Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020)

Background: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research.Methods: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion.Results: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder.Conclusions: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.</p

Clinicopathological Correlation of <i>MAML2</i> Rearrangement in PMECs.

<p>Abbreviations: MAML2, mastermind-like gene 2; PMECs, pulmonary mucoepidermoid carcinomas; TNM, tumor-nodal-metastasis; LN, lymph node.</p

Immunostaining for FLT1, HES1 and NR4A2 in pulmonary mucoepidermoid carcinomas (400×).

<p><i>A–C</i>, Immnostaining for FLT1 in low (<i>A</i>), intermediate (<i>B</i>) and high (<i>C</i>) grades of tumors. <i>D–F</i>, Immnostaining for HES1 in low (<i>D</i>), intermediate (<i>E</i>) and high (<i>F</i>) grade tumors. <i>G–I</i>, Immnostaining for NR4A2 in low (<i>G</i>), intermediate (<i>H</i>) and high (<i>I</i>) grade tumors.</p

Kaplan-Meier curves for overall survival (OS) and disease-free survival (DFS) in patients with pulmonary mucoepidermoid carcinoma.

<p><i>A–B</i>, OS (<i>A</i>) and DFS (<i>B</i>) for the <i>MAML2</i> rearrangement. <i>C–D</i>, OS (<i>C</i>) and DFS (<i>D</i>) for the immunoreactivity of FLT1.</p

Prognostic Factors for Survival in Multivariate Analysis.

<p>Abbreviations: TNM, tumor-nodal-metastasis; LN, lymph node.</p

FISH analysis for <i>MAML2</i> gene.

<p>Arrows indicate spit signals showing the rearrangement of <i>MAML2</i>. <i>A</i>, Case of pulmonary mucoepidermoid carcinoma. <i>B</i>, Case of adenosquamous carcinoma.</p

Table_1_Development of an autoantibody panel for early detection of lung cancer in the Chinese population.DOCX

IntroductionTumor-associated autoantibodies have been revealed as promising biomarkers for the early detection of lung cancer. This study was designed to develop an autoantibody panel for early detection of lung cancer in the Chinese population.MethodsRecruited prospectively in three clinical centers, the subjects (n = 991) who had a definite diagnosis during follow-up were included in the development of the autoantibody panel. The levels of 14 autoantibody candidates in plasma were detected.ResultsA panel of nine autoantibody markers (named as CN9), namely, P53, SOX2, SSX1, HuD, NY-ESO-1, CAGE, MAGE-A4, P62, and CK20, was preferably selected from 14 candidates. The overall specificity, sensitivity, and AUC were 90.5%, 40.8%, and 0.64, respectively. The CN9 panel demonstrated a reasonable detection rate in lung cancer patients at all stages, histological types, sizes of lesions, and risk levels. Its estimated overall accuracy is 85.5% and 90%, with PPV at 0.32 and 0.04, and NPV at 0.93 and 0.99 in the scenario of pulmonary nodules' characterizing and lung cancer screening, respectively. Two risk models were developed within the subgroups of malignant and benign pulmonary nodules in this study. By adding the CN9 result to the Mayo model indicators, it achieved a sensitivity of 41.3% and an AUC of 0.74 at a specificity of 91.3%. By adding the CN9 result to the Brock model indicators, it achieved a sensitivity of 47.7% and an AUC of 0.78 at a specificity of 91.3%. Both were improved compared with either the standalone Mayo or Brock model.DiscussionThis multi-center prospective study indicates a panel of nine autoantibody markers that can help in the detection of lung cancer and the classification of pulmonary nodules in the Chinese population.</p

Co-treatment reduced DDP sensitivity in a p53-dependent manner.

<p>(A) The p53, p21 and pRb in lysates made from A549 and H292 cells was determined by Western-blot, equivalent protein loading between lanes was confirmed by Western analysis of GAPDH levels. (B) Changes of mRNA expression levels of p53 after DDP treatment in the presence or absence of DEX were detected by quantitative real time PCR. Fold changes were calculated from β-actin normalized Ct values. (C) Cells were transiently transfected with p53 promoter-luciferase reporter plasmid. The luciferase activity in whole cell lysates was determined 24 hours post-transfection. Data shown are mean (± standard error of mean) of the ratio firefly luciferase activity over renilla luciferase activity and normalized to the ratio of vehicle group. (D) A549 and H292 cells transfected with a p53 expression vector (pcDNA3.1-/p53) were treated with DDP in the presence or absence of DEX. SA-β-gal activity was analyzed by microscopy at day 3 after drug wash. Percentage of SA-β-gal cells was presented in the histogram. (E) H1299 (p53 deficient type) cells were used to detect whether DDP insensitivity occurred in p53 dependent manner by CCK-8 assay using various doses of DDP (0 µM, 1 µM, 2 µM, 4 µM, 8 µM, 16 µM, 32 µM, 64 µM, 128 µM). The p53 statuses were confirmed by examining p21^CIP1 and hdm2 expressions. (F) SA-β-Gal activity was detected in H1299 cells treated with DDP in the presence or absence of DEX. (G) The effect of siRNAs designed against p53 was measured by western-blot in A549 cells. SA-β-Gal activity was detected and analyzed. Data represent means of six determinations ± standard error of mean (SEM). *<i>p</i><0.05 and **<i>p</i><0.01 analyzed by one-way analysis of variance (ANOVA).</p

DEX protected cell survival in response to cytotoxic drugs in non-small cell lung cancer cells.

<p>(A) The detection of IC50 by CCK-8 assay. NSCLC cell lines were cultured in a medium containing various doses of DDP (0 µM, 1 µM, 2 µM, 4 µM, 8 µM, 16 µM, 32 µM, 64 µM, 128 µM) as indicated in the absence or presence of 1 µM DEX for two days, and then the viability of cells was monitored. (B) Cell viability assay in response to the indicated DDP concentrations (0 M, 5×10⁻⁷ M, 1×10⁻⁶ M, 2×10⁻⁶ M, 4×10⁻⁶ M and 8×10⁻⁶ M) was measured by CCK-8 assay for 5 days, including 2 days of DDP treatment and 3 additional days of drug free medium incubation. (C) Representative fluorescence microscopic images of A549 and H292 cells after TUNEL assay (left) and quantitative analysis of apoptosis (right). (D) The detection of increased percentage of total cell numbers by Cell-IQ and CCK-8. Total cell numbers of A549 and H292 were measured 72 hours after cultured with different drugs. (E) BrdU incorporation of A549 and H292 cells. BrdU was incubated for 24 hours, and then cells were fixed and detected with BrdU. For quantity analysis of BrdU incorporation, relative OD values were assayed compared with vehicle group. (F) Western blot analysis showed PCNA protein levels in A549 and H292 cells and quantitative data of PCNA protein levels. Data represent means of six determinations ± standard error of mean (SEM). *<i>p</i><0.05 and **<i>p</i><0.01 analyzed by one-way analysis of variance (ANOVA).</p

DEX co-treatment reduced DDP sensitivity <i>in vivo</i>.

<p>(A) The tumors in the nude mice (n = 15 in each group). A549 and H292 cells were subcutaneously injected into nude mice and tumors were harvested 6 weeks after treatment. (B) Tumor volume was measured weekly with a caliper and tumor volume (cm³) calculated. Tumor growth was significantly increased in DEX cotreatment group compared with DDP alone group. (C) For 42 days post-inoculation, mouse survival was monitored daily. Survival data were plotted on a Kaplan-Meier curve. Co-treatment with DEX significantly decreased survival when compared to DDP alone group. (D) Frozen sections were stained for SA-β-gal (blue) and paraffin sections were stained for p53 and NF-κB p65. (E) Correlation analysis between SA-β-gal and p53, NF-κB p65 expression in tumor of nude mice. (F) Representative SA-β-gal staining and immunohistochemistry p53 and NF-κB p65 staining (20×) in human lung tumor tissue. (G) Correlation analysis between SA-β-gal and p53, NF-κB p65 expression in NSCLC tissue. Data represent means of six determinations ± standard error of mean (SEM). *<i>p</i><0.05 and **<i>p</i><0.01 analyzed by one-way analysis of variance (ANOVA).</p