.709, 0.745, and 0.781 for KL-6, ferritin, and KL-6 + ferritin, respectively). CONCLUSIONS: The combination of both markers accurately predicted COVID-19 severity.

Critical pathomechanisms of NSAID-exacerbated respiratory disease (N-ERD) clarified by treatment with omalizumab, an anti-IgE antibody.

Characteristic symptoms of NSAID-exacerbated respiratory disease (N-ERD) include asthma, chronic eosinophilic rhinosinusitis with nasal polyposis, cysteinyl LT (CysLT) overproduction and NSAIDs hypersensitivity. Some N-ERD patients present with episodic treatment-resistant extra-respiratory symptoms (CysLT-associated coronary artery vasospasm, gastroenteritis, or skin rash). Even when using standard treatments for respiratory and extra-respiratory symptoms, including systemic corticosteroids and aspirin desensitization, it is difficult to control the clinical symptoms and severe type 2 inflammation involved with mast cells, eosinophils, ILC2s, and platelet activation. Few treatment options are applicable in a clinical setting. Therefore, identifying effective treatments is essential for managing N-ERD patients who suffer from these conditions. Our previous observational study demonstrated 12-month omalizumab treatment of N-ERD was clinically effective against respiratory symptoms. Despite the remaining eosinophilia, omalizumab significantly reduced urinary LTE4 and PGD2 metabolites to near normal levels at steady state. Based on the preliminary study, we demonstrated that omalizumab induced tolerance to aspirin in N-ERD patients 3 months after therapy initiation and suppressed activation of mast cells during 24 h of initiation in a randomized manner. Moreover, omalizumab had significant efficacy against extra-respiratory symptoms at baseline (lacking aspirin exposure) as well as throughout aspirin challenge. This review addresses the latest discoveries related to N-ERD pathogenesis and the significant effectiveness of omalizumab on N-ERD as a mast cell stabilizer. Our findings regarding omalizumab-associated mast cell inhibitory effects are indirect evidence that mast cell dysregulation and, possibly, IgE are pivotal components of N-ERD.

Blood eosinophil count correlates with alveolar damage in emphysema-predominant COPD.

BACKGROUND: Although blood eosinophil count is recognized as a useful biomarker for the management of chronic obstructive pulmonary disease (COPD), the impact of eosinophils in COPD has not been fully elucidated. Here we aimed to investigate the relationships between the blood eosinophil count and various clinical parameters including lung structural changes. METHODS: Ninety-three COPD patients without concomitant asthma were prospectively enrolled in this study. Blood eosinophil count, serum IgE level, serum periostin level, and chest computed tomography (CT) scans were evaluated. Eosinophilic COPD was defined as COPD with a blood eosinophil count ≧ 300/µL. We examined the correlation between the blood eosinophil count and structural changes graded by chest CT, focusing specifically on thin airway wall (WT thin) and thick airway wall (WT thick) groups. In a separate cohort, the number of eosinophils in the peripheral lungs of COPD patients with low attenuation area (LAA) on chest CT was assessed using lung resection specimens. RESULTS: The mean blood eosinophil count was 212.1/µL, and 18 patients (19.3%) were categorized as having eosinophilic COPD. In the whole group analysis, the blood eosinophil count correlated only with blood white blood cells, blood basophils, C-reactive protein level, and sputum eosinophils. However, the blood eosinophil count positively correlated with the percentage of LAA and negatively correlated with the diffusing capacity for carbon monoxide in the WT thin group. Lung specimen data showed an increased number of eosinophils in the peripheral lungs of COPD patients with LAA on chest CT scans compared to normal controls. CONCLUSIONS: Some COPD patients without concomitant asthma showed a phenotype of high blood eosinophils. Alveolar damage may be related to eosinophilic inflammation in patients with COPD without asthma and thickening of the central airway wall.

The providing multidisciplinary ILD diagnoses (PROMISE) study - study design of the national registry of Japan facilitating interactive online multidisciplinary discussion diagnosis.

BACKGROUND: Multidisciplinary discussion (MDD), in which physicians, radiologists, and pathologists communicate and diagnose together, has been reported to improve diagnostic accuracy compared to diagnoses made solely by physicians. However, even among experts, diagnostic concordance of MDD is not always good, and some patients may not receive a specific diagnosis due to insufficient findings. A provisional diagnosis based on the ontology with a diagnostic confidence level has recently been proposed. Additionally, we developed an artificial intelligence model to differentiate idiopathic pulmonary fibrosis (IPF) from other chronic interstitial lung diseases (ILD)s, which needs validation in a broader population. METHODS: This prospective nationwide ILD registry has recruited patients with newly diagnosed ILD at the referral respiratory hospitals in Japan and provides rapid MDD diagnoses and treatment recommendations through a central online MDD platform with a 3-year follow-up period. A modified diagnostic ontology is used. If no diagnosis reaches more than 50% certainty, the diagnosis is unclassifiable ILD. If multiple diseases are expected, the diagnosis with a high probability takes precedence. If the confidence levels for the top two possible diagnoses are equal, the diagnosis can be unclassifiable. The registry uses tentative diagnostic criteria for nonspecific interstitial pneumonia with organising pneumonia and smoking-related ILD not otherwise specified as possible new entities. Central MDD diagnosticians review the clinical data, test results, radiology images, and pathological specimens on a dedicated website and conduct MDD diagnoses using online meetings with a cloud-based reporting system. This study aims to (1) provide MDD diagnoses with treatment recommendations; (2) determine the overall ILD rates in Japan; (3) clarify the reasons for unclassifiable ILDs; (4) evaluate possible new disease entities; (5) identify progressive phenotypes and create a clinical prediction model; (6) measure the agreement rate between institutional and central diagnoses in ILD referral and non-referral centres; (7) identify key factors for each specific ILD diagnosis; and (8) create a new disease classification system based on treatment strategies, including the use of antifibrotic drugs. DISCUSSION: This study will provide ILD frequencies, including new entities, using central MDD on dedicated online systems, and develop a machine learning model for ILD diagnosis and prognosis prediction. TRIAL REGISTRATION: UMIN-CTR Clinical Trial Registry (UMIN000040678).

Chronic obstructive pulmonary disease, asthma, and mechanical ventilation are risk factors for dyspnea in patients with long COVID: A Japanese nationwide cohort study.

BACKGROUND: Patients often experience multiple prolonged symptoms following acute coronavirus disease 2019 (COVID-19) recovery, defined as long coronavirus disease (COVID). Patients with long COVID may experience dyspnea during acute and post-acute phases. Therefore, this study aimed to identify specific risk factors for dyspnea in patients with long COVID. METHODS: Hospitalized patients with COVID-19, aged ≥18 years, were enrolled in this multicenter cohort study conducted at 26 medical institutions across Japan. Clinical data during hospitalization and patient-reported outcomes after discharge at the 3, 6, and 12-month follow-ups were retrieved from medical records and paper-based or smartphone application-based questionnaires, respectively. RESULTS: Generalized linear mixed model (GLMM) analysis of prolonged dyspnea at each time point during follow-up showed that this symptom was associated with chronic obstructive pulmonary disease (COPD) (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.31-5.74), asthma (OR, 2.21; 95%CI, 1.17-4.16), and ventilator management (OR, 3.10; 95%CI, 1.65-5.83). In addition, patients with COPD (44.4%) and ventilator management (25.0%) were more frequently associated with delayed dyspnea onset. The generalized estimating equations analysis results with multiple imputed datasets, conducted as a sensitivity analysis, confirmed the adjusted GLMM analysis results. CONCLUSIONS: Prolonged dyspnea was associated with COPD, asthma, and severe infection that required mechanical ventilation in the Japanese population with long COVID. Further investigation is needed to clarify its mechanism and develop prophylactic and therapeutic strategies for dyspnea in patients with long COVID.

Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance.

Studying the genetic regulation of protein expression (through protein quantitative trait loci (pQTLs)) offers a deeper understanding of regulatory variants uncharacterized by mRNA expression regulation (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood mRNA and 2,932 plasma samples of protein expression, as part of the Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 variants validated with a massively parallel reporter assay. Fine-mapped pQTLs (n = 582) were enriched for missense variations on structured and extracellular domains, although the possibility of epitope-binding artifacts remains. Trans-eQTL and trans-pQTL analysis highlighted associations of class I HLA allele variation with KIR genes. We contrast the multi-tissue origin of plasma protein with blood mRNA, contributing to the limited colocalization level, distinct regulatory mechanisms and trait relevance of eQTLs and pQTLs. We report a negative correlation between ABO mRNA and protein expression because of linkage disequilibrium between distinct nearby eQTLs and pQTLs.

Diagnostic Value and Safety of Addition of Transbronchial Needle Aspiration to Transbronchial Biopsy Through Endobronchial Ultrasonography Using a Guide Sheath Under Virtual Bronchoscopic Navigation for the Diagnosis of Peripheral Pulmonary Lesions.

BACKGROUND: The diagnostic yield of peripheral pulmonary lesions (PPLs) through endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) under virtual bronchoscopic navigation is unsatisfactory because radial EBUS probe is not always located within the lesion. Transbronchial needle aspiration with a guide sheath (GS-TBNA) has the potential to overcome the lower diagnostic yield by improving the relationship between the probe and the lesion and enabling repeated sampling while maintaining the location of a GS near the lesion. However, there are few data regarding the diagnostic yield and safety for diagnosing PPLs in this procedure. METHODS: We retrospectively analyzed consecutive 363 lesions (83 lesions underwent GS-TBNA/EBUS-GS TBB and 280 lesions underwent EBUS-GS TBB) at our institution between April 1, 2019 and March 31, 2022. We investigated the diagnostic efficacy and complications of GS-TBNA/EBUS-GS TBB and compared them with those of EBUS-GS TBB. RESULTS: The lesion size, distance from the hilum, presence of bronchus leading to the lesion, and EBUS images during the examination differed significantly between the two procedures. Logistic regression analysis adjusted for these 4 covariates revealed that GS-TBNA/EBUS-GS TBB was a significant factor affecting the diagnostic success of PPLs compared with EBUS-GS TBB (odds ratio=2.43, 95% CI=1.16-5.07, P=0.018). Neither procedure differed significantly in terms of complications (6.0% vs. 5.7%, P>0.999). CONCLUSION: GS-TBNA performed in addition to EBUS-GS TBB might be a promising sampling method for improving the diagnostic yield for PPLs without increasing the incidence of complications.

Efficacy of Immune Checkpoint Inhibitors in Postoperative Recurrence of Wild-type EGFR Non-Small Cell Lung Cancer.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of non-small cell lung cancer (NSCLC), but specific outcomes of ICIs treatment among patients with postoperative recurrence of NSCLC remain unclear. The objective of the study was to compare the efficacy of ICIs and chemotherapy with conventional chemotherapy only in patients with postoperative recurrence of epidermal growth factor receptor (EGFR) wild-type NSCLC. PATIENTS AND METHODS: A retrospective analysis was performed on patients who underwent anatomical lung resection at the Nagoya University Hospital and were treated for postoperative recurrence of wild-type EGFR NSCLC. This study evaluated the prognosis for postoperative recurrence, including ICIs treatment and other clinicopathological factors. RESULTS: Of the 83 patients included in the analysis, 20 patients underwent chemotherapy and 63 patients underwent chemotherapy combined with ICIs. The combination of ICIs and chemotherapy significantly prolonged survival after recurrence (median survival: 33.1 months vs. 22.0 months, p=0.01). In the ICIs group, no significant differences in survival were detected between patients with different programmed death ligand 1 (PD-L1) status (Tumor Proportion Scores: <1%, 1%-49%, ≥50%, p=0.27). Multivariate analysis revealed that postoperative distant recurrence was a significant poor prognostic factor for survival after recurrence (HR=1.85, 95% CI=1.06-3.25, p=0.03), and combining ICIs with chemotherapy significantly improved survival after recurrence (HR=0.43, 95% CI=0.24-0.78, p<0.01). CONCLUSION: Combination of ICIs with chemotherapy significantly prolonged survival of postoperative recurrence with wild-type EGFR NSCLC regardless of PD-L1 status.

Degranulation and expression of cytokines were modulated by diazinon in activated mast cells.

Diazinon is an organophosphorus (OP) insecticides used in agriculture, home gardening and indoor pest control in Japan. It can activate macrophages and induce pro-inflammatory responses and has been reported to cause airway hyper-reactivity, suggesting the possibility of asthma exacerbation from exposure to OP insecticides. Despite the correlation between insecticide use and the pathogenesis of allergic diseases, there have been no reports on the effects of diazinon on mast cell function. Therefore, in this study, we investigated the effects of diazinon on mast cell function in rat basophilic leukemia (RBL)-2H3 cells. Surprisingly, we found that diazinon inhibited mast cell activation, although the degree of inhibition varied with concentration. Diazinon induced reactive oxygen species (ROS) generation and HO-1 expression at a concentration of 150 µM without affecting cell viability. Diazinon inhibited A23187-mediated degranulation and Tnf and Il4 expression in RBL-2H3 cells but did not affect calcium influx. Suppression of degranulation by diazinon was reversed when the culture supernatant was removed. As a signaling event downstream of calcium influx, diazinon inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) induced by A23187, whereas the phosphorylation of p38 had little effect. IgE cross-linking-mediated degranulation as well as the induction of Tnf and IL4 expression was significantly inhibited by diazinon, while diazinon had little effect on calcium influx. In conclusion, diazinon inhibited mast cell activation, including degranulation and cytokine expression. When evaluating the in vivo effects of diazinon, its potential to inhibit mast cell activation should be considered in the pathophysiology and development of allergic diseases in terms of basic and clinical aspects, respectively, although the effect of diazinon varies depending on the cell type.

Social impact of brain fog and analysis of risk factors: Long COVID in Japanese population.

OBJECTIVE: To reveal the clinical features and assess risk factors linked to brain fog and its societal implications, including labor productivity, providing valuable insights for the future care of individuals who have experienced coronavirus disease 2019 (COVID-19). METHODS: We analyzed a comprehensive cohort dataset comprising 1,009 patients with COVID-19 admitted to Japanese hospitals. To assess brain fog, we analyzed patients who responded to a questionnaire indicating symptoms such as memory impairment and poor concentration. RESULTS: The prevalence of brain fog symptoms decreased 3 months posthospitalization but remained stable up to 12 months. Neurological symptoms such as taste and smell disorders and numbness at hospitalization correlated with a higher frequency of identifying brain fog as a long COVID manifestation. Our findings indicated that advanced age, female sex, a high body mass index, oxygen required during hospitalization, chronic obstructive pulmonary disease, asthma, and elevated C-reactive protein and elevated D-dimer levels were risk factors in patients exhibiting brain fog. Additionally, we demonstrated the negative impact of brain fog on labor productivity by presenteeism scores. INTERPRETATIONS: This study clarified the clinical characteristics of patients experiencing brain fog as a long COVID manifestation, specifically emphasizing neurological symptoms during hospitalization and their correlation with brain fog. Additionally, the study identified associated risk factors for its onset and revealed that the emergence of brain fog was linked to a decline in labor productivity.

Bronchial occlusion with endobronchial Watanabe spigots using a two-scope technique for massive haemoptysis.

Massive haemoptysis is a life-threatening condition whose cause needs to be identified rapidly so that prompt interventions can ensue. Bronchial occlusion with endobronchial Watanabe spigots (EWSs) may be useful when endovascular treatment or surgery proves to be difficult. An 84-year-old woman developed massive haemoptysis during percutaneous mitral valve repair for refractory heart failure due to severe mitral regurgitation (MR). Interventional radiology (IVR) and surgery were contraindicated, and bronchial occlusion with EWSs was attempted to control bleeding. The bleeding was so persistent that it was difficult to secure the visual field without aspiration with a bronchoscope. Herein, we report a two-scope technique, also used in cryobiopsy of peripheral lung lesions, to control bleeding and perform bronchial occlusion with EWSs.

Disease-specific autoantibody production in the lungs and salivary glands of anti-synthetase syndrome.

Interstitial lung disease is a common complication of anti-synthetase syndrome (ASS), and lymphocytic infiltration is often observed in the lesion. We have recently reported that disease-specific autoantibodies are produced by infiltrating lymphocytes in some autoimmune diseases. Here, we investigate the antigen specificity of B cells in the lung lesions of ASS patients. A total of 177 antibodies were produced from antibody-secreting cells in bronchoalveolar fluid (BALF) of three each of serum anti-Jo-1 and serum anti-EJ antibody-positive patients. Twelve to 30% and 50 to 62% of these antibodies were disease-specific autoantibodies, respectively. These autoantibodies recognized conformational epitopes of the whole self-antigen and had affinity maturations, indicating that self-antigens themselves are the target of humoral immunity. In addition, 100 antibodies were produced from two salivary gland tissues, obtained by chance, of ASS patients. Salivary glands are not generally recognized as lesions of ASS, but unexpectedly, ASS-related autoantibody production was also observed similar to that of BALF. Immunostaining confirmed the presence of ASS-related autoantibody-producing cells in salivary glands. Our results suggest that disease-specific autoantibody production at lesion sites is a common pathogenesis of autoimmune diseases, and that tissue-specific production of autoantibodies can provide insights regarding the distribution of organ manifestations in autoimmune diseases.

Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study.

BACKGROUND: Anti-programmed cell death-1 (ligand-1) antibody [PD-(L)1-Ab] can cause destructive thyroiditis and/or hypothyroidism. In addition, tyrosine kinase inhibitors (TKIs) frequently induce hypothyroidism. The aim of this prospective study is to examine the incidence and clinical characteristics of thyroid dysfunction induced by combination therapy of a PD-(L)1-Ab and TKI [PD-(L)1-Ab/TKI]. METHODS: A total of 757 patients treated with PD-(L)1-Ab or PD-(L)1-Ab/TKI were evaluated for anti-thyroid antibodies (ATAs) at baseline and for thyroid function for 48 weeks after treatment initiation and then observed until the last visit. RESULTS: The cumulative incidences of destructive thyroiditis [4/23 (17.4%) vs. 45/734 (6.1%) patients, p < 0.001], isolated hypothyroidism [10/23 (43.5%) vs. 29/734 (4.0%) patients, p < 0.001], and all thyroid dysfunction [14/23 (60.9%) vs. 74/734 (10.1%) patients, p < 0.001] were significantly higher in the PD-(L)1-Ab/TKI group than PD-(L)1-Ab group, respectively. All patients positive for ATAs at baseline developed thyroid dysfunction after PD-(L)1-Ab/TKI treatment, a significantly higher incidence than that in those negative for ATAs at baseline [4/4 (100%) vs. 10/19 (52.6%) patients, p = 0.026]. CONCLUSIONS: The addition of TKIs increased the risk of thyroid dysfunction induced by PD-(L)1-Ab, with the risk being higher in patients positive for baseline ATAs.

Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade.

BACKGROUND: The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs. METHODS: We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models. RESULTS: High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs. CONCLUSION: Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

Prognostic significance of chronic kidney disease and impaired renal function in Japanese patients with COVID-19.

BACKGROUND: Renal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes. METHODS: This retrospective study included 3,637 patients with COVID-19 classified into three groups by CKD history and estimated glomerular filtration rate (eGFR) on referral: Group 1 (n = 2,460), normal renal function without a CKD history; Group 2 (n = 905), impaired renal function without a CKD history; and Group 3 (n = 272), history of CKD. We compared the clinical characteristics of these groups and assessed the effect of CKD and impaired renal function on critical outcomes (requirement for respiratory support with high-flow oxygen devices, invasive mechanical ventilation, or extracorporeal membrane oxygen, and death during hospitalization) using multivariable logistic regression. RESULTS: The prevalence of comorbidities (hypertension, diabetes, and cardiovascular disease) and incidence of inflammatory responses (white blood counts, and C-reactive protein, procalcitonin, and D-dimer levels) and complications (bacterial infection and heart failure) were higher in Groups 2 and 3 than that in Group 1. The incidence of critical outcomes was 10.8%, 17.7%, and 26.8% in Groups 1, 2, and 3, respectively. The mortality rate and the rate of requiring IMV support was lowest in Group 1 and highest in Group 3. Compared with Group 1, the risk of critical outcomes was higher in Group 2 (adjusted odds ratio [aOR]: 1.32, 95% confidence interval [CI]: 1.03-1.70, P = 0.030) and Group 3 (aOR: 1.94, 95% CI: 1.36-2.78, P < 0.001). Additionally, the eGFR was significantly associated with critical outcomes in Groups 2 (odds ratio [OR]: 2.89, 95% CI: 1.64-4.98, P < 0.001) and 3 (OR: 1.87, 95% CI: 1.08-3.23, P = 0.025) only. CONCLUSIONS: Clinicians should consider pre-existing CKD and impaired renal function at the time of COVID-19 diagnosis for the management of COVID-19.

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study.

BACKGROUND: Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. METHODS: Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. RESULTS: mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. CONCLUSIONS: Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

CT-derived vertebral bone mineral density is a useful biomarker to predict COVID-19 outcome.

The low vertebral bone computed tomography (CT) Hounsfield unit values measured on CT scans reflect low bone mineral density (BMD) and are known as diagnostic indicators for osteoporosis. The potential prognostic significance of low BMD defined by vertebral bone CT values for the coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to assess the impact of BMD on the clinical outcome in Japanese patients with COVID-19 and evaluate the association between BMD and critical outcomes, such as high-flow nasal cannula, non-invasive and invasive positive pressure ventilation, extracorporeal membrane oxygenation, or death. We examined the effects of COVID-19 severity on the change of BMD over time. This multicenter retrospective cohort study enrolled 1132 inpatients with COVID-19 from the Japan COVID-19 Task Force database between February 2020 and September 2022. The bone CT values of the 4th, 7th, and 10th thoracic vertebrae were measured from chest CT images. The average of these values was defined as BMD. Furthermore, a comparative analysis was conducted between the BMD on admission and its value 3 months later. The low BMD group had a higher proportion of critical outcomes than did the high BMD group. In a subanalysis stratifying patients by epidemic wave according to onset time, critical outcomes were higher in the low BMD group in the 1st-4th waves. Multivariable logistic analysis of previously reported factors associated with COVID-19 severity revealed that low BMD, chronic kidney disease, and diabetes were independently associated with critical outcomes. At 3 months post-infection, patients with oxygen demand during hospitalization showed markedly decreased BMD than did those on admission. Low BMD in patients with COVID-19 may help predict severe disease after the disease onset. BMD may decrease over time in patients with severe COVID-19, and the impact on sequelae symptoms should be investigated in the future.