Tomoyuki Kakugawa

Background: Frailty impacts the prognosis of respiratory diseases but lacks standardized evaluation criteria. This pilot study aimed to develop a frailty assessment method using unsupervised clustering of various physical function tests. Methods: Clinical data, handgrip strength (HS), lower limb strength (LLS), the 6 min walk test (6 min WT), the 5 m walk test (5 m WT), body composition, such as skeletal muscle mass index (SMI), whole-body phase angle (WBPhA), and pulmonary function variables were measured. Frailty status was evaluated in three groups (frail, pre-frail, and robust) using the J-CHS and Kihon Checklist. Unsupervised hierarchical clustering was performed, followed by dimensionality reduction using Principal Component Analysis. Results: Ninety-eight patients and healthy volunteers (70 males, 28 females; mean age, 57.5 years) were divided into four clusters, ranging from robust to pronounced frailty. On the 2-principal component plane, data points formed clusters across the four regions. The biplot showed variables aggregating in two directions: one including %FEV₁, FEV₁%, 6 min WT, and 5 m WT speed (exercise tolerance), and the other including HS, LLS, SMI, and WBPhA (physical elements). Tracking 39 participants (mean, 636 days later) showed cluster shifts that were broadly reproducible, although the small follow-up sample warrants cautious interpretation. Conclusions: As an exploratory, hypothesis-generating pilot study with a small single-center sample, this novel frailty model may offer a more granular assessment to help guide management; however, external validation in larger cohorts is required before clinical application.

Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor used to treat steroid‐refractory graft‐versus‐host disease, wherein pulmonary alveolar proteinosis (PAP) is a rare complication. We report the case of a 47‐year‐old woman developing respiratory failure 8 months after commencing ruxolitinib treatment. Chest computed tomography revealed bilateral ground‐glass opacities. Bronchoalveolar lavage fluid was milky and periodic acid–Schiff–positive, and Mycobacterium intracellulare was detected. Anti‐granulocyte–macrophage colony‐stimulating factor antibodies were negative, and the patient was diagnosed with secondary PAP. Ruxolitinib withdrawal led to initial radiological and clinical improvement, prior to initiating antimycobacterial therapy. To date, only three cases of ruxolitinib‐associated secondary PAP have been reported, all complicated by nontuberculous mycobacterial infection. This case represents a unique clinical course of ruxolitinib‐associated secondary PAP, wherein initial radiological and clinical improvements occurred following drug withdrawal, prior to antimycobacterial therapy. This case highlights the need to consider PAP as a rare complication in patients receiving ruxolitinib.

Background: The factors contributing to physical inactivity in patients with asthma remain unclear. We aimed to explore the pulmonary and extra-pulmonary factors associated with physical activity (PA) in these patients, with stratification by activity intensity. Methods: Patient demographics, Charlson Comorbidity Index, lung function, bronchial and alveolar nitric oxide (NO) levels, six-minute walk test (6 MWT), and PA were cross-sectionally evaluated in healthy participants (n = 14) and patients with asthma (n = 29). The desaturation–distance ratio (DDR) was measured as an index derived from travel distance and desaturation levels during the 6 MWT. Results: Patients with asthma had significantly lower PA than healthy participants, regardless of activity intensity (≥2 metabolic equivalents [METs]: 198 min vs. 240 min, p < 0.05; ≥3 METs: 54 min vs. 86 min, p < 0.05; ≥4 METs: 10 min vs. 26 min, p < 0.01). Extra-pulmonary factors (age, comorbidities, and 6 MW distance) showed higher correlation coefficients with PA as activity intensity increased. Contrastingly, pulmonary factors (asthma severity, airflow limitation, and alveolar exhaled NO) showed lower correlation coefficients with PA as activity intensity increased. The DDR was negatively associated with active time across all activity intensities. Conclusions: Our findings suggest that aging and comorbidities are potential limiting factors for moderate-to-vigorous physical activity, whereas asthma severity and airway dysfunction restrict daily life in patients with asthma. Moreover, the DDR could facilitate detection of real-life physical inactivity in patients with asthma.

Aim: To identify risk factors for pneumonia among institutionalized older adults with severe functional dependency, using routinely available clinical information from the standardized “Doctor's Written Opinion” for long‐term care insurance. Methods: This retrospective observational study included 257 institutionalized older adults with severe functional dependency (median age, 88 years; 55 men and 202 women) residing in a Japanese nursing home between January 2014 and May 2020. Risk factors for pneumonia were analyzed using medical records and data from the standardized “Doctor's Written Opinion” for long‐term care insurance. Results: During a median follow‐up of 2.1 years, 51 residents (19.8%) developed pneumonia, which was associated with lower overall survival (log‐rank test, p = 0.001). Among the 102 residents who died during this period, pneumonia was the most common cause of death (37% of deaths). Multivariate Cox regression analysis revealed male sex (hazard ratio [HR] 4.692, 95% confidence interval [CI] 2.352–9.357), serum albumin level (HR 0.368, 95% CI 0.151–0.898), cognitive ability for daily decision‐making (HR 1.626 per one‐point worsening on a four‐point scale, 95% CI 1.082–2.444), and recent weight loss (≥ 3% over the past 6 months) (HR 2.645, 95% CI 1.195–5.858) as significant risk factors. Conclusions: Male sex, lower serum albumin level, impaired cognitive ability for daily decision‐making, and recent weight loss were associated with an increased risk of pneumonia. Information routinely available in standardized long‐term care assessments may support the identification of individuals at increased risk of pneumonia in resource‐limited long‐term care settings where comprehensive geriatric assessments are not feasible.

Frailty is increasingly recognized as a systemic complication in patients with obstructive pulmonary diseases (OPDs), yet its molecular basis remains unclear. Extracellular vesicles (EVs), which transport small RNAs, may offer mechanistic insight into this comorbidity. This study investigated the association between serum-derived EV small RNAs and frailty in OPD. Sixty-eight patients with OPD were enrolled, and EVs isolated from 29 patients (13 with chronic obstructive pulmonary disease [COPD], four with COPD and asthma, and 12 with asthma; median age 72 years) were analyzed. Based on the Kihon Checklist, patients were classified as frail (n = 11) or non-frail (n = 18). Small RNA sequencing and differential expression analyses were conducted, followed by age-adjusted correlation with physical factors and Ingenuity Pathway Analysis (IPA). A total of 108 small RNAs were differentially expressed between frail and non-frail groups (p < 0.05, fold change < 0.8 or >1.2). IPA linked these RNAs to lung fibrosis and transforming growth factor-beta (TGF-β) signaling pathways. Eleven small RNAs correlated with lower limb strength, and three—miR-125b-5p, miR-369-3p, and miR-615-3p—emerged as key candidates associated with frailty. These findings suggest that EV-derived small RNAs may contribute to frailty development in OPD through TGF-β–related molecular mechanisms.

Background: The magnitude and durability of cell-mediated immunity in older and severely frail individuals following coronavirus disease 2019 (COVID-19) vaccination remain unclear. A controlled immune response could be the key to preventing severe COVID-19; however, it is uncertain whether vaccination induces an anti-inflammatory cellular immune response. To address these issues, a 48-week-long prospective longitudinal study was conducted. A total of 106 infection-naive participants (57 long-term care facility [LTCF] residents [median age; 89.0 years], 28 outpatients [median age; 72.0 years], and 21 healthcare workers [median age; 51.0 years]) provided peripheral blood mononuclear cell (PBMC) samples for the assessment of spike-specific PBMC responses before primary vaccination, 24 weeks after primary vaccination, and three months after booster vaccination. Cellular immune responses to severe acute respiratory syndrome coronavirus 2 spike protein were examined by measuring interferon (IFN)-γ, tumor necrosis factor (TNF), interleukin (IL)-2, IL-4, IL-6, and IL-10 levels secreted from the spike protein peptide-stimulated PBMCs of participants. Results: LTCF residents exhibited significantly lower IFN-γ, TNF, IL-2, and IL-6 levels than healthcare workers after the primary vaccination. Booster vaccination increased IL-2 and IL-6 levels in LTCF residents comparable to those in healthcare workers, whereas IFN-γ and TNF levels in LTCF residents remained significantly lower than those in healthcare workers. IL-10 levels were not significantly different from the initial values after primary vaccination but increased significantly after booster vaccination in all subgroups. Multivariate analysis showed that age was negatively associated with IFN-γ, TNF, IL-2, and IL-6 levels but not with IL-10 levels. The levels of pro-inflammatory cytokines, including IFN-γ, TNF, IL-2, and IL-6, were positively correlated with humoral immune responses, whereas IL-10 levels were not. Conclusions: Older and severely frail individuals may exhibit diminished spike-specific PBMC responses following COVID-19 vaccination compared to the general population. A single booster vaccination may not adequately enhance cell-mediated immunity in older and severely frail individuals to a level comparable to that in the general population. Furthermore, booster vaccination may induce not only a pro-inflammatory cellular immune response but also an anti-inflammatory cellular immune response, potentially mitigating detrimental hyperinflammation.

Background/Objectives: COPD patients who are frail have been reported to develop brain atrophy, but no non-invasive diagnostic tool has been developed to detect this condition. Our study aimed to explore the diagnostic utility of the Kihon Checklist (KCL), a frailty questionnaire, in assessing hippocampal volume loss in patients with COPD. Methods: We recruited 40 COPD patients and 20 healthy individuals using the KCL to assess frailty across seven structural domains. Hippocampal volumes were obtained from T1-weighted MRI images, and ROC analysis was performed to detect hippocampal atrophy. Results: Our results showed that patients with COPD had significantly greater atrophic left hippocampal volumes than healthy subjects (p < 0.05). The univariate correlation coefficient between the left hippocampal volume and KCL (1–20), which pertains to instrumental and social activities of daily living, was the largest (ρ = −0.54, p < 0.0005) among the KCL subdomains. Additionally, both KCL (1–25) and KCL (1–20) demonstrated useful diagnostic potential (93% specificity and 90% sensitivity, respectively) for identifying individuals in the lowest 25% of the left hippocampal volume (AUC = 0.82). Conclusions: Our study suggests that frailty questionnaires focusing on daily vulnerability, such as the KCL, can effectively detect hippocampal atrophy in COPD patients.

(1) Background: Reduced lung function in early adulthood is associated with future risks to health outcomes that have not been fully explored by gender. We investigated gender-specific relationships between lung function and extrapulmonary variables, assessing their potential as screening markers for respiratory dysfunction in young adults. (2) Methods: The participants were 151 medical students. Clinical data, handgrip strength (HS); body composition parameters such as skeletal muscle mass index (SMI), whole-body phase angle (WBPhA), and bone mineral content (BMC); and pulmonary function variables, vital capacity (VC), forced VC (FVC), and forced expiratory volume in one second (FEV₁), were measured. (3) Results: FEV₁ was significantly correlated with BMI, SMI, WBPhA, BMC, and both left and right HS (p < 0.0001, respectively) across all participants. According to gender, FEV₁ had the strongest positive association with left HS in males (p < 0.0001) and BMC in females (p < 0.0001). The area under the curve for detecting the bottom quartile of FEV₁ was 0.705 (cut-off 41.0 kg, sensitivity 91%) for left HS in males and 0.742 (cut-off 2.11 kg, sensitivity 81%) for BMC in females. (4) Conclusions: Gender-specific relationships between intrapulmonary and extrapulmonary factors such as left HS and BMC could be useful for screening suspected respiratory dysfunction in early adulthood.