Daily Respiratory Research Analysis

BACKGROUND: Sarcopenia, an important complication of chronic obstructive pulmonary disease (COPD), is significantly associated with increased mortality. Systemic inflammation is an important trigger of COPD-related skeletal muscle dysfunction. Calprotectin is a damage-associated molecular pattern involved in the inflammatory response, but its exact role and mode of action in COPD-related skeletal muscle dysfunction remain unclear. This study aimed to determine whether calprotectin is involved in COPD-related sarcopenia. METHODS: In this study, 235 patients with stable COPD were divided into the development (n = 117) and validation (n = 118) groups, and serum calprotectin concentrations were measured by enzyme-linked immunosorbent assays (ELISAs). Paquinimod, an oral calprotectin-specific inhibitor, was used to investigate the involvement of calprotectin in cigarette smoke (CS)-induced skeletal muscle dysfunction in vivo. RESULTS: Handgrip strength and quadriceps muscle strength, essential indicators of muscle strength, were negatively correlated with serum calprotectin levels (r = -0.367, p < 0.001; r = -0.409, p < 0.001). The 5-time sit-to-stand test results, which reflect endurance and physical strength, were positively correlated with serum calprotectin levels (r = 0.290, p = 0.006). Ultrasound measurement of the rectus femoris muscle revealed negative correlations of serum calprotectin levels with both muscle thickness (r = -0.448, p < 0.001) and cross-sectional area (r = -0.495, p < 0.001). Furthermore, serum calprotectin levels were significantly greater in patients with sarcopenia than in those without sarcopenia (90.09 ± 25.72 ng/mL vs. 59.56 ± 23.22 ng/mL, p < 0.001). Importantly, serum calprotectin levels could effectively predict sarcopenia in COPD patients in the development set (AUC = 0.811) and validation set (AUC = 0.805). In C57BL/6 mice with CS-induced muscle dysfunction, paquinimod (10 mg/kg/day) reduced CS-induced muscle mass loss (skeletal muscle weight 1.15% ± 0.09% vs. 1.33% ± 0.09%; p = 0.005) and increased the muscle cross-sectional area (1375 ± 536.9 μm CONCLUSIONS: Serum calprotectin levels can be used to accurately predict sarcopenia in patients with COPD, and the calprotectin inhibitor paquinimod is a potential treatment for CS-induced skeletal muscle dysfunction.

BACKGROUND: Pulmonary infections in tuberculosis (TB)-endemic settings are heterogeneous and commonly polymicrobial. Nanopore-targeted sequencing (NTS) enables detection of mycobacteria, bacteria, and fungi in a single targeted assay. However, performance across pathogen classes in TB-endemic cohorts remains limited. METHODS: We conducted a prospective study at a specialized TB hospital, enrolling adults with suspected pulmonary infections across five predefined diagnostic categories: pulmonary TB, nontuberculous mycobacterial pulmonary disease, bacterial, fungal, and polymicrobial infection. Respiratory specimens (n=312) from 305 patients were tested in parallel by conventional microbiological testing (CMT) and NTS. Blinded clinical diagnoses served as the reference standard. RESULTS: Among 283 paired cases, NTS identified the adjudicated pathogens in 263 cases, whereas culture identified them in 185 cases. NTS showed a sensitivity/specificity of 83.0%/99.4% for Mycobacterium tuberculosis, 89.8%/98.2% for nontuberculous mycobacteria, 92.9%/91.1% for fungi, and 97.4%/57.8% for bacteria. In 72 polymicrobial infections, NTS detected all adjudicated pathogens in 77.8% versus 62.5% for CMT, a non-significant difference (P=0.06). Overall, NTS provided a 12.2% incremental diagnostic yield. CONCLUSIONS: NTS offers sensitive, single-assay detection of diverse pulmonary pathogens in TB-endemic settings. By streamlining workflows and improving detection of fastidious or co-infecting organisms, it may complement conventional methods. However, bacterial NTS findings in non-sterile respiratory specimens require clinical correlation.

Long COVID affects a substantial proportion of survivors of acute infection with severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), who suffer a variety of symptoms that limit their quality of life and economic activity. Although the aetiology of long COVID is obscure, it appears to be a chronic inflammatory condition. Complement dysregulation is a prevalent feature of long COVID. Specifically, markers of classical, alternative, and terminal pathway activation are often elevated in patients with this condition. Here, we used a sensitive assay for mannan-binding lectin-associated serine protease-2 (MASP-2)/C1Inh complexes to analyse lectin pathway activation in a previously characterised cohort of patients with long COVID (n = 159) and healthy convalescent individuals with no persistent symptoms after infection with SARS-CoV-2 (n = 76). The data were combined with those from the most predictive complement analytes identified previously to delineate potential biomarkers of long COVID. MASP-2/C1Inh complexes were significantly elevated in patients with long COVID (p = 0.0003). Generalised linear modelling further identified an optimal set of four markers, namely iC3b (alternative pathway), TCC (terminal pathway), MASP-2/C1Inh (lectin pathway), and the complement regulator properdin, which had a receiver operating characteristic predictive power of 0.796 (95% confidence interval = 0.664-0.905). Combinations of the classical pathway markers C4, C1q, and C1s/C1Inh were poorly predictive of long COVID. These findings demonstrate that activation of the lectin complement pathway, which occurs upstream of the alternative and terminal pathways and can be inhibited therapeutically, is a salient feature of long COVID.