Immunometabolic features of natural killer cells are associated with infection outcomes in critical illness.

Immunosuppression increases the risk of nosocomial infection in patients with chronic critical illness. This exploratory study aimed to determine the immunometabolic signature associated with nosocomial infection during chronic critical illness. We prospectively recruited patients who were admitted to the respiratory care center and who had received mechanical ventilator support for more than 10 days in the intensive care unit. The study subjects were followed for the occurrence of nosocomial infection until 6 weeks after admission, hospital discharge, or death. The cytokine levels in the plasma samples were measured. Single-cell immunometabolic regulome profiling by mass cytometry, which analyzed 16 metabolic regulators in 21 immune subsets, was performed to identify immunometabolic features associated with the risk of nosocomial infection. During the study period, 37 patients were enrolled, and 16 patients (43.2%) developed nosocomial infection. Unsupervised immunologic clustering using multidimensional scaling and logistic regression analyses revealed that expression of nuclear respiratory factor 1 (NRF1) and carnitine palmitoyltransferase 1a (CPT1a), key regulators of mitochondrial biogenesis and fatty acid transport, respectively, in natural killer (NK) cells was significantly associated with nosocomial infection. Downregulated NRF1 and upregulated CPT1a were found in all subsets of NK cells from patients who developed a nosocomial infection. The risk of nosocomial infection is significantly correlated with the predictive score developed by selecting NK cell-specific features using an elastic net algorithm. Findings were further examined in an independent cohort of COVID-19-infected patients, and the results confirm that COVID-19-related mortality is significantly associated with mitochondria biogenesis and fatty acid oxidation pathways in NK cells. In conclusion, this study uncovers that NK cell-specific immunometabolic features are significantly associated with the occurrence and fatal outcomes of infection in critically ill population, and provides mechanistic insights into NK cell-specific immunity against microbial invasion in critical illness.

Oral uracil-tegafur compared with intravenous chemotherapy as adjuvant therapy for resected early-stage non-small cell lung cancer patients.

BACKGROUND: Studies comparing the effectiveness of either adjuvant oral uracil-tegafur (UFT) or intravenous chemotherapy on early-stage (stage I and II) non-small cell lung cancer (NSCLC) patients treated with complete surgical treatment remain limited. METHODS: From January 2011 to December 2017, patients with early-stage NSCLC (defined as tumor size >3 cm without mediastinal lymph node involvement or any distant metastasis) receiving either adjuvant oral UFT or intravenous chemotherapy after surgical resection were identified from the Taiwan Cancer Registry. Overall survival (OS) and relapse-free survival (RFS) were the primary and secondary outcomes, respectively. Propensity matching was used for controlling confounders. RESULTS: A total of 840 patients receiving adjuvant therapy after surgery (including 595 oral UFT and 245 intravenous chemotherapy) were enrolled. Before matching, patients using oral UFT had significantly longer OS (HR: 0.69, 95% CI: 0.49-0.98, p = 0.0387) and RFS (HR: 0.79, 95% CI: 0.61-0.97, p = 0.0392) than those with intravenous chemotherapy. A matched cohort of 352 patients was created using 1:1 propensity score-matching. In the Cox regression analysis, the UFT and the matched chemotherapy groups had similar OS (HR: 0.80, 95% CI: 0.48-1.32, p = 0.3753) and RFS (HR: 0.98, 95% CI: 0.72-1.34, p = 0.9149). Among subgroup analysis, oral UFT use was associated with longer RFS among the subgroups of non-drinker (HR: 0.66, 95% CI: 0.34-0.99, p = 0.0478) and patients with stage IB disease (HR: 0.67, 95% CI: 0.42-0.97, p = 0.0341). CONCLUSIONS: This population-based study in the real-world setting of Taiwan demonstrates comparable effectiveness between oral UFT and intravenous chemotherapy in terms of clinical outcomes for early-stage NSCLC patients after surgery.

Incidence of and Risk Factors for Acute Kidney Injury During Antituberculosis Treatment: A Prospective Cohort Study and Literature Review.

INTRODUCTION: Acute kidney injury (AKI) is occasionally detected in patients receiving anti-tuberculosis (TB) treatment. This prospective cohort study is the first to investigate the incidence, risk factors, and renal outcomes of AKI during anti-TB treatment. METHODS: This study was conducted from January 1, 2016, to May 31, 2018. Patients with a new diagnosis of TB and on standard anti-TB treatment were enrolled, and the patients received regular laboratory monitoring. AKI was defined according to the Kidney Disease: Improving Global Outcome (KDIGO) criteria. Urinalysis, renal ultrasonography, blood erythrocyte morphology, and fractional excretion of sodium were performed at AKI onset. The TB treatment regimen was adjusted by the primary physician if necessary. Risk factors for AKI were identified through Cox regression. RESULTS: In total, 106 patients were recruited (mean age 52.6 years, 71.7% men). Eleven (10.3%) patients experienced AKI. Increased serum uric acid and hemoglobin levels were noted at AKI onset. All patients with AKI achieved renal recovery and completed anti-TB treatment containing rifampin. Age [hazard ratio (HR) 1.06 (1.02-1.11)], a higher baseline estimated glomerular filtration rate [eGFR; HR 1.04 (1.02-1.06)], and a blood eosinophil count > 350 (109/L) [HR 10.99 (2.28-53.02)] were associated with a higher risk of AKI during TB treatment. CONCLUSION: Regular pharmacovigilant monitoring revealed an incidence of renal impairment during anti-TB treatment that was higher than expected. AKI was more common in older patients with a higher eGFR and blood eosinophil count. However, the complications had no influence on TB treatment completion, and no permanent renal impairment occurred.

Impact of ventilator settings during venovenous extracorporeal membrane oxygenation on clinical outcomes in influenza-associated acute respiratory distress syndrome: a multicenter retrospective cohort study.

Background: Patients with influenza-associated acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (vv-ECMO) support have a high mortality rate. Ventilator settings have been known to have a substantial impact on outcomes. However, the optimal settings of mechanical ventilation during vv-ECMO are still unknown. Methods: This multicenter retrospective cohort study was conducted in the intensive care units (ICUs) of three tertiary referral hospitals in Taiwan between July 2009 and December 2019. It aims to describe the effect of ventilator settings during vv-ECMO on patient outcomes. Results: A total of 93 patients with influenza receiving ECMO were screened. Patients were excluded if they: were receiving venoarterial ECMO, died within three days of vv-ECMO initiation, or were transferred to the tertiary referral hospital >24 hours after vv-ECMO initiation. A total of 62 patients were included in the study, and 24 (39%) died within six months. During the first three days of ECMO, there were no differences in tidal volume (5.1 vs. 5.2 mL/kg, p = 0.833), dynamic driving pressure (15 vs. 14 cmH2O, p = 0.146), and mechanical power (11.3 vs. 11.8 J/min, p = 0.352) between survivors and non-survivors. However, respiratory rates were significantly higher in non-survivors compared with survivors (15 vs. 12 breaths/min, p = 0.013). After adjustment for important confounders, a higher mean respiratory rate of >12 breaths/min was still associated with higher mortality (adjusted hazard ratio = 3.31, 95% confidence interval = 1.10-9.97, p = 0.034). Conclusions: In patients with influenza-associated ARDS receiving vv-ECMO support, we found that a higher respiratory rate was associated with higher mortality. Respiratory rate might be a modifiable factor to improve outcomes in this patient population.

Effectiveness of Endobronchial Ultrasound-Guided Transbronchial Biopsy Combined With Tissue Culture for the Diagnosis of Sputum Smear-Negative Pulmonary Tuberculosis.

Background: Microorganisms of tuberculosis (TB) are frequently difficult to identify from the airway specimen; therefore, lung biopsy for further histologic and microbiologic study is required. Endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB) is used for the diagnosis of pulmonary malignancy, but is rarely in the TB population. The purpose of this study was to verify the effectiveness and safety of EBUS-TBB with histologic study and tissue culture in the diagnosis of sputum smear-negative pulmonary TB. Methods: Patients who underwent EBUS-TBB with histologic study and TB tissue culture for clinically suspected, but sputum smear-negative pulmonary TB from January 2016 to December 2018, were included. The accuracy of each diagnostic modality was calculated, respectively. Factors that might influence the positive rate of TB culture (washing fluid and tissue specimen) were also evaluated. Results: One hundred sixty-one patients who underwent EBUS-TBB for clinically suspected, but sputum smear-negative pulmonary TB, were enrolled, and 43 of them were finally diagnosed as having pulmonary TB. The sensitivity of washing fluid (a combination of smear, culture, and polymerase chain reaction for TB) and tissue specimen (a combination of pathology and tissue culture) via EBUS-TBB for TB diagnosis were 48.8 and 55.8%, respectively. The sensitivity for TB diagnosis would be elevated to 67.4% when both washing fluid and tissue specimens are used. The positive TB culture rate would not statistically increase with a combination of tissue specimens and washing fluid. Univariate analysis revealed that TB microorganisms would be more easily cultivated when lesions had an abscess or cavity on the computed tomography (CT) image (presence vs. absence; 62.5 vs. 26.3%, p = 0.022), heterogeneous echogenicity on the EBUS finding (heterogeneous vs. homogeneous; 93.3 vs. 21.4%, p = 0.001), or a necrotic pattern via histologic study (presence vs. absence; 70.6 vs. 30.8%, p = 0.013). Heterogeneous echogenicity in the EBUS finding was the independent predictor according to the results of multivariate analysis. None of our patients encountered major adverse events or received further intensive care after EBUS-TBB. Conclusion: Endobronchial ultrasound-guided transbronchial biopsy is safe and effective for use in diagnosing sputum smear-negative pulmonary TB. EBUS echoic feature is also a predictor of the positive TB culture rate in pulmonary TB. However, tissue culture via EBUS-TBB has little effect in improving the positive TB culture rate.

Outcomes of daytime nurse practitioner-staffed versus resident-staffed nonsurgical intensive care units: A retrospective observational study.

BACKGROUND: Rapid developments in medical care-such as monitoring devices, medications, and working hours restrictions for intensive care personnel-have dramatically increased the demand for intensive care physicians. Therefore, nurse practitioner (NP)-staffed care is becoming increasingly important. This study was aimed to compare the outcomes of daytime NP-staffed and daytime resident-staffed nonsurgical intensive care units (ICU). METHODS: We retrospectively assessed patients admitted to a nonsurgical ICU from March 2017 to December 2017. We collected basic patient data, including age, sex, admission diagnosis, transferring unit, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Primary endpoints were ICU mortality, hospital mortality, and 30-day mortality. Secondary endpoints were 48-h readmission, discharge to nonhome locations, and lengths of ICU and hospital stay. RESULTS: A total of 838 subjects were analysed: 334 subjects in the NP-staffed group and 504 in the resident-staffed group. The NP-staffed group was more likely to come from inpatient units (38.3% vs 16.5% for resident-staffed group; p < 0.001) and had lower disease severity (APACHE II score, 13.9 ± 8.4 vs 15.1 ± 8.2 for resident-staffed group; p = 0.047). After adjusting for age, sex, location before ICU admission, APACHE II score, and significantly different basic characteristics, there were no differences in ICU mortality, hospital mortality, or 30-day mortality between the two groups. Secondary analysis showed the NP-staffed group had a lower discharge rate to nonhome locations (2.1% vs 6.3%; p = 0.023) and shorter hospital stay (12.1 ± 14.1 vs 14.2 ± 14.3 days; p = 0.015). CONCLUSIONS: We observed no difference in mortality between daytime NP-staffed and resident-staffed nonsurgical ICUs. Daytime NP-staffed care is an effective, safe, feasible method for staffing nonsurgical ICUs.

Establishing Aspergillus-Specific IgG Cut-Off Level for Chronic Pulmonary Aspergillosis Diagnosis: Multicenter Prospective Cohort Study.

OBJECTIVES: Aspergillus-specific IgG (Asp-IgG) cut-off level in diagnosing chronic pulmonary aspergillosis (CPA) remains unknown. METHODS: We prospectively recruited participants with clinical suspicion of CPA in three centers in Taiwan during 2019 June to 2020 August. Serum Aspergillus fumigatus-specific IgG (Asp-IgG) (Phadia, Uppsala, UPPS, Sweden) was examined. Optimal cut-off level was determined by Youden's index and validated. RESULTS: A total of 373 participants were recruited. In the derivation cohort (n = 262), Asp-IgG had an area under the receiver-operating-characteristic curve (AUC) of 0.832. The optimal cut-off level was 40.5 mgA/L. While applying this cut-off level to the validation cohort (n = 111), the sensitivity and specificity were 86.7% and 80.2%. Lowering the cut-off level from 40.5 to 27 mgA/L, the sensitivity was steady (30/36, 83.3% to 31/36, 86.1%) while specificity dropped from 81.9% (276/337) to 63.5% (214/337). Restricting CPA diagnosis to only chronic cavitary pulmonary aspergillosis (CCPA) and chronic fibrosing pulmonary aspergillosis (CFPA) yielded a cut-off level of 42.3 mgA/L in the derivation cohort with a sensitivity of 100% and specificity of 84.4% in the validation cohort. CONCLUSIONS: Serum Asp-IgG performs well for CPA diagnosis and provides a low false-positive rate when using a higher cut-off level (preferably around 40 mgA/L).

Functional Status After Pulmonary Rehabilitation as a Predictor of Weaning Success and Survival in Patients Requiring Prolonged Mechanical Ventilation.

Background: Comprehensive rehabilitation programs are recommended for patients with prolonged mechanical ventilation (PMV) to facilitate functional recovery and ventilator weaning, but whether the functional status after rehabilitation influences outcome has not been clearly evaluated. This study aimed to investigate the association between post-rehabilitation functional status and weaning and survival outcome in PMV patients. Methods: We retrospectively enrolled PMV patients admitted to the respiratory care center (RCC), a post-ICU weaning facility with protocolized rehabilitation program, from January 2016 through December 2017. Functional status was measured by the de Morton Mobility Index (DEMMI), with a cut-off value set at 20 points. The primary outcomes were the weaning status at RCC discharge and hospital survival. The secondary outcomes were overall survival and survival at 3 months after RCC discharge. We followed patients until 3 months after RCC discharge or death. Logistic and Cox regressions were performed to identify significant parameters associated with weaning success and survival. Results: In total, 320 patients were enrolled. The weaning success rate was 71.6%. The survival rate at RCC discharge, hospital discharge, and 3 months after RCC discharge was 89.1, 77.5, and 66.6%, respectively. Post-rehabilitation DEMMI ≥ 20 (odds ratio [OR], 3.514; 95% confidence interval [CI], 1.436-8.598; P = 0.006) was the most significantly associated with weaning success. The weaning success and higher post-rehabilitation DEMMI were the two most significant independent factors associated with both hospital survival (weaning success, OR, 12.272; 95% CI, 5.281-28.517; P < 0.001; post-rehabilitation DEMMI ≥ 20, OR, 6.298; 95% CI, 1.302-30.477; P = 0.022) and survival at 3 months after RCC discharge (weaning success, OR, 38.788; 95% CI, 11.505-130.762; P < 0.001; post-rehabilitation DEMMI ≥ 20, OR, 4.830; 95% CI, 1.072-21.756; P = 0.040). Post-rehabilitation DEMMI ≥ 20 remained significantly association with overall survival at 3 months after RCC discharge (hazard ratio, 0.237; 95% CI, 0.072-0.785; P = 0.018). Conclusions: Post-rehabilitation functional status of PMV patients was independently associated with weaning success, as well as hospital and 3-month overall survival after RCC discharge. Post-rehabilitation, but not pre-rehabilitation, functional status was a significant parameter associated with weaning success and survival in patients requiring PMV.

Exploring Volatile Organic Compounds in Breath for High-Accuracy Prediction of Lung Cancer.

(1) Background: Lung cancer is silent in its early stages and fatal in its advanced stages. The current examinations for lung cancer are usually based on imaging. Conventional chest X-rays lack accuracy, and chest computed tomography (CT) is associated with radiation exposure and cost, limiting screening effectiveness. Breathomics, a noninvasive strategy, has recently been studied extensively. Volatile organic compounds (VOCs) derived from human breath can reflect metabolic changes caused by diseases and possibly serve as biomarkers of lung cancer. (2) Methods: The selected ion flow tube mass spectrometry (SIFT-MS) technique was used to quantitatively analyze 116 VOCs in breath samples from 148 patients with histologically confirmed lung cancers and 168 healthy volunteers. We used eXtreme Gradient Boosting (XGBoost), a machine learning method, to build a model for predicting lung cancer occurrence based on quantitative VOC measurements. (3) Results: The proposed prediction model achieved better performance than other previous approaches, with an accuracy, sensitivity, specificity, and area under the curve (AUC) of 0.89, 0.82, 0.94, and 0.95, respectively. When we further adjusted the confounding effect of environmental VOCs on the relationship between participants' exhaled VOCs and lung cancer occurrence, our model was improved to reach 0.92 accuracy, 0.96 sensitivity, 0.88 specificity, and 0.98 AUC. (4) Conclusion: A quantitative VOCs databank integrated with the application of an XGBoost classifier provides a persuasive platform for lung cancer prediction.

Treatment Options of First-Line Tyrosine Kinase Inhibitors and Subsequent Systemic Chemotherapy Agents for Advanced EGFR Mutant Lung Adenocarcinoma Patients: Implications From Taiwan Cancer Registry Cohort.

OBJECTIVES: Large-scale, population-based real-world studies on the treatment outcomes of first-line tyrosine kinase inhibitors (TKIs) and subsequent systemic chemotherapy agents for lung adenocarcinoma (with activating epidermal growth factor receptor [EGFR] mutations) remain limited. MATERIALS AND METHODS: From March 2014 to December 2016, patients with advanced lung adenocarcinoma, identified from the Taiwan Cancer Registry were included in this study if they received any of the three TKIs as first-line treatment. The primary outcome was overall survival (OS). The secondary outcome was time-to-treatment discontinuation (TTD). RESULTS: A total of 4,889 patients (median age: 67 years and two-thirds with distant metastasis) were recruited (1,778 gefitinib, 1,599 erlotinib, and 1,512 afatinib users). A 1:1 propensity score (PS)-matched cohorts of 1,228 afatinib/erlotinib and 1054 afatinib/gefitinib was created. After PS matching, it was found that afatinib was not associated with better OS (afatinib vs. erlotinib, HR: 0.96, 95% CI: 0.86-1.07; afatinib vs. gefitinib, HR: 0.91, 95% CI: 0.81-1.02). In the subgroup analysis, afatinib demonstrated a survival benefit in patients with active smoking (afatinib vs. erlotinib, HR: 0.69, 95% CI: 0.51-0.93; afatinib vs. gefitinib, HR: 0.67, 95% CI: 0.48-0.94) and ECOG > 1 (afatinib vs. erlotinib, HR: 0.79, 95% CI: 0.63-0.99; afatinib vs. gefitinib, HR: 0.78, 95% CI: 0.62-0.98). A total of 41.1% (n = 1992) of first-line TKI users received subsequent chemotherapy. Among the three TKI groups, pemetrexed usage was associated with better OS compared with other chemotherapy agents, with the exception of gemcitabine in the afatinib and gefitinib groups. Pemetrexed and gemcitabine had the longest TTD of 3-4 months. CONCLUSIONS: Among patients with EGFR mutant lung adenocarcinoma, afatinib use may not provide longer OS compared with first-generation TKIs. Afatinib may be preferably considered among patients with active smoking and should not be withheld among those with worse performance status. With 40% of patients receiving subsequent chemotherapy, pemetrexed may be the preferred agent, while gemcitabine can be a reasonable alternative.

Diagnosis of mediastinal tuberculous lymphadenitis using endobronchial ultrasound-guided transbronchial needle aspiration with rinse fluid polymerase chain reaction.

BACKGROUND/PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been gradually introduced in the diagnosis of mediastinal tuberculous (TB) lymphadenitis. The purposes of this study were to evaluate the utility of polymerase chain reaction for Mycobacterium tuberculosis (TB-PCR) using EBUS-TBNA rinse fluid and to explore the factors that influence the accuracy of EBUS-TBNA. METHODS: A retrospective study with prospective data collection was carried out with patients with unselected mediastinal lymphadenopathy who underwent EBUS-TBNA and a TB-PCR study from April 2010 to July 2017. Patients without TB were excluded. The diagnostic accuracy rate for each diagnostic modality (pathology, smear, culture, and TB-PCR) was calculated respectively. The characteristics of the lymph node (LN) and the pathologic findings were analyzed as possible impact factors. RESULTS: 240 consecutive patients who received EBUS-TBNA were enrolled, and in the end, 21 patients with a diagnosis of TB lymphadenitis were included. When combined with histologic results and traditional microbiologic studies, the diagnostic accuracy of EBUS-TBNA was 57.1%. If TB-PCR was also utilized, the diagnostic accuracy would significantly increase to 71.4% (p < 0.001). Univariate and multivariate regression analysis revealed that pathology showing necrosis had a higher positive microbiologic result when using EBUS-TBNA rinse fluid. CONCLUSION: EBUS-TBNA is a valuable tool for diagnosis of mediastinal TB lymphadenitis. Using TB-PCR assay and targeting LNs with a necrotic component would improve the diagnostic performance of EBUS-TBNA.