Multi-center validation of an artificial intelligence system for detection of COVID-19 on chest radiographs in symptomatic patients.

OBJECTIVES: While chest radiograph (CXR) is the first-line imaging investigation in patients with respiratory symptoms, differentiating COVID-19 from other respiratory infections on CXR remains challenging. We developed and validated an AI system for COVID-19 detection on presenting CXR. METHODS: A deep learning model (RadGenX), trained on 168,850 CXRs, was validated on a large international test set of presenting CXRs of symptomatic patients from 9 study sites (US, Italy, and Hong Kong SAR) and 2 public datasets from the US and Europe. Performance was measured by area under the receiver operator characteristic curve (AUC). Bootstrapped simulations were performed to assess performance across a range of potential COVID-19 disease prevalence values (3.33 to 33.3%). Comparison against international radiologists was performed on an independent test set of 852 cases. RESULTS: RadGenX achieved an AUC of 0.89 on 4-fold cross-validation and an AUC of 0.79 (95%CI 0.78-0.80) on an independent test cohort of 5,894 patients. Delong's test showed statistical differences in model performance across patients from different regions (p < 0.01), disease severity (p < 0.001), gender (p < 0.001), and age (p = 0.03). Prevalence simulations showed the negative predictive value increases from 86.1% at 33.3% prevalence, to greater than 98.5% at any prevalence below 4.5%. Compared with radiologists, McNemar's test showed the model has higher sensitivity (p < 0.001) but lower specificity (p < 0.001). CONCLUSION: An AI model that predicts COVID-19 infection on CXR in symptomatic patients was validated on a large international cohort providing valuable context on testing and performance expectations for AI systems that perform COVID-19 prediction on CXR. KEY POINTS: • An AI model developed using CXRs to detect COVID-19 was validated in a large multi-center cohort of 5,894 patients from 9 prospectively recruited sites and 2 public datasets. • Differences in AI model performance were seen across region, disease severity, gender, and age. • Prevalence simulations on the international test set demonstrate the model's NPV is greater than 98.5% at any prevalence below 4.5%.

Mitochondrial Transfer Regulates Bioenergetics in Healthy and Chronic Obstructive Pulmonary Disease Airway Smooth Muscle.

Mitochondrial dysfunction has been reported in chronic obstructive pulmonary disease (COPD). Transfer of mitochondria from mesenchymal stem cells to airway smooth muscle cells (ASMCs) can attenuate oxidative stress-induced mitochondrial damage. It is not known whether mitochondrial transfer can occur between structural cells in the lungs or what role this may have in modulating bioenergetics and cellular function in healthy and COPD airways. Here, we show that ASMCs from both healthy ex-smokers and subjects with COPD can exchange mitochondria, a process that happens, at least partly, via extracellular vesicles. Exposure to cigarette smoke induces mitochondrial dysfunction and leads to an increase in the donation of mitochondria by ASMCs, suggesting that the latter may be a stress response mechanism. Healthy ex-smoker ASMCs that receive mitochondria show increases in mitochondrial biogenesis and respiration and a reduction in cell proliferation, irrespective of whether the mitochondria are transferred from healthy ex-smoker or COPD ASMCs. Our data indicate that mitochondrial transfer between structural cells is a homeostatic mechanism for the regulation of bioenergetics and cellular function within the airways and may represent an endogenous mechanism for reversing the functional consequences of mitochondrial dysfunction in diseases such as COPD.

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster.

BACKGROUND: An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. METHODS: In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done. FINDINGS: From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3-6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats. INTERPRETATION: Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions. FUNDING: The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).

Quitting Smoking in Mainland China: A New Role for Hospital-Based Nurses.

China has more than 300 million cigarette smokers and 1 million deaths every year attributed to smoking. Despite its huge economic implications, the lack of smoking and associated lifestyle-related data on China's outpatients makes it difficult for health care professionals to provide individualized assessments and targeted interventions. This study aimed to identify factors to inform nurse-led smoking behavioral assessments and cessation interventions. Clinical data from new patients attending the family medicine outpatient department from a large tertiary hospital in a major Southern China city were collected between March and December 2015. Data including basic demographics, medical history, vaccination history, current medication, and information on lifestyle risk factors were collected by frontline nurses during nursing assessment on their initial visit. Chi-square and Student's t tests were used as univariate analysis and post hoc regression analysis to explore which factors contributed toward smoking cessation. Of 7913 eligible visits, smokers and ex-smokers accounted for 13.5% and 2.4% of new patients, respectively, with a majority of them being young and male (gender ratio of 8:1) smokers. Multiple behavioral risks and comorbidities such as hypertension and diabetes mellitus in smokers were common; for example, 17.9% of smokers were also current drinkers, making alcohol users 8.5 to 16.7 times more likely to have smoked. Ex-smokers were more likely to be divorced, to be ex-drinkers, or to have higher diastolic blood pressure and concurrent hypertension. Smoking and associated lifestyle risk assessments run by registered nurses should be incorporated into current outpatient health histories and in targeted smoking cessation intervention programs.

The Impact of Obstructive Sleep Apnea and Tobacco Smoking on Endothelial Function.

BACKGROUND: Endothelial dysfunction has been recognized to occur in the context of obstructive sleep apnea (OSA) or tobacco smoking. However, the deleterious effect on vascular function with concurrence of both conditions is largely unknown. OBJECTIVE: To investigate whether the concurrence of OSA and smoking poses an additive detriment to endothelial dysfunction. METHODS: Chinese men without a history of chronic medical illness were invited to complete a questionnaire including smoking pack-year exposure, polysomnography and peripheral arterial tonometry (PAT) for endothelial function. Serum 8-isoprostane, advanced oxidation protein products (AOPP) and monocyte chemo-attractant protein-1 (MCP-1) were measured. RESULTS: 114 men were successfully enrolled. PAT ratio, adjusted for age and body mass index, correlated inversely with overall severity of OSA: apnea-hypopnea index (AHI), r = -0.160 (p = 0.092); oxygen desaturation index, r = -0.214 (p = 0.024); duration of oxygen saturation <90%, r = -0.219 (p = 0.020); and minimum oxygen saturation, r = 0.250 (p = 0.008). The PAT ratio decreased with increasing pack-year group (p = 0.018). It was lower with concurrent smoking history and moderate-severe OSA (AHI ≥15/h) compared to having one or neither factor (p = 0.011). Serum levels of 8-isoprostane and AOPP were positively related to severity of OSA, while MCP-1 correlated with smoking quantity. Multiple linear regression analyses showed that severity of intermittent hypoxia, MCP-1 and pack-year exposure were independent predictors of PAT ratio. CONCLUSION: While OSA, in particular intermittent hypoxemia, and tobacco smoking were independent risk factors, the concurrence of moderate-severe OSA and smoking was associated with the most severe impairment in endothelial function.

Bacteria in sputum of stable severe asthma and increased airway wall thickness.

BACKGROUND: Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness. METHODS: In 56 patients with stable severe asthma, sputum specimens obtained either spontaneously or after induction with hypertonic saline were cultured for bacteria and thoracic HRCT scans obtained. Wall thickness (WT) and area (WA) expressed as a ratio of airway diameter (D) and total area, respectively, were measured at five levels. RESULTS: Positive bacterial cultures were obtained in 29 patients, with H. influenzae, P. aeruginosa and S. aureus being the commonest strains. Logistic regression analysis showed that this was associated with the duration of asthma and the exacerbations during the past year. In airways > 2 mm, there was no significant difference in WA (67.5 ± 5.4 vs 66.4 ± 5.4) and WT/D (21.6 ± 2.7 vs 21.3 ± 2.4) between the culture negative versus positive groups. Similarly, in airways (≤ 2 mm), there were no significant differences in these parameters. The ratio of √wall area to Pi was negatively correlated with FEV1% predicted (p < 0.05). CONCLUSIONS: Bacterial colonization of the lower airways is common in patients with chronic severe asthma and is linked to the duration of asthma and having had exacerbations in the past year, but not with an increase in airway wall thickness.

Issues in pulmonary function testing for the screening and diagnosis of chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: The purpose of this review article is to provide an up-to-date summary on the current evidence for or against the use of lung function tests as screening and diagnostic tools for airflow obstruction in chronic obstructive pulmonary disease (COPD), and to consider the relevant issues in context. RECENT FINDINGS: COPD is characterized by chronic respiratory symptoms and airflow limitation with only partial reversibility on lung function testing. However, screening on a population basis or of an enriched 'at-risk' subset like chronic smokers is not supported by findings from previous epidemiological studies, screening trials or in currently published clinical management guidelines by professional societies and review bodies. The definition of airflow obstruction and the classification of disease severity of COPD also differ slightly between guidelines and statements from different professional societies. SUMMARY: Given the experience from previous screening trials and controversial classification of airflow obstruction by severity, it is impossible to have accurate screening results for COPD based on lung function tests alone. Clinical respiratory symptoms should be taken into consideration in terms of the diagnosis and management of COPD, as well as in any screening trial or programme that is to be attempted or implemented.

Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells.

Hydrogen sulfide (H(2)S) is synthesized intracellularly by the enzymes cystathionine-γ-lyase and cystathionine-ß-synthase (CBS), and is proposed to be a gasotransmitter with effects in modulating inflammation and cellular proliferation. We determined a role of H(2)S in airway smooth muscle (ASM) function. ASM were removed from resection or transplant donor lungs and were placed in culture. Proliferation of ASM was induced by FCS and the proinflammatory cytokine, IL-1ß. Proliferation of ASM and IL-8 release were measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H(2)S "donors" inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H(2)S, increased DNA synthesis induced by FCS and IL-1ß. In addition, methemoglobin increased IL-8 release induced by FCS, but not by IL-1ß, indicating a role for endogenous H(2)S in these systems. Inhibition of CBS, but not cystathionine-γ-lyase, reversed the inhibitory effect of H(2)S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H(2)S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H(2)S production. Finally, we found that exogenous H(2)S inhibited the phosphorylation of extracellular signal-regulated kinase-1/2 and p38, which could represent a mechanism by which H(2)S inhibited cellular proliferation and IL-8 release. In summary, H(2)S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H(2)S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma.

Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses.

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.

Role of Metabolic Reprogramming in Pulmonary Innate Immunity and Its Impact on Lung Diseases.

Lung innate immunity is the first line of defence against inhaled allergens, pathogens and environmental pollutants. Cellular metabolism plays a key role in innate immunity. Catabolic pathways, including glycolysis and fatty acid oxidation (FAO), are interconnected with biosynthetic and redox pathways. Innate immune cell activation and differentiation trigger extensive metabolic changes that are required to support their function. Pro-inflammatory polarisation of macrophages and activation of dendritic cells, mast cells and neutrophils are associated with increased glycolysis and a shift towards the pentose phosphate pathway and fatty acid synthesis. These changes provide the macromolecules required for proliferation and inflammatory mediator production and reactive oxygen species for anti-microbial effects. Conversely, anti-inflammatory macrophages use primarily FAO and oxidative phosphorylation to ensure efficient energy production and redox balance required for prolonged survival. Deregulation of metabolic reprogramming in lung diseases, such as asthma and chronic obstructive pulmonary disease, may contribute to impaired innate immune cell function. Understanding how innate immune cell metabolism is altered in lung disease may lead to identification of new therapeutic targets. This is important as drugs targeting a number of metabolic pathways are already in clinical development for the treatment of other diseases such as cancer.

Patterns of Inpatient Antibiotic Use Among Public Hospitals in Hong Kong from 2000 to 2015.

BACKGROUND: Studies have demonstrated that higher rates of antibiotic resistance are found in countries with higher antibiotic consumption. The global increase in antibiotic consumption is a major public health concern. OBJECTIVES: The objective of this study was to describe the antibiotic dispensing patterns in public hospitals in Hong Kong from 2000 to 2015. METHODS: We acquired data on all hospital admissions with any antibiotics dispensed from 2000 to 2015 from the Hong Kong public hospitals. The annual proportion of hospital admissions with antibiotics dispensed was estimated and stratified by age group. An interrupted time series analysis was conducted to examine any potential change in tetracycline dispensing after the release of the new clinical practice guideline. RESULTS: A total of 35,535,506 antibiotic prescriptions were dispensed among 2,161,360 unique hospitalized patients from 2000 to 2015. Antibiotics were dispensed in 29.2% of all hospital admissions in the public hospitals, the annual proportions of hospital admissions with antibiotics dispensed increased over the study period from 27.87% in 2000 to 31.39% in 2015, ranging from 27.17 to 31.39%. However, a significant increase was only observed in age groups of 5-19, 20-44, and 85 years or above when stratifying by age. In the interrupted time series analysis, a change in trend was detected for tetracycline dispensing that coincided with the time of publication of the new clinical practice guideline. CONCLUSIONS: We found that the overall volume of antibiotic use increased between 2000 and 2015. The rise in the dispensing of carbapenems in our study is concerning. The significant change in tetracycline use after being recommended as one of the preferred regimens demonstrated that the change in the clinical practice guideline had an immediate effect on the antibiotic prescribing practice in Hong Kong public hospitals.

Imaging Profile of the COVID-19 Infection: Radiologic Findings and Literature Review.

PURPOSE: To present the findings of 21 coronavirus disease 2019 (COVID-19) cases from two Chinese centers with CT and chest radiographic findings, as well as follow-up imaging in five cases. MATERIALS AND METHODS: This was a retrospective study in Shenzhen and Hong Kong. Patients with COVID-19 infection were included. A systematic review of the published literature on radiologic features of COVID-19 infection was conducted. RESULTS: The predominant imaging pattern was of ground-glass opacification with occasional consolidation in the peripheries. Pleural effusions and lymphadenopathy were absent in all cases. Patients demonstrated evolution of the ground-glass opacities into consolidation and subsequent resolution of the airspace changes. Ground-glass and consolidative opacities visible on CT are sometimes undetectable on chest radiography, suggesting that CT is a more sensitive imaging modality for investigation. The systematic review identified four other studies confirming the findings of bilateral and peripheral ground glass with or without consolidation as the predominant finding at CT chest examinations. CONCLUSION: Pulmonary manifestation of COVID-19 infection is predominantly characterized by ground-glass opacification with occasional consolidation on CT. Radiographic findings in patients presenting in Shenzhen and Hong Kong are in keeping with four previous publications from other sites.© RSNA, 2020See editorial by Kay and Abbara in this issue.

Incident Type 2 Diabetes in OSA and Effect of CPAP Treatment: A Retrospective Clinic Cohort Study.

BACKGROUND: The relationship between OSA and glucose metabolism remains controversial. This retrospective study investigated the relationship between OSA and incident type 2 diabetes (T2D) in a clinic cohort of Chinese adults in Hong Kong, and the effect of long-term CPAP treatment. METHODS: Data for diagnosis of incident T2D and CPAP usage were obtained from the territory-wide electronic health administration system and records of protocolized evaluation of CPAP adherence at the sleep clinic. The relationship between baseline OSA and incident T2D and the effect of CPAP therapy were examined by Cox regression models. Risk of incident T2D over the continuum of apnea-hypopnea index was examined with cubic spline analysis. RESULTS: Of 1,206 subjects with overnight sleep studies and clinical assessment in 2006 through 2013, 152 developed diabetes (median follow-up, 7.3 years). In fully adjusted models, untreated moderate or patients with severe OSA had higher risk of developing diabetes, hazard ratios 2.01 (95% CI, 1.06-3.81) and 2.62 (95% CI, 1.40-4.93) respectively, with a trend to plateau in those with severe OSA. No interaction was demonstrated between OSA and obesity. Regular CPAP use, which was attained in about one-third of subjects with moderate-severe OSA, was associated with reduction of diabetes incidence from 3.41 to 1.61 per 100 person-years, and of adjusted hazard risk to that of non-OSA. CONCLUSIONS: OSA severity independently predicted incident diabetes. Regular long-term CPAP use was associated with reduced risk of incident T2D, after adjustment for various baseline metabolic risk factors and subsequent body weight change.

Use of influenza antivirals in patients hospitalized in Hong Kong, 2000-2015.

OBJECTIVES: We aimed to describe patterns in the usage of antivirals to treat influenza virus infection in hospitals in Hong Kong from 2000 through 2015. METHODS: We analyzed centralized electronic health records that included dispensation information and diagnosis codes. Information collected on admissions included patient age, sex, admission year and month, and medications dispensed, and were matched with the first 15 discharge diagnosis codes. We divided monthly admission episodes by relevant population denominators to obtain admission rates, and stratified analyses by drug type, age group, and diagnosis codes. RESULTS: Amantadine was used for influenza treatment in the early 2000s but changed with recommendations to avoid its use in 2006, and is now mainly used to treat Parkinson's disease. Oseltamivir usage increased substantially in 2009 and is now commonly used, with almost 40,000 hospitalizations treated with oseltamivir in the years 2012 through 2015, 66% of which was in persons ≥65 years of age. During the entire study period, of the 98,253 admission episodes in which oseltamivir was dispensed, 40,698 (41%) included a diagnosis code for influenza, and 80,283 (82%) included any diagnosis code for respiratory illness. CONCLUSIONS: The amount of oseltamivir used from 2012-15 was comparable to a separate ecological estimate of around 13,000 influenza-associated hospitalizations per year on average. We did not have access to individual patient laboratory testing data.

Plasma EGFR Mutation Detection Associated With Survival Outcomes in Advanced-Stage Lung Cancer.

UNLABELLED: We confirmed the performance of an array method for plasma epidermal growth factor receptor (EGFR) mutation detection and showed the association of plasma EGFR mutation with survival outcomes. BACKGROUND: Noninvasive detection of epidermal growth factor receptor (EGFR) mutation in plasma is feasible and could be adjunct for therapeutic monitoring especially when repeated biopsy of tumor tissue is challenging. The aims of this study were to establish the diagnostic performance of peptide nucleic acid-locked nucleic acid polymerase chain reaction followed by custom array for plasma EGFR mutation and to evaluate the association of detection with clinical characteristics and survival outcomes. MATERIALS AND METHODS: Plasma genomic DNA from consecutive advanced lung cancer subjects was tested for EGFR mutations before anticancer treatment, and compared with mutation status in tumor tissue. Clinical characteristics were compared between patients who were EGFR-mutant and wild type; and within EGFR mutants, whether EGFR mutations could be detected in plasma. RESULTS: In 74 lung cancer patients, the sensitivity, specificity, and positive and negative predictive values of plasma EGFR detection were 79.1%, 96.8%, 97.1%, and 76.9%, respectively. EGFR mutants with concomitant detection of plasma EGFR mutation showed worse survival compared with mutants with no concomitant plasma mutation detected in biopsy specimens. CONCLUSION: Plasma EGFR mutation detected using this method demonstrated high diagnostic performance. In EGFR mutants, plasma EGFR mutation detection correlated not only EGFR mutation status in biopsy but was also associated with worse prognosis compared with EGFR mutant without plasma EGFR mutation detection.