Publications by authors named "Nanshan Zhong"

338 Publications

Analysis of pathological changes in the epithelium in COVID-19 patient airways.

ERJ Open Res 2021 Apr 6;7(2). Epub 2021 Apr 6.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

https://bit.ly/2M2NcdO.
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http://dx.doi.org/10.1183/23120541.00690-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898030PMC
April 2021

Upregulation of Piezo1 (Piezo Type Mechanosensitive Ion Channel Component 1) Enhances the Intracellular Free Calcium in Pulmonary Arterial Smooth Muscle Cells From Idiopathic Pulmonary Arterial Hypertension Patients.

Hypertension 2021 Apr 5:HYPERTENSIONAHA12016629. Epub 2021 Apr 5.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, China (J. Liao, W.L., Yuqin Chen, C.Z., X. Luo, Z.L., J.C., S.L., H.Y., Yilin Chen, H.F., D.Z., X.C., Z.Z., Q.Y., X. Liu, H.T., N.Z., K.Y., J.W.).

Emerging studies have reported the mechanosensitive Piezo1 (piezo type mechanosensitive ion channel component 1) plays essential roles in regulating the vascular tone through mechanistic actions on intracellular calcium homeostasis. However, the specific roles of Piezo1 in pulmonary vessels remain incompletely understood. We aim to investigate whether and how Piezo1 regulates the intracellular calcium homeostasis in human pulmonary arterial smooth muscle cells (PASMCs) under normal and pulmonary arterial hypertension (PAH) conditions. Cultured human PASMCs isolated from both control donors and idiopathic PAH patients were used as cell models. Fura-2 based intracellular calcium imaging was performed to measure the intracellular free calcium concentration ([Ca]). Results showed that activation of Piezo1 by Yoda1 increases [Ca] by inducing both intracellular calcium release from internal calcium stores through the intracellular (intra-) Piezo1 localized at the subcellular organelles, including endoplasmic reticulum/sarcoplasmic reticulum, mitochondria, and nucleus; as well as extracellular calcium influx through the plasma membrane-localized Piezo1 in a mechanism independent of the store-operated calcium entry. Moreover, the Piezo1-mediated increase of [Ca] is linked to increased contraction and proliferation of PASMCs. Yoda1 induces dose-dependent vasocontraction in endothelium-denuded rat intrapulmonary arteries. Significant upregulation and increased activity of Piezo1 were observed in idiopathic PAH-PASMCs versus donor-PASMCs, contributing to the increased [Ca] and excessive proliferation of idiopathic PAH-PASMCs. In summary, Piezo1 mediates the increase of [Ca] by triggering both intracellular calcium release and extracellular influx. The enhanced Piezo1 expression and activity accounts, at least partially, for the abnormally elevated [Ca] and proliferation in idiopathic PAH-PASMCs.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16629DOI Listing
April 2021

A Highly Automated Mobile Laboratory for On-site Molecular Diagnostics in the COVID-19 Pandemic.

Clin Chem 2021 03;67(4):672-683

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.

Background: Infectious disease outbreaks such as the COVID-19 (coronavirus disease 2019) pandemic call for rapid response and complete screening of the suspected community population to identify potential carriers of pathogens. Central laboratories rely on time-consuming sample collection methods that are rarely available in resource-limited settings.

Methods: We present a highly automated and fully integrated mobile laboratory for fast deployment in response to infectious disease outbreaks. The mobile laboratory was equipped with a 6-axis robot arm for automated oropharyngeal swab specimen collection; virus in the collected specimen was inactivated rapidly using an infrared heating module. Nucleic acid extraction and nested isothermal amplification were performed by a "sample in, answer out" laboratory-on-a-chip system, and the result was automatically reported by the onboard information platform. Each module was evaluated using pseudovirus or clinical samples.

Results: The mobile laboratory was stand-alone and self-sustaining and capable of on-site specimen collection, inactivation, analysis, and reporting. The automated sampling robot arm achieved sampling efficiency comparable to manual collection. The collected samples were inactivated in as short as 12 min with efficiency comparable to a water bath without damage to nucleic acid integrity. The limit of detection of the integrated microfluidic nucleic acid analyzer reached 150 copies/mL within 45 min. Clinical evaluation of the onboard microfluidic nucleic acid analyzer demonstrated good consistency with reverse transcription quantitative PCR with a κ coefficient of 0.979.

Conclusions: The mobile laboratory provides a promising solution for fast deployment of medical diagnostic resources at critical junctions of infectious disease outbreaks and facilitates local containment of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) transmission.
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http://dx.doi.org/10.1093/clinchem/hvab027DOI Listing
March 2021

Scientific guidance to fight the pandemic: the Coronavirus Disease 2019 (COVID-19).

J Thorac Dis 2021 Feb;13(2):505-510

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

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http://dx.doi.org/10.21037/jtd-2021-02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947505PMC
February 2021

FGFR/RACK1 interacts with MDM2, promotes P53 degradation, and inhibits cell senescence in lung squamous cell carcinoma.

Cancer Biol Med 2021 Mar 12. Epub 2021 Mar 12.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.

Objective: FGFR is considered an important driver gene of lung squamous cell carcinoma (LSCC). Thus, identification of the biological events downstream of FGFR is important for the treatment of this malignancy. Our previous study has shown that the FGFR/RACK1 complex interacts with PKM2 and consequently promotes glycolysis in LSCC cells. However, the biological functions of the FGFR/RACK1 complex remain poorly understood.

Methods: Anchorage-independent assays and tumorigenesis assays were performed to evaluate cancer cell malignancy. Distant seeding assays were performed to evaluate cancer cell metastasis. β-gal staining was used to examine cell senescence, and immunoprecipitation assays were performed to examine the interactions among FGFR, RACK1, and MDM2.

Results: FGFR/RACK1 was found to regulate the senescence of LSCC cells. Treatment with PD166866, an inhibitor of FGFR, or knockdown of RACK1 induced senescence in LSCC cells ( < 0.01). A molecular mechanistic study showed that FGFR/RACK1/MDM2 form a complex that promotes the degradation of p53 and thus inhibits cell senescence. PD166866 and RG7112, an MDM2/p53 inhibitor, cooperatively inhibited the colony formation and distal seeding of LSCC cells ( < 0.01), and upregulated the expression of p53 and p21.

Conclusions: Together, our findings revealed the regulatory roles and mechanisms of FGFR/RACK1 in cell senescence. This understanding should be important in the treatment of LSCC.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0389DOI Listing
March 2021

Population Bottlenecks and Intra-host Evolution During Human-to-Human Transmission of SARS-CoV-2.

Front Med (Lausanne) 2021 15;8:585358. Epub 2021 Feb 15.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

The emergence of the novel human coronavirus, SARS-CoV-2, causes a global COVID-19 (coronavirus disease 2019) pandemic. Here, we have characterized and compared viral populations of SARS-CoV-2 among COVID-19 patients within and across households. Our work showed an active viral replication activity in the human respiratory tract and the co-existence of genetically distinct viruses within the same host. The inter-host comparison among viral populations further revealed a narrow transmission bottleneck between patients from the same households, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions.
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http://dx.doi.org/10.3389/fmed.2021.585358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917136PMC
February 2021

Trends of pulmonary fungal infections from 2013 to 2019: an AI-based real-world observational study in Guangzhou, China.

Emerg Microbes Infect 2021 Dec;10(1):450-460

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.

Recently, the prevalence trend of pulmonary fungal infection (PFI) has rapidly increased. Changes in the risk factors for, distributions of underlying diseases associated with and clinical characteristics of some individual PFIs have been reported in the past decade. However, data regarding PFIs remain uncertain. This study reports the epidemiological characteristics and trends of PFIs over time in recent years. We applied an automated natural language processing (NLP) system to extract clinically relevant information from the electronic health records (EHRs) of PFI patients at the First Affiliated Hospital of Guangzhou Medical University. Then, a trend analysis was performed. From January 1, 2013, to December 31, 2019, 40,504 inpatients and 219,414 outpatients with respiratory diseases were screened, in which 1368 inpatients and 1313 outpatients with PFI were identified. These patients were from throughout the country, but most patients were from southern China. Upward trends in PFIs were observed in both hospitalized patients and outpatients (<0.05). The stratification by age showed that the incidence of hospitalized patients aged 14-30 years exhibited the most obvious upward trend, increasing from 9.5 per 1000 patients in 2013 to 88.3 per 1000 patients in 2019. Aspergillosis (56.69%) was the most common PFI, but notably, the incidence rates of , which used to be considered uncommon, exhibited the most rapid increases. In younger PFI patients, the incidence and trend of PFIs have increased. Infection by previously uncommon pathogens has also gradually increased. Increased attention should be paid to young PFI patients and uncommon PFI pathogen infections.
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http://dx.doi.org/10.1080/22221751.2021.1894902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971272PMC
December 2021

Intra-host variation and evolutionary dynamics of SARS-CoV-2 populations in COVID-19 patients.

Genome Med 2021 02 22;13(1):30. Epub 2021 Feb 22.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.

Background: Since early February 2021, the causative agent of COVID-19, SARS-CoV-2, has infected over 104 million people with more than 2 million deaths according to official reports. The key to understanding the biology and virus-host interactions of SARS-CoV-2 requires the knowledge of mutation and evolution of this virus at both inter- and intra-host levels. However, despite quite a few polymorphic sites identified among SARS-CoV-2 populations, intra-host variant spectra and their evolutionary dynamics remain mostly unknown.

Methods: Using high-throughput sequencing of metatranscriptomic and hybrid captured libraries, we characterized consensus genomes and intra-host single nucleotide variations (iSNVs) of serial samples collected from eight patients with COVID-19. The distribution of iSNVs along the SARS-CoV-2 genome was analyzed and co-occurring iSNVs among COVID-19 patients were identified. We also compared the evolutionary dynamics of SARS-CoV-2 population in the respiratory tract (RT) and gastrointestinal tract (GIT).

Results: The 32 consensus genomes revealed the co-existence of different genotypes within the same patient. We further identified 40 intra-host single nucleotide variants (iSNVs). Most (30/40) iSNVs presented in a single patient, while ten iSNVs were found in at least two patients or identical to consensus variants. Comparing allele frequencies of the iSNVs revealed a clear genetic differentiation between intra-host populations from the respiratory tract (RT) and gastrointestinal tract (GIT), mostly driven by bottleneck events during intra-host migrations. Compared to RT populations, the GIT populations showed a better maintenance and rapid development of viral genetic diversity following the suspected intra-host bottlenecks.

Conclusions: Our findings here illustrate the intra-host bottlenecks and evolutionary dynamics of SARS-CoV-2 in different anatomic sites and may provide new insights to understand the virus-host interactions of coronaviruses and other RNA viruses.
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http://dx.doi.org/10.1186/s13073-021-00847-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898256PMC
February 2021

Clinical types of checkpoint inhibitor-related pneumonitis in lung cancer patients: a multicenter experience.

Transl Lung Cancer Res 2021 Jan;10(1):415-429

State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Background: Checkpoint inhibitor-related pneumonitis (CIP) is not well classified according to clinical factors. We propose different clinical sub-types of CIP based on clinical factors and investigated the corresponding clinical features, treatments, and outcomes.

Methods: We conducted a multicenter retrospective study of patients with lung cancer (including non-small cell lung cancer and small cell lung cancer) who developed CIP. The clinical characteristics, radiologic features, treatments, and outcomes of CIP were analyzed.

Results: A total of 55 patients developed CIP and were classified into 3 groups as follows: 21 in the pure type (PT) group, 14 in the induced type (IT) group, and 20 in the mixed type (MT) group. The incidence of severe (grade 3-5) pneumonitis was significantly higher in the IT group than in the PT and MT groups (71.4% 14.3% 50.0%, P=0.002). Antiviral therapy was significantly more frequent in the IT group than in the PT and MT groups. Antibiotic therapy was administered in 23.8%, 71.4%, and 80.0% of patients with the PT, IT, and MT, respectively. The improvement time in the PT group was longer than that in the IT and MT groups (0.9 0.5 0.3 months, P=0.028). Patients with the PT had a better tumor response to immune checkpoint inhibitors (ICIs) than those with the other 2 types [overall response rate (ORR), 78% 31% 44%, P=0.027].

Conclusions: The clinical classification of CIP may favor strategies for treatments and predict the tumor response to ICIs.
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http://dx.doi.org/10.21037/tlcr-20-1258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867788PMC
January 2021

Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19.

ERJ Open Res 2021 Jan 1;7(1). Epub 2021 Feb 1.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: Critically ill coronavirus disease 2019 (COVID-19) patients may suffer persistent systemic inflammation and multiple organ failure, leading to a poor prognosis.

Research Question: To examine the relevance of the novel inflammatory factor heparin-binding protein (HBP) in critically ill COVID-19 patients, and evaluate the correlation of the biomarker with disease progression.

Study Design And Methods: 18 critically ill COVID-19 patients who suffered from respiratory failure and sepsis, including 12 cases who experienced a rapidly deteriorating clinical condition and six cases without deterioration, were investigated. They were compared with 15 age- and sex- matched COVID-19-negative patients with respiratory failure. Clinical data were collected and HBP levels were investigated.

Results: HBP was significantly increased in critically ill COVID-19 patients following disease aggravation and tracked with disease progression. HBP elevation preceded the clinical manifestations for up to 5 days and was closely correlated with patients' pulmonary ventilation and perfusion status.

Interpretation: HBP levels are associated with COVID-19 disease progression in critically ill patients. As a potential mediator of disease aggravation and multiple organ injuries that are triggered by continuing inflammation and oxygen deficits, HBP warrants further study as a disease biomarker and potential therapeutic target.
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http://dx.doi.org/10.1183/23120541.00741-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667727PMC
January 2021

COVID-19-associated coagulopathy: thromboembolism prophylaxis and poor prognosis in ICU.

Exp Hematol Oncol 2021 Feb 1;10(1). Epub 2021 Feb 1.

State Key Lab of Respiratory Diseases, Guangzhou Institute of Respiratory Health, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120, Guangzhou, China.

Background: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities which are indicators of higher mortality especially in severe cases.

Methods: We studied patients with proven COVID-19 disease in the intensive care unit of Jinyintan Hospital, Wuhan, China from 30 to 2019 to 31 March 2020.

Results: Of 180 patients, 89 (49.44 %) had died, 85 (47.22 %) had been discharged alive, and 6 (3.33 %) were still hospitalised by the end of data collection. A D-dimer concentration of > 0.5 mg/L on admission was significantly associated with 30 day mortality, and a D-dimer concentration of > 5 mg/L was found in a much higher proportion of non-survivors than survivors. Sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC) scoring systems were dichotomised as < 4 or ≥ 4 and < 5 or ≥ 5, respectively, and the mortality rate was significantly different between the two stratifications in both scoring systems. Enoxaparin was administered to 68 (37.78 %) patients for thromboembolic prophylaxis, and stratification by the D-dimer concentration and DIC score confirmed lower mortality in patients who received enoxaparin when the D-dimer concentration was > 2 than < 2 mg/L or DIC score was ≥ 5 than < 5. A low platelet count and low serum calcium concentration were also related to mortality.

Conclusions: A D-dimer concentration of > 0.5 mg/L on admission is a risk factor for severe disease. A SIC score of > 4 and DIC score of > 5 may be used to predict mortality. Thromboembolic prophylaxis can reduce mortality only in patients with a D-dimer concentration of > 2 mg/L or DIC score of ≥ 5.
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http://dx.doi.org/10.1186/s40164-021-00202-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848868PMC
February 2021

Rapid visualized assessment of drug efficacy in live mice with a selectable marker-free autoluminescent Klebsiella pneumoniae.

Biosens Bioelectron 2021 Apr 12;177:112919. Epub 2021 Jan 12.

State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Klebsiella pneumoniae is an opportunistic pathogen that is responsible for community acquired infections and nosocomial infections. Antibiotic-resistant K. pneumoniae and/or hypervirulent K. pneumoniae are emerging as a serious threat to public health. For the sake of alleviating and conquering current dilemma, discovery of effective new drugs against K. pneumoniae is a tough challenge. However, traditional anti-K. pneumoniae drug discovery methods cost considerable amount of time, animals, labor and so on. So an efficient technique for in vitro and in vivo drug screening with the least time duration, animals and labor cost is highly needed for the discovery of new effective compounds. Hence, in this study we constructed a selectable marker-free autoluminescent K. pneumoniae (SfAlKp) harboring luxCDABE by combining Tn7 transposon and Xer-dif system. SfAlKp can be used for discovery of new drugs via detecting luminescence intensity as a surrogate marker. The energy-consuming autoluminescent reaction catalyzed by the LuxAB enzymes which use the substrates produced by LuxCDE using the metabolites of the bacteria. Tn7 can insert exogenous genes into the bacterial genome and the DNA fragment in between dif sequences can be recognized and removed by endogenous XerCD recombinases of K. pneumoniae. The drug susceptibility and growth rate of SfAlKp are identical to its parent strain, meanwhile the luminescence intensity and stability are also significant characteristics of SfAlKp. Compared to conventional techniques, the autoluminescence-based measurement is more applicable to high throughput screening for compounds both in vitro as well as in vivo in animal model.
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http://dx.doi.org/10.1016/j.bios.2020.112919DOI Listing
April 2021

A narrative review of electrical impedance tomography in lung diseases with flow limitation and hyperinflation: methodologies and applications.

Ann Transl Med 2020 Dec;8(24):1688

State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, Guangzhou Medical University, the First Affiliated Hospital of Guangzhou Medical University, Department of Crit Care Med, Guangzhou, China.

Electrical impedance tomography (EIT) is a functional radiation-free imaging technique that measures regional lung ventilation distribution by calculating the impedance changes in the corresponding regions. The aim of the present review was to summarize the current literature concerning the methodologies and applications of EIT in lung diseases with flow limitation and hyperinflation. PubMed was searched up to May 2020 to identify studies investigating the use of EIT in patients with asthma, bronchiectasis, bronchitis, bronchiolitis, chronic obstructive pulmonary disease, and cystic fibrosis. The extracted data included study design, EIT methodologies, interventions, validation and comparators, population characteristics, and key findings. Of the 44 included studies, seven were related to simulation, animal experimentation, or reconstruction algorithm development with evaluation on patients; 27 studies had the primary objective of validating EIT technique and measures including regional ventilation distribution, regional EIT-spirometry parameters, end-expiratory lung impedance, and regional time constants; and 10 studies had the primary objective of applying EIT to monitor the response to therapeutic interventions, including various ventilation supports, patient repositioning, and airway suctioning. In pediatric and adult patients, EIT has been successfully validated for assessing spatial and temporal ventilation distribution, measuring changes in lung volume and flow, and studying regional respiratory mechanics. EIT has also demonstrated potential as an alternative or supplement to well-established measurement modalities (e.g., conventional pulmonary function testing) to monitor the progression of obstructive lung diseases, although the existing literature lacks prediction values as references and lacks clinical outcome evidence.
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http://dx.doi.org/10.21037/atm-20-4984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812189PMC
December 2020

Mapping and role of T cell response in SARS-CoV-2-infected mice.

J Exp Med 2021 04;218(4)

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Virus-specific T cells play essential roles in protection against multiple virus infections, including SARS-CoV and MERS-CoV. While SARS-CoV-2-specific T cells have been identified in COVID-19 patients, their role in the protection of SARS-CoV-2-infected mice is not established. Here, using mice sensitized for infection with SARS-CoV-2 by transduction with an adenovirus expressing the human receptor (Ad5-hACE2), we identified SARS-CoV-2-specific T cell epitopes recognized by CD4+ and CD8+ T cells in BALB/c and C57BL/6 mice. Virus-specific T cells were polyfunctional and were able to lyse target cells in vivo. Further, type I interferon pathway was proved to be critical for generating optimal antiviral T cell responses after SARS-CoV-2 infection. T cell vaccination alone partially protected SARS-CoV-2-infected mice from severe disease. In addition, the results demonstrated cross-reactive T cell responses between SARS-CoV and SARS-CoV-2, but not MERS-CoV, in mice. Understanding the role of the T cell response will guide immunopathogenesis studies of COVID-19 and vaccine design and validation.
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http://dx.doi.org/10.1084/jem.20202187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814348PMC
April 2021

The proteomic characteristics of airway mucus from critical ill COVID-19 patients.

Life Sci 2021 Mar 14;269:119046. Epub 2021 Jan 14.

State Key Laboratory of Respiratory Diseases, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. Electronic address:

Background: The pandemic of the coronavirus disease 2019 (COVID-19) has brought a global public health crisis. However, the pathogenesis underlying COVID-19 are barely understood.

Methods: In this study, we performed proteomic analyses of airway mucus obtained by bronchoscopy from severe COVID-19 patients. In total, 2351 and 2073 proteins were identified and quantified in COVID-19 patients and healthy controls, respectively.

Results: Among them, 92 differentiated expressed proteins (DEPs) (46 up-regulated and 46 down-regulated) were found with a fold change >1.5 or <0.67 and a p-value <0.05, and 375 proteins were uniquely present in airway mucus from COVID-19 patients. Pathway and network enrichment analyses revealed that the 92 DEPs were mostly associated with metabolic, complement and coagulation cascades, lysosome, and cholesterol metabolism pathways, and the 375 COVID-19 only proteins were mainly enriched in amino acid degradation (Valine, Leucine and Isoleucine degradation), amino acid metabolism (beta-Alanine, Tryptophan, Cysteine and Methionine metabolism), oxidative phosphorylation, phagosome, and cholesterol metabolism pathways.

Conclusions: This study aims to provide fundamental data for elucidating proteomic changes of COVID-19, which may implicate further investigation of molecular targets directing at specific therapy.
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http://dx.doi.org/10.1016/j.lfs.2021.119046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806453PMC
March 2021

Narrative review of the novel coronavirus SARS-CoV-2: update on genomic characteristics, transmissions and animal model.

J Thorac Dis 2020 Dec;12(12):7454-7466

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Two outbreaks of severe respiratory infection caused by severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) caused global pandemics and highlighted the importance of preparedness for respiratory CoVs. Recently, a third highly pathogenic CoV, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, Hubei, China and posed a public health crisis worldwide. Here, we focus on the recent advances of the novel CoV, and discuss its genomic similarity with other CoVs, transmission, animal model and clinical treatment of coronavirus disease 2019 (COVID-19) induced by SARS-CoV-2, which help epidemic prevention and control, and guide treatment strategies.
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http://dx.doi.org/10.21037/jtd-20-2084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797876PMC
December 2020

Corrigendum: Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients.

Front Immunol 2020 21;11:633815. Epub 2020 Dec 21.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

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http://dx.doi.org/10.3389/fimmu.2020.633815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780884PMC
December 2020

Association of change in air quality with hospital admission for acute exacerbation of chronic obstructive pulmonary disease in Guangdong, China: A province-wide ecological study.

Ecotoxicol Environ Saf 2021 Jan 11;208:111590. Epub 2020 Nov 11.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. Electronic address:

Aims: To assess possible effect of air quality improvements, we investigated the temporal change in hospital admissions for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) associated with pollutant concentrations.

Methods: We collected daily concentrations of particulate matter (i.e., PM, PM and PM), sulfur dioxide (SO), nitrogen dioxide (NO), carbon monoxide (CO), ozone (O), and admissions for AECOPD for 21 cities in Guangdong from 2013 to 2017. We examined the association of air pollution with AECOPD admissions using two-stage time-series analysis, and estimated the annual attributable fractions, numbers, and direct hospitalization costs of AECOPD admissions with principal component analysis.

Results: From 2013-2017, mean daily concentrations of SO, PM and PM declined by nearly 40%, 30%, and 26% respectively. As the average daily 8 h O concentration increased considerably, the number of days exceeding WHO target (i.e.,100 μg/m³) increased from 103 in 2015-152 in 2017. For each interquartile range increase in pollutant concentration, the relative risks of AECOPD admission at lag 0-3 were 1.093 (95% CI 1.06-1.13) for PM, 1.092 (95% CI 1.08-1.11) for O, and 1.092 (95% CI 1.05-1.14) for SO. Attributable fractions of AECOPD admission advanced by air pollution declined from 9.5% in 2013 to 4.9% in 2016, then increased to 6.0% in 2017. A similar declining trend was observed for direct AECOPD hospitalization costs.

Conclusion: Declined attributable hospital admissions for AECOPD may be associated with the reduction in concentrations of PM, PM and SO in Guangdong, while O has emerged as an important risk factor. Summarizes the main finding of the work: Reduction in PM may result in declined attributable hospitalizations for AECOPD, while O has emerged as an important risk factor following an intervention.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111590DOI Listing
January 2021

Response.

Chest 2020 Dec;158(6):2700-2701

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2020.08.2107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713537PMC
December 2020

Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features.

BMC Pulm Med 2020 Dec 2;20(1):315. Epub 2020 Dec 2.

Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, 151 Yanjiang West Road, Guangzhou, 510120, China.

Background: Some patients with interstitial pneumonia with autoimmune features (IPAF) showed a progressive course despite therapy. This study aimed to evaluate whether serial changes in the serum levels of surfactant protein-A (SP-A) and Krebs von den Lungen-6 (KL-6) can predict disease progression.

Methods: Sixty-four patients with IPAF and 41 patients with non-fibrotic lung disease (non-FLD) were examined. Based on long-term changes in lung function, 36 IPAF patients who were followed up for more than 3 months were divided into a progressive group (n = 9), an improvement group (n = 13), and a stable group (n = 14). Serum KL-6 and SP-A levels were measured. The sensitivity, specificity, cut-off value, and area under the curve (AUC) value for each of the indices were determined using receiver operating characteristic (ROC) curve analysis. The expression differences in these biomarkers and their correlation with disease severity were analyzed.

Results: Compared with non-FLD patients, serum SP-A and KL-6 levels in IPAF patients were increased significantly [SP-A: (p < 0.001); KL-6: (p < 0.001)] and negatively correlated with DLCO (SP-A: r = - 0.323, p = 0.018; KL-6: r = - 0.348, p = 0.0011). In patients with progressive disease, the posttreatment serum SP-A and KL-6 levels were increased significantly compared with pretreatment levels [SP-A: (p = 0.021); KL-6: (p = 0.008)]. In patients showing improvement, the levels were decreased significantly [SP-A (p = 0.007) and KL-6 (p = 0.002)]. Changes in serum biomarkers (Delta SP-A and Delta KL-6) were significantly negatively correlated with changes in lung function (Delta FVC, Delta DLCO and Delta FEV1) (r = 0.482, p < 0.05). A significant positive correlation was found between Delta SP-A and Delta KL-6 (r = 0.482, p < 0.001).

Conclusions: Serum SP-A and KL-6 offer high sensitivity and specificity for the diagnosis of IPAF. The decrease in serum SP-A and/or KL-6 levels in patients with IPAF is related to the improvement in pulmonary function. SP-A and KL-6 may be important biomarkers for predicting disease progression in patients with IPAF.
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http://dx.doi.org/10.1186/s12890-020-01336-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709263PMC
December 2020

Critical Care Response to the Outbreak of COVID-19: The Experience From Guangdong Province, China.

Front Public Health 2020 11;8:576528. Epub 2020 Nov 11.

State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

In December 2019, human infection with a novel coronavirus, known as SARS-CoV-2, was confirmed in Wuhan, China, and spread rapidly beyond Wuhan and around the world. By 7 May 2020, a total of 84,409 patients were infected in mainland China, with 4,643 deaths, according to a Chinese Center for Disease Control and Prevention report. Recent studies reported that critically ill patients were presented with high mortality. However, the clinical experiences of patients with coronavirus disease 2019 (COVID-19) have not been described in Guangdong Province, where by 7 May 2020, 1,589 people had been confirmed as having COVID-19 but with a very low mortality of 8 death (0.5%). Here, we describe the experience of critical care response to the outbreak of SARS-CoV-2 in Guangdong Province in the following points: Early intervention by the government, Establishment of a Multidisciplinary Working Group, Prompt intensive care interventions, Adequate ICU beds and Human resource in ICU, Infection control practices.
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http://dx.doi.org/10.3389/fpubh.2020.576528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686027PMC
November 2020

Evaluating the diagnostic accuracy of a ctDNA methylation classifier for incidental lung nodules: protocol for a prospective, observational, and multicenter clinical trial of 10,560 cases.

Transl Lung Cancer Res 2020 Oct;9(5):2016-2026

National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: Lung nodules are a diagnostic challenge. Current clinical management of lung nodule patients is inefficient and therefore causes patient misclassification, which increases healthcare expenses. However, a precise and robust lung nodule classifier to minimize discomfort for patients and healthcare costs is still lacking. The aim of the present protocol is to evaluate the effectiveness of using a liquid biopsy classifier to diagnose nodules compared to physician estimates and whether the classifier can reduce the number of unnecessary biopsies in benign cases.

Methods: A prospective cohort of 10,560 patients enrolled at 23 clinical centers in China with non-calcified pulmonary nodules, ranging from 0.5 to 3 cm in diameter, indicated by LDCT or CT will be included. After signed consent forms, the participants' pulmonary nodules will be assessed using three evaluation tools: (I) physician cancer probability estimates (II) validated lung nodule risk models, including Mayo Clinic and Veteran's Affairs models (III) ctDNA methylation classifier previously established. Each patient will undergo LDCT/CT follow-ups for 2 to 3 years and their information and one blood sample will be collected at baseline, 3, 6, 12, 24 and 36 months. The primary study outcomes will be the diagnostic accuracy of the methylation classifier in the cohort. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) will be used to compare the diagnostic value of each testing tool in differentiating benign and malignant pulmonary nodules.

Discussion: We are conducting an observational study to explore the accuracy of using a ctDNA methylation classifier for incidental lung nodules diagnosis.

Trial Registration: Clinicaltrials.gov NCT03651986.
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http://dx.doi.org/10.21037/tlcr-20-701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653103PMC
October 2020

Clinical Findings of COVID-19 Patients Admitted to Intensive Care Units in Guangdong Province, China: A Multicenter, Retrospective, Observational Study.

Front Med (Lausanne) 2020 19;7:576457. Epub 2020 Oct 19.

State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Information about critically ill patients with coronavirus disease 2019 (COVID-19) in China but outside of Wuhan is scarce. We aimed to describe the clinical features, treatment, and outcomes of patients with COVID-19 admitted to the intensive care unit (ICU) in Guangdong Province. In this multicenter, retrospective, observational study, we enrolled consecutive patients with COVID-19 who were admitted to seven ICUs in Guangdong Province. Demographic data, symptoms, laboratory findings, comorbidities, treatment, and outcomes were collected. Data were compared between patients with and without intubation. A total of 45 COVID-19 patients required ICU admission in the study hospitals [mean age 56.7 ± 15.4 years, 29 males (64.4%)]. The most common symptoms at onset were fever and cough. Most patients presented with lymphopenia and elevated lactate dehydrogenase. Treatment with antiviral drugs was initiated in all patients. Thirty-six patients (80%) developed acute respiratory distress syndrome at ICU admission, and 15 (33.3%) septic shock. Twenty patients (44.4%) were intubated, and 10 (22.2%) received extracorporeal membrane oxygenation. The 60-day mortality was 4.4% (2 of 45). COVID-19 patients admitted to ICU were characterized by fever, lymphopenia, acute respiratory failure, and multiple organ dysfunction. The mortality of ICU patients in Guangdong Province was relatively low with a small sample size.
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http://dx.doi.org/10.3389/fmed.2020.576457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604321PMC
October 2020

Qualitative and quantitative assessment of pendelluft: a simple method based on electrical impedance tomography.

Ann Transl Med 2020 Oct;8(19):1216

Department of Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, State Key Lab of Respiratory Diseases, Guangzhou Institute of Respiratory Health, Guangzhou, China.

Background: Pendelluft, defined as asynchronous alveolar ventilation, is caused by different regional time constants or dynamic pleural pressure variations. The aim of the present study was to propose a simple method to evaluate pendelluft based on electrical impedance tomography (EIT). The efficacy of this method was demonstrated in well-known pendelluft scenarios in 6 patients.

Methods: Two patients with flail chest after accidents, two patients with acute respiratory distress syndrome (ARDS) and two patients with acutely exacerbated obstructive lung disease were prospectively included. EIT measurements were performed before and after surgery (in patients with flail chest, who had video-assisted thoracoscopic surgery with ribs fixation), or at two different levels of positive end-expiratory pressure (PEEP; ARDS patients), or two different time points (obstructive lung disease). Pendelluft was assessed by regional phase shift (defined as time difference between global and regional impedance-time curves) and amplitude differences (defined as the impedance difference between sum of all regional tidal variation and the global tidal variation).

Results: In patients with flail chest, pendelluft diminished several days after surgery (pendelluft amplitude normalized to tidal impedance variation reduced from 88% to 2% in one patient, 12% to 2% in the other). Increased PEEP reduced the amplitude of pendelluft (from 3% to 0% in one patient, 20% to 2% in the other) but not necessarily the phase shifts (average time differences were <0.1 second for both patients for both ins- and expiration) in ARDS patients. Pendelluft assessment in obstructive lung diseases reflected the change in airway resistance (from 5% to 1% in one patient after broncholytic medication administration, as airway resistance fell from 15 to 11 cmHO/L/s; from 9% to 35% in the other patient with acute exacerbation, the corresponding airway resistance increased from 15 to 22 cmHO/L/s).

Conclusions: The proposed EIT-based method can be used to evaluate the degree of pendelluft in dimension of phase shift and amplitude difference.
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http://dx.doi.org/10.21037/atm-20-4182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607126PMC
October 2020

The incidence, risk factors and prognosis of acute kidney injury in severe and critically ill patients with COVID-19 in mainland China: a retrospective study.

BMC Pulm Med 2020 Nov 9;20(1):290. Epub 2020 Nov 9.

Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: The clinical correlates, prognosis and determinants of acute kidney injury (AKI) in patients with coronavirus disease 2019 (Covid-19) remain largely unclear.

Methods: We retrospectively reviewed medical records of all adult patients with laboratory-confirmed Covid-19 who were admitted to the intensive care unit (ICU) between January 23rd 2020 and April 6th 2020 at Wuhan JinYinTan Hospital and The First Affiliated Hospital of Guangzhou Medical University.

Results: Among 210 patients, 131 were males (62.4%). The median Age was 64 years (IQR: 56-71). Of 92 (43.8%) patients who developed AKI during hospitalization, 13 (14.1%), 15 (16.3%) and 64 (69.6%) were classified as being at stage 1, 2 and 3, respectively. 54 patients (58.7%) received continuous renal replacement therapy. Age, sepsis, nephrotoxic drug, invasive mechanical ventilation and elevated baseline serum creatinine levels were associated with the occurrence of AKI. Renal recovery during hospitalization was identified among 16 patients with AKI (17.4%), who had a significantly shorter time from admission to AKI diagnosis, lower incidence of right heart failure and higher ratio of partial pressure of oxygen to the fraction of inspired oxygen. Of 210 patients, 93 deceased within 28 days of ICU admission. AKI stage 3, critical disease, greater Age and the lowest ratio of partial pressure of oxygen to the fraction of inspired oxygen being < 150 mmHg were independently associated with death.

Conclusions: Among patients with Covid-19, the incidence of AKI was high. Our findings of the risk factors of the development of AKI and factors associated with renal function recovery may inform clinical management of patients with critical illness of Covid-19.
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http://dx.doi.org/10.1186/s12890-020-01305-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649893PMC
November 2020

Association of hospital admission for bronchiectasis with air pollution: A province-wide time-series study in southern China.

Int J Hyg Environ Health 2021 Jan 3;231:113654. Epub 2020 Nov 3.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong Province, China. Electronic address:

The relation of acute fluctuations of air pollution to hospital admission for bronchiectasis remained uncertain, and large-scale studies were needed. We collected daily concentrations of particulate matter (PM), sulfur dioxide (SO), nitrogen dioxide (NO), carbon monoxide (CO), ozone (O), and daily hospitalizations for bronchiectasis for 21 cities across Guangdong Province from 2013 through 2017. We examined their association using two-stage time-series analysis. Our analysis was stratified by specific sub-diagnosis, sex and age group to assess potential effect modifications. Relative risks of hospitalization for bronchiectasis were 1.060 (95%CI 1.014-1.108) for PM at lag0-6, 1.067 (95%CI 1.020-1.116) for PM at lag0-6, 1.038 (95%CI 1.005-1.073) for PM at lag0-6, 1.058 (95%CI 1.015-1.103) for SO at lag0-4, 1.057 (95%CI 1.030-1.084) for NO at lag0 and 1.055 (95%CI 1.025-1.085) for CO at lag0-6 per interquartile range increase of air pollution. Specifically, acute fluctuations of air pollution might be a risk factor for bronchiectasis patients with lower respiratory infection but not with hemoptysis. Patients aged ≥65 years, and female patients appeared to be particularly susceptible to air pollution. Acute fluctuations of air pollution, particularly PM may increase the risk of hospital admission for bronchiectasis exacerbations, especially for the patients complicated with lower respiratory infection. This study strengthens the importance of reducing adverse impact on respiratory health of air pollution to protect vulnerable populations.
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http://dx.doi.org/10.1016/j.ijheh.2020.113654DOI Listing
January 2021

TB47 and clofazimine form a highly synergistic sterilizing block in a second-line regimen for tuberculosis in mice.

Biomed Pharmacother 2020 Nov 25;131:110782. Epub 2020 Sep 25.

State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; University of Chinese Academy of Sciences (UCAS), Beijing 100049, China. Electronic address:

Multidrug-resistant tuberculosis (MDR-TB) remains a serious public health threat worldwide. To date, the anti-TB activity of TB47 (T), an imidazopyridine amide class of antibiotics targeting QcrB in the electron transport chain, has not been systematically evaluated, especially in a new regimen against MDR-TB. This study employed both macrophage infection and a mouse model to test the activity of T alone or in combination with other antimicrobial agents. Different regimens containing amikacin (A), levofloxacin (L), ethambutol (E), and pyrazinamide (Z) + clofazimine (C)/T were evaluated in the mouse model. The bacterial burdens of mice from different groups were monitored at different time points while relapse was assessed 6 months after treatment cessation. Colonies obtained at relapse underwent drug susceptibility testing. We found that T exhibited highly synergistic bactericidal activity with C in all models. Adding T to ALEZC might shorten the MDR-TB treatment duration from ≥ 9 months to ≤ 5months, as five months of treatment with ALEZCT achieved zero relapse rates in 2 animal experiments. These findings indicate that T exhibits a highly synergistic sterilizing activity when combined with C. All isolates from relapsing mice remained sensitive to each drug, suggesting that the relapse was not due to drug resistance but rather associated with the type of regimen.
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http://dx.doi.org/10.1016/j.biopha.2020.110782DOI Listing
November 2020

Single inhaler triple therapy (FF/UMEC/VI) versus FF/VI and UMEC/VI in patients with COPD: subgroup analysis of the China cohort in the IMPACT trial.

Curr Med Res Opin 2021 Jan 7;37(1):145-155. Epub 2020 Dec 7.

GSK, Collegeville, PA, USA.

Objectives: Chronic obstructive pulmonary disease (COPD) is becoming a leading cause of morbidity and mortality in China. In the IMPACT trial, fluticasone furoate[FF]/umeclidinium[UMEC]/vilanterol[VI] single-inhaler triple therapy demonstrated lower rates of moderate/severe exacerbations than dual therapy with FF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations. This analysis investigates the China cohort and its consistency with the overall ITT population.

Methods: 10,355 patients were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg for 52 weeks. Endpoints included: annual rates of exacerbations, time-to-first on-treatment moderate/severe exacerbation and change from baseline in trough forced expiratory volume in 1 s (FEV) at Week-52. Clinical trial registration is NCT02164513 (CTT116855).

Results: 535 patients (5.2%) were from China. Annual on-treatment moderate/severe exacerbation rate was 0.81 with FF/UMEC/VI versus 0.96 with FF/VI (rate ratio: 0.84; 95% confidence interval [CI]: 0.64, 1.11;  = .227) and 0.80 with UMEC/VI (rate ratio: 1.02; 95% CI: 0.72, 1.44;  = .929). Hazard ratio for time-to-first moderate/severe exacerbation was 0.84 (95% CI: 0.63, 1.11;  = .218) for FF/UMEC/VI versus FF/VI and 0.89 (95% CI: 0.62, 1.27;  = .516) versus UMEC/VI. Significant improvements in mean change from baseline in trough FEV were observed for FF/UMEC/VI versus FF/VI (treatment difference 137 mL; 95% CI: 86, 188;  < .001) and UMEC/VI (63 mL; 0, 125;  = .050). Health status was improved with FF/UMEC/VI versus both dual therapies. Results were similar to the overall ITT population. No new safety signals were identified.

Conclusions: Single-inhaler triple therapy with FF/UMEC/VI versus FF/VI or UMEC/VI reduced the rate and risk of exacerbations, and improved lung function and health status in the China cohort similar to the overall ITT population. No new safety signals were identified.
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http://dx.doi.org/10.1080/03007995.2020.1844646DOI Listing
January 2021