Pre-existing Interstitial Lung Abnormalities and Immune Checkpoint Inhibitor-Related Pneumonitis in Solid Tumors: A Retrospective Analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. MATERIALS AND METHODS: Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. RESULTS: Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). CONCLUSION: This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.

Longitudinal significance of six-minute walk test in patients with nontuberculous mycobacterial pulmonary disease: an observational study.

BACKGROUND: The long-term exercise tolerance changes in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) are of great interest because of its chronic course. This study aimed to characterize the associations between changes over time in six-minute walking test (6MWT) parameters and clinical parameters in patients with NTM-PD. METHODS: Overall, 188 patients with NTM-PD, visiting outpatient clinics at Keio University Hospital from April 2012 to March 2020 were included in the study. Data were collected using the St. George's Respiratory Questionnaire (SGRQ), pulmonary function test (PFT), blood tests, and the 6MWT at registration and at least once after that. The association of the anchors and clinical indicators with the 6MWT parameters was assessed. RESULTS: The median age [interquartile range] of the patients was 67 [63-74] years. The median baseline six-minute walk distance (6MWD) and final Borg scale (FBS) were 413 [361-470] m and 1 [0-2], respectively. In the correlation analysis, ΔSGRQ total/year (yr), Δforced vital capacity (FVC, % predicted)/yr, Δforced expiratory volume in 1 s (FEV1, % predicted)/yr, and Δdiffusing capacity for carbon monoxide (DLCO, % predicted)/yr correlated with both Δ6MWD/yr and ΔFBS/yr in the longitudinal analysis (|Rho| > 0.20). When stratified into three quantiles of changes in each anchor, the 6MWT parameters worsened over time in the bottom 25% group by mixed-effects model. Specifically, Δ6MWD was affected by SGRQ activity, SGRQ impacts, PFT (FVC, FEV1, and DLCO), and C-reactive protein (CRP). ΔFBS was affected by all SGRQ components, total score, and PFT. Anchor scores and variables at baseline that worsened Δ6MWD were higher SGRQ scores, lower FVC (% predicted), lower DLCO (% predicted), higher Krebs von den Lungen-6, old age, and undergoing treatment at registration. Similarly, these clinical parameters and elevated CRP, excluding undergoing treatment at registration, worsened ΔFBS. CONCLUSIONS: The decreased walking distance and exacerbation of dyspnea on exertion over time in patients with NTM-PD may reflect a deterioration of health-related quality of life and pulmonary function. Thus, the change in 6MWT over time can be used as an indicator to accurately assess the patient's condition and tailor their healthcare environment.

Complications of a lung biopsy for severe respiratory failure: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the complications of lung biopsy in patients with acute respiratory failure (ARF), including acute respiratory distress syndrome (ARDS). METHODS: We searched the MEDLINE and Cochrane Central Register of Controlled Trials. The primary outcomes were biopsy-related death, respiratory failure, cardiac complications, bleeding, and other major complications. We used the McMaster Quality Assessment Scale of Harms (McHarm) to evaluate the risk of bias. A random-effects model was used to calculate the pooled frequencies. RESULTS: Thirteen studies (consisting of 574 patients) were included in the meta-analysis. Furthermore, most of the included studies had a high or unclear risk of bias in half of the items in McHarm. All included studies evaluated surgical lung biopsies. The median overall hospital mortality was 53% (range: 17%-90%). The pooled frequencies of biopsy-related death, respiratory failure, cardiac complication, bleeding, and other major complications were 0.00% (95% confidence interval [CI]: 0.00%-0.21%), 1.30% (95% CI: 0.00%-5.69%), 1.03% (95% CI: 0.00%-3.73%), 1.46% (95% CI: 0.16%-3.56%), and 4.26% (95% CI: 0.00%-13.0%), respectively. CONCLUSIONS: The results of this study will be valuable information in considering the indications of lung biopsy in patients with ARF, including ARDS. TRIAL REGISTRATION: The protocol was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN 000040650).

Differences in lung and lobe volumes between supine and upright computed tomography in patients with idiopathic lung fibrosis.

No clinical study has compared lung or lobe volumes on computed tomography (CT) between the supine and standing positions in patients with idiopathic lung fibrosis (IPF). This study aimed to compare lung and lobe volumes between the supine and standing positions and evaluate the correlations between the supine/standing lung volumes on CT and pulmonary function in patients with IPF. Twenty-three patients with IPF underwent a pulmonary function test and both low-dose conventional (supine position) and upright CT (standing position) during inspiration breath-holds. The volumes of the total lungs and lobes were larger in the standing than in the supine position in patients with IPF (all p < 0.05). Spearman's correlation coefficients between total lung volumes on chest CT in supine/standing positions and vital capacity (VC) or forced VC (FVC) were 0.61/0.79 or 0.64/0.80, respectively. CT-based volumes on upright CT were better correlated with VC and FVC than those on supine CT. Lung and lobe volumes in the standing position may be useful biomarkers to assess disease severity or therapeutic effect in patients with IPF.

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

DOCK2 is involved in the host genetics and biology of severe COVID-19.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

Diagnostic accuracy of urinary antigen tests for pneumococcal pneumonia among patients with acute respiratory failure suspected pneumonia: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Urinary antigen tests have been used for the rapid identification of Streptococcus pneumoniae infection in patients with pneumonia, thereby leading to earlier targeted therapy than when using conventional diagnostic culture methods. This study aimed to update the knowledge on the diagnostic accuracy of urinary antigen tests for S. pneumoniae among patients with acute respiratory failure suspected of pneumonia based on a systematic review and meta-analysis. METHODS: A systematic search was performed using MEDLINE and the Cochrane Central Register of Controlled Trials for studies published up to 3 June 2020. Prospective and retrospective cohort studies (in English) that reported on the diagnostic performance of urinary antigen tests versus culture or smear diagnostic methods in adult patients with clinically diagnosed pneumonia were selected and analysed. The QUADAS-2 tool was used to assess the risk of bias, and a bivariate random effects model was applied to perform a meta-analysis of the selected studies. RESULTS: A total of 2179 studies were screened, of which 30 met the eligibility criteria for quality assessment and meta-analysis. Overall, data from 12 366 patients, including 1548 patients (12.5%) with the target condition and suspected pneumococcal pneumonia, were included in the analysis. The overall quality of the included studies was determined to be serious. The calculated pooled sensitivity and specificity were of 0.66 (95% CI 0.62 to 0.69) and 0.90 (95% CI 0.85 to 0.93), respectively. CONCLUSIONS: The urinary antigen test is useful for achieving a definitive diagnosis of S. pneumoniae infection in patients with pneumonia.

ARDS Clinical Practice Guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html ). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

Predictive value of computed tomography for short-term mortality in patients with acute respiratory distress syndrome: a systematic review.

The best available evidence and the predictive value of computed tomography (CT) findings for prognosis in patients with acute respiratory distress syndrome (ARDS) are unknown. We systematically searched three electronic databases (MEDLINE, CENTRAL, and ClinicalTrials.gov). A total of 410 patients from six observational studies were included in this systematic review. Of these, 143 patients (34.9%) died due to ARDS in short-term. As for CT grade, the CTs used ranged from 4- to 320-row. The index test included diffuse attenuations in one study, affected lung in one study, well-aerated lung region/predicted total lung capacity in one study, CT score in one study and high-resolution CT score in two studies. Considering the CT findings, pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 62% (95% confidence interval [CI] 30-88%), 76% (95% CI 57-89%), 2.58 (95% CI 2.05-2.73), 0.50 (95% CI 0.21-0.79), and 5.16 (95% CI 2.59-3.46), respectively. This systematic review revealed that there were major differences in the definitions of CT findings, and that the integration of CT findings might not be adequate for predicting short-term mortality in ARDS. Standardisation of CT findings and accumulation of further studies by CT with unified standards are warranted.

ARDS clinical practice guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D); we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D); we suggest against routinely implementing NO inhalation therapy (GRADE 2C); and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jrs.or.jp/publication/jrs_guidelines/). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

Osteoporosis in nontuberculous mycobacterial pulmonary disease: a cross-sectional study.

BACKGROUND: Since nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels. METHODS: We have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017-September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis. RESULTS: Osteoporosis (T-score ≤ - 2.5) and osteopenia (T-score - 1 to - 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50-59-, 60-69-, and 70-79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07-1.18), female sex (aOR = 36.3; 95% CI = 7.57-174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14-1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07-41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis. CONCLUSIONS: Middle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

Diagnostic accuracy of urinary antigen tests for legionellosis: A systematic review and meta-analysis.

BACKGROUND: Urinary antigen tests (UATs) have been used for the early detection of legionellosis and have demonstrated moderate sensitivity and high specificity. However, the most recent systematic review and meta-analysis published in 2009 evaluated the accuracy of UATs; since then, UAT accuracy may have changed owing to advances and developments in UAT technology and epidemiological changes in the frequency of Legionella species that cause legionellosis. Therefore, this systematic review and meta-analysis aimed to update the accuracy of UATs for legionellosis among patients with suspected pneumonia. METHODS: Overall, 1326 studies were screened, 21 of which fulfilled the eligibility criteria for quality assessment and meta-analysis. Data from 5772 patients, including 1368 (23.7%) with the target condition (i.e., suspected legionellosis), were included in the analysis. The overall quality of the included studies, which was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, was unclear. RESULTS: The calculated pooled sensitivity and specificity were 0.79 (95% confidence interval [CI], 0.71-0.85) and 1.00 (95% CI, 0.99-1.00), respectively. Subpopulation analysis revealed that the accuracy of UATs for sensitivity and specificity for Legionella pneumophilia serogroup 1 was 0.86 (95% CI, 0.78-0.91) and 1.00 (95% CI, 0.99-1.00), respectively. CONCLUSIONS: This study demonstrated that the sensitivity and specificity of UATs were moderate and high, respectively, which is comparable to the results reported in 2009. Therefore, UATs may be a useful method for the early detection of legionellosis caused by Legionella pneumophila serogroup 1. CLINICAL TRIAL REGISTRATION: The review protocol was prospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000041080).

Safety and harms of bronchoalveolar lavage for acute respiratory failure: A systematic review and meta-analysis.

BACKGROUND: This review aimed to investigate whether bronchoalveolar lavage (BAL) is safe in patients with severe acute respiratory failure (ARF). METHODS: We searched the MEDLINE, CENTRAL, and other databases up to June 2, 2021 for studies that examined BAL for severe ARF. We included all cohort studies and randomized or non-randomized trials, while we excluded case-control studies, case reports, and case series. We evaluated the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: We included 17 studies (1085 patients) in the meta-analysis. The integrated frequency of death was 0.000% (95% confidence interval [CI]: 0.000-0.045%, I2 = 0.0%). The pooled risk of severe complications of respiratory system, cardiovascular system, and major bleeding was 1.32% (95% CI: 0.000-4.41%, I2 = 84.8%), 0.040% (95% CI: 0.000-0.71%, I2 = 9.3%), and 0.000% (95% CI: 0.000-0.27%, I2 = 0.0%), respectively. In the subgroup analysis with mechanical ventilation during BAL, there were few severe complications of the respiratory system (3/717 patients in 13 studies) and almost no heterogeneity (I2 = 0.0%). CONCLUSIONS: Our study suggests that severe complications of BAL for severe ARF are probably rare, particularly in patients receiving mechanical ventilation. After considering the risks and benefits, it would be worthwhile to consider performing BAL in patients with severe ARF of unknown etiology to pursue its cause. TRIAL REGISTRATION: The protocol was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000040600).

Adverse events during intrahospital transport of critically ill patients: A systematic review and meta-analysis.

INTRODUCTION: Intrahospital transport of critically ill patients is often necessary for diagnostic procedures, therapeutic procedures, or admission to the intensive care unit. The aim of this study was to investigate and describe safety and adverse events during intrahospital transport of critically ill patients. MATERIAL AND METHODS: A systematic search was performed of MEDLINE and the Cochrane Central Register of Controlled Trials for studies published up to June 3, 2020, and of the International Clinical Trials Platform Search Portal and ClinicalTrials.gov for ongoing trials. We selected prospective and retrospective cohort studies published in English on intrahospital transport of critically ill patients, and then performed a meta-analysis. The primary outcome was the incidence of all adverse events that occurred during intrahospital transport. The secondary outcomes were death due to intrahospital transport or life-threatening adverse events, minor events in vital signs, adverse events related to equipment, durations of ICU and hospital stay, and costs. RESULTS: A total of 12,313 intrahospital transports and 1898 patients from 24 studies were included in the meta-analysis. Among 24 studies that evaluated the primary outcome, the pooled frequency of all adverse events was 26.2% (95% CI: 15.0-39.2) and the heterogeneity among these studies was high (I2 = 99.5%). The pooled frequency of death due to intrahospital transport and life-threatening adverse events was 0% and 1.47% each, but heterogeneity was also high. CONCLUSIONS: Our findings suggest that adverse events can occur during intrahospital transport of critically ill patients, and that the frequency of critical adverse events is relatively low. The results of this meta-analysis could assist in risk-benefit analysis of diagnostic or therapeutic procedures requiring intrahospital transport of critically ill patients. TRIAL REGISTRATION: UMIN000040963.

Clinical Utility of Surgical Lung Biopsy for Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Surgical lung biopsy (SLB) is performed in patients with acute respiratory distress syndrome (ARDS); however, its clinical utility remains unclear. OBJECTIVES: We categorized the pathological diagnoses and investigated the predictive value for short-term mortality. METHOD: Three electronic databases (MEDLINE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) were searched for the included studies. The QUADAS-2 was used to evaluate the risk of bias and its applicability. The types and populations of pathological diagnoses were investigated. The pooled sensitivity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) were estimated at a fixed specificity. Hierarchical summary receiver operating characteristic curves were drawn. RESULTS: A total of 16 studies that enrolled 758 patients were included. The pathological diagnoses were as follows: diffuse alveolar damage (DAD) 29.9%; infection 24.7%; interstitial lung disease 17.2%; malignancy 3.6%; cardiovascular disease 3.6%; drug toxicity 2.3%; connective tissue disease 2.2%; allergic disease 1.1%; and nonspecific diagnosis 15.4%. To predict short-term mortality, 13 studies that enrolled 613 patients used DAD as an index test and recorded a mortality rate of 56.9% (349 of 613 patients). A total of 3 studies that used index tests other than DAD were excluded. The pooled sensitivity, fixed specificity, LR+, LR-, and DOR were 0.46 (95% confidence interval [CI]: 0.29-0.56), 0.69, 1.48 (95% CI: 0.92-1.81), 0.78 (95% CI: 0.63-1.03), and 1.90 (95% CI: 0.89-2.86), respectively. CONCLUSIONS: SLB is unlikely to provide a specific diagnosis and should not be recommended for confirming DAD or predicting ARDS prognosis.

Diagnostic Performance of Computed Tomography Imaging for COVID-19 in a Region with Low Disease Prevalence.

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in December 2019 as an outbreak of pneumonia of unknown origin. Previous studies have suggested the utility of chest computed tomography (CT) in the diagnosis of COVID-19 because of its high sensitivity (93%-97%), relatively simple procedure, and rapid test results. This study, performed in Japan early in the epidemic when COVID-19 prevalence was low, evaluated the diagnostic accuracy of chest CT in a population presenting with lung diseases having CT findings similar to those of COVID-19. We retrospectively included all consecutive patients (≥18 years old) presenting to the outpatient department of Keio University Hospital between March 1 and May 31, 2020, with fever and respiratory symptoms. We evaluated the performance of diagnostic CT for COVID-19 by using polymerase chain reaction (PCR) results as the reference standard. We determined the numbers of false-positive (FP) results and assessed the clinical utility using decision curve analysis. Of the 175 patients, 22 were PCR-positive. CT had a sensitivity of 68% and a specificity of 57%. Patients with FP results on CT diagnosis were mainly diagnosed with diseases mimicking COVID-19, e.g., interstitial lung disease. Decision curve analysis indicated that the clinical utility of CT imaging was limited. The diagnostic performance of CT for COVID-19 was inadequate in an area with low COVID-19 prevalence and a high prevalence of other lung diseases with chest CT findings similar to those of COVID-19. Considering this insufficient diagnostic performance, CT findings should be evaluated in the context of additional medical information to diagnose COVID-19.

Protocol for a systematic review and meta-analysis of studies on the use of brain natriuretic peptide and N-terminal brain natriuretic peptide levels in the diagnosis of cardiopulmonary edema in acute respiratory failure.

BACKGROUND: Dyspnea with bilateral pulmonary edema is common among patients in emergency departments (EDs) or intensive care units (ICUs). For the initial management of patients with this condition, cardiopulmonary edema (CPE) must be differentiated from acute respiratory distress syndrome (ARDS) in clinical settings. Brain natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (NT-proBNP) are useful in distinguishing these conditions. However, current data about the use of these indexes are limited. Hence, we planned to perform a systematic review and meta-analysis to determine the accuracy of the two indexes for the diagnosis of CPE. METHODS: We designed and registered a study protocol for a systematic review and meta-analysis. This study aims to determine the diagnostic accuracy of BNP and NT-proBNP based on the standards of the methodology of the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy and the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies in reporting the findings of this review. We will search PubMed (MEDLINE), Cochrane Library, Embase, www.ClinicalTrials.gov , International Clinical Trials Registry Platform, and Google Scholar. Randomized controlled trials, cross-sectional studies, and observational cohort studies reporting the accuracy in diagnosing CPE among adult patients with dyspnea and bilateral pulmonary edema will be included in the analysis. There will be no limits regarding language and publication date for this review. Two reviewers will independently screen articles, extract data, evaluate for quality and bias using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2), and use Grading of Recommendations Assessment, Development and Evaluation to summarize the strength of body of evidence. Then, a meta-analysis will be performed, and different statistical methods will be used to investigate heterogeneity among studies. A subgroup analysis of elderly patients with left ventricular dysfunction or chronic renal dysfunction will be performed. In the meta-analysis, a hierarchical summary receiver operating characteristic model or a bivariate model will be used in each index test, as appropriate. DISCUSSION: A systematic review and meta-analysis of the accuracy of BNP and NT-proBNP for the diagnosis of CPE will be conducted. The result of this study can help clinicians to identify an appropriate initial treatment for patients with acute respiratory failure, including those with ARDS and CPE. To the best of our knowledge, this will be the first comprehensive systematic review focusing on ARDS management in a specific population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID CRD42020201576.

Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: study protocol.

INTRODUCTION: The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. METHODS AND ANALYSIS: In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. ETHICS AND DISSEMINATION: This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population.

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-α, IL-1ß, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.