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PURPOSE: To summarize the clinical features and effective therapy of severe COVID-19 patients PATIENTS AND METHODS: In this retrospective, multicenter study, the medical records of COVID-19 patients in Hunan, from January 21, 2020 to February 19, 2020 were reviewed RESULTS: Of the 350 COVID-19 patients, 13 7% were severe cases On admission, compared with non-severe patients, more severe patients had a neutrophil/lymphocyte ratio > 3 (58 3% vs 33 8%, P=0 001), D-dimer > 1 mg/L (41 7% vs 13 6%, P

Background. Metagenomic next-generation sequencing (mNGS) has made a revolution in the mode of pathogen identification. We decided to explore the diagnostic value of blood and bronchoalveolar lavage fluid (BALF) as mNGS samples in pneumonia. Methods. We retrospectively reviewed 467 mNGS results and assessed the diagnostic performance of paired blood and BALF mNGS in 39 patients with pneumonia. Results. For bacteria and fungi, 16 patients had culture-confirmed pathogen diagnosis, while 13 patients were culture-negative. BALF mNGS was more sensitive than blood mNGS (81.3% vs. 25.0%, p=0.003), and the specificity in BALF and blood mNGS was not statistically significant different (76.9% vs. 84.6%, p=0.317). For 10 patients without culture test, treatments were changed in 2 patients. For viruses, Epstein-Barr virus was positive in blood mNGS in 9 patients. Human adenovirus was detected in both BALF and blood mNGS in 3 patients. Conclusion. Our study suggests that BALF mNGS is more sensitive than blood mNGS in detecting bacteria and fungi, but blood also has advantages to identify the pathogens of pneumonia, especially for some viruses.

Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.

In children, Langerhans cell histiocytosis (LCH), which is the most prevalent histiocytic disorder, exhibits a wide variety of manifestations and outcomes. There is no standard prognosis evaluation system for LCH. We investigated the combined predictive significance of complete blood counts (CBCs),A cohort of 71 childhood LCH patients was retrospectively studied. The prognosis predictive significance of platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), systemic inflammation response index (SIRI), systemic immune inflammation index (SII),Histiocyte Society (HS) classification of LCH patients was correlated with NLR, SIRI, and progression free survival (PFS), bone involvement was correlated with SIRI, liver involvement was correlated with NLR, SII, SIRI, and PFS, spleen involvement was correlated with SIRI, lung involvement was correlated with NLR and PFS, CNS involvement was correlated with PFS, whileThe risk model combined with CBCs

Objectives. The efficacy of conventional treatments plus acupuncture for asthma in adult and adolescent is uncertain. Literature reports are conflicting; therefore, the aim of this study was to determine the efficacy of conventional treatments plus acupuncture versus conventional treatments alone using a meta-analysis of all published randomized clinical trials (RCTs).Methods. Two reviewers independently performed a comprehensive literature search from multiple electronic sources (1990–2018), including PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WanFang databases. RCTs in which adult and adolescent patients with asthma (age ≥12 years) were divided into conventional treatments plus acupuncture and conventional treatments alone were included.Results. Nine studies were included. The results showed that conventional treatments plus acupuncture as a complementary therapy could improve the symptom response rate (OR = 7.87, 95% CI = [4.13, 14.99], p < 0.00001) and significantly decrease interleukin-6 (IL-6) levels (MD = -11.42; 95% CI = [-15.28, -7.56], p < 0.00001). However, indices of pulmonary function, including the forced expiratory volume in one second (FEV1) (MD = 0.22, 95% CI = [-0.11, 0.56], p = 0.19) and FEV1/forced vital capacity (FVC) (MD = 8.62, 95% CI = [-0.35, 17.59], p = 0.06), failed to be improved with conventional treatments plus acupuncture.Conclusion. Conventional treatments plus acupuncture are associated with significant benefits for adult and adolescent patients with asthma. Therefore, we suggest the use of conventional treatments plus acupuncture for asthma patients.

Cardiac involvement has been reported in patients with COVID-19, which may be reflected by electrocardiographic (ECG) changes. Two COVID-19 cases in our report exhibited different ECG manifestations as the disease caused deterioration. The first case presented temporary SIQIIITIII morphology followed by reversible nearly complete atrioventricular block, and the second demonstrated ST-segment elevation accompanied by multifocal ventricular tachycardia. The underlying mechanisms of these ECG abnormalities in the severe stage of COVID-19 may be attributed to hypoxia and inflammatory damage incurred by the virus.

BackgroundCoronavirus disease 2019 (COVID-19) has developed into a worldwide pandemic. This study aimed to retrospectively describe the use of corticosteroids in treating COVID-19.MethodsFor this multicenter retrospective study, medical records from 488 symptomatic COVID-19 patients were reviewed. Patients were divided into severe and nonsevere groups. Baseline characteristics, signs and symptoms, laboratory findings, treatments, and disease outcomes were compared. Specific data for corticosteroid treatment were further analyzed.ResultsFour hundred fifty COVID-19 patients were included in this study, including 82 severe patients and 368 nonsevere cases. Out of the 450 patients, 126 (28.0%) received corticosteroid treatment. In the 126 patients treated with corticosteroids, the median daily dose of corticosteroid therapy was 56.6 [interquartile range (IQR): 40.0–78.4] mg and median corticosteroid therapy duration was 5.0 (IQR: 3.0–7.0) days. Among nonsevere cases, patients treated with corticosteroids were significantly older in comparison with patients who did not receive corticosteroid treatment (p0.05).ConclusionOur study indicates that corticosteroids are regarded as one of treatments in the general clinical practice of COVID-19. However, corticosteroid use may be accompanied by increased use of antibiotics, longer hospitalization, and prolonged viral shedding.

Tracheobronchopathia osteochondroplastica (TBO) is a rare disease with unknown etiology characterized by ossifying nodules in the trachea and bronchial walls without involvement of the posterior wall of trachea. A 35-year-old woman admitted to Second Xiangya Hospital, Central South University, in August 2018 was diagnosed as TBO. She complained of dyspnea for over two years, worsening in autumn and winter, and was detected with tracheal ossification via bronchoscopy and biopsy. The patient received no special treatment, and no improvement or deterioration of symptoms was observed during the 3-month follow-up. We reviewed 60 TBO cases and found that 60% of them were female, with ages of 20-80 (53.62±15.97) years. The involved lesion sites were from the vocal cords to the bronchial segments, mainly in the trachea and bilateral main trachea, and the lower part of the trachea was more common. Combined respiratory symptoms were common. The diagnosis mainly depends on bronchoscopy and biopsy. Symptomatic treatment is the main strategy for symptomatic TBO patients, including endoscopic intervention and surgery. It is generally believed that the short-term prognosis of TBO is good, but the long-term prognosis still needs to be further studied.骨化性气管支气管病(tracheobronchopathia osteochondroplastica，TBO)是一种罕见、病因未明的疾病，以气管和支气管管壁出现骨化结节而不累及后壁为特点。2018年8月中南大学湘雅二医院收治了1例35岁的女性TBO患者，其主诉为呼吸困难2年余，秋冬更甚，支气管镜检及活检病理检查可见气管骨化。患者未接受特殊治疗，随访3个月，症状无好转或恶化。回顾已有发表的60例TBO病例报道发现：TBO患者60%为女性，年龄20~80(53.62±15.97)岁，病变累及范围从声带至段支气管，主要在气管和双侧主气管，气管下部更常见。以组合性呼吸道症状多见。诊断主要依靠支气管镜检及病理活检。治疗上，对于有症状的TBO患者主要给予对症治疗，包括内镜下治疗及外科手术。一般认为TBO近期预后良好，远期预后仍需进一步研究。.

Background: The rapid spreading of coronavirus disease 2019 (COVID-19) is an emerging threat to the global public health. Optimal treatment for severe COVID-19 pneumonia is extremely urgent. We conducted this study to evaluate the safety, feasibility and effect of pulmonary rehabilitation (PR) intervention in the treatment of patients with severe or critically severe COVID-19 pneumonia. Methods: In this retrospective study, 43 patients with severe or critically severe COVID-19 pneumonia were included and divided into conserved intervention group (C-I group) and advanced intervention group (A-I group) according to the initiation time of PR intervention. The PR intervention includes education, respiratory rehabilitation, physical training, psychological counseling and nutrition management. Oxygenation Index (OI), blood d-dimer level, lymphocyte count and other laboratory findings were recorded. Findings: The median age of 43 patients was 54 years (range 21 to 75 years); of them, 11 (25.6%) were 65 or older. 24 (55.8%) were male. All patients safely finished a certain course of pulmonary rehabilitation training. The OI could increase to moderate level (>300mmHg) during ICU treatment, and the A-I group showed a faster trend. The time of OI increased to moderate level was significantly shorter than that in C-I group (p=0.02). Lymphocytopenia occurred in 35 patients. The time of lymphocytopenia recovery was shorter in A-I group than that in C-I group. 25 patients had elevated blood d-dimer level during ICU stay. Only one DVT case was found in C-I group by ultrasound examination, no significant differences were found. Interpretation: With good safety and feasibility, pulmonary rehabilitation intervention can bring benefits in the treatment of patients with severe or critically severe COVID-19 pneumonia. Funding Statement: This study was funded by the Emergency Project of Prevention and Control for COVID-19 of Central South University, No. 502701002. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study protocol was approved by the institutional ethics committee of the First Hospital of Changsha (KL-2020005) and the Second Xiangya Hospital of Central South University (2020-010), and informed consent was waived because of the retrospective design.

The lack of circulating epinephrine (EPI) in the pathogenesis of asthma has long been attributed to the lack of adrenergic nerves in human airways. However, in this study we considered that EPI levels are regulated by EPI release in addition to synthesis. Nicotinic acetylcholine receptors (nAChRs) have been shown to control EPI release, and we hypothesized that redistribution of nAChR subunits modulates EPI release and circulating EPI levels. Using a mouse model of asthma, circulating EPI levels were measured by enzyme-linked immunosorbent assays. Changes in the expression of nAChR subunits in the adrenal medulla were observed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Expression of phenylethanolamine N-methyltransferase, tyrosine hydroxylase and galanin was detected by RT-qPCR. Lung pathology, airway resistance (RL) and EPI levels were also assessed after treatment with an α7 nAChR agonist or antagonist. α7 nAChR mRNA expression in the adrenal medulla was increased by more than 2-fold (P

To explore the effect of double-stranded RNA-dependent kinase (PKR) in acute lung injury (ALI) and resultant acute respiratory distress syndrome (ARDS). A mouse model of lipopolysaccharide (LPS)-induced ALI was used to evaluate the levels of phosphorylated (p)-PKR and NLRP3 in lung tissue, and the protective effects of a PKR inhibitor on lung injury. And in vitro, macrophages were incubated with LPS, with or without PKR inhibitor pre-treatment. It was observed that the levels of p-PKR protein and NLRP3 protein were significantly increased compared with those in control tissues after LPS administration. Meanwhile, treatment with PKR inhibitor decreased inflammation, injury score, wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein levels, neutrophil count in BALF, myeloperoxidase activity and expression of high-mobility group box1(HMGB1) and interleukin(IL)-1β in the lungs of LPS-challenged mice. In vitro, we demonstrated that the levels of p-PKR and NLRP3, and cell mortality rate were increased in macrophages which were incubated with LPS compared with those without LPS administration, and PKR inhibitor significantly suppressed the level of NLRP3, caspase-1, HMGB1 and IL-1β. These results indicate that PKR plays a key role in ALI through NLRP3-pyrotosis pathway and pharmacological inhibition of PKR may have potential therapeutic effects in the treatment of patients with ALI and ARDS.

Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is downregulated in the airway epithelium of asthma patients. Specific ITGB4 deficiency in AECs induces exaggerated Th2 responses, severe allergen-induced airway inflammation and airway hyperresponsiveness (AHR) in mouse model of allergic asthma. However, the underlying mechanisms remain unexplored. In this study, we determine the role of ITGB4 of AECs in the regulation of Th2 response and in the induction of asthma and identify the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated Th2 cells infiltration, inflammation and AHR and higher production of CCL17 in HDM treated mice. ITGB4-regulated CCL17 production in AECs was regulated by EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 by antibody inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated that ITGB4 of AECs negatively regulates the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway.

Nerve growth factor (NGF) and dendritic cells (DCs) have been hypothesized to modulate T cell responses in a mouse model of asthma. However, whether NGF plays a role in regulating the maturation and polarization of lung DCs remains unclear. In the present study, the effect of NGF inhibition on the maturation and phenotype of lung DCs was investigated in a mouse model of asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and subsequently received anti-NGF treatment. At 24 h following the last challenge, airway responsiveness and inflammation were examined. The concentrations of NGF, interferon (IFN)-γ and interleukin (IL)-4 were analyzed. In addition, maturation and CD103 expression in the lung DCs were investigated. Anti-NGF treatment was found to significantly reduce airway hyperreactivity and inflammation in asthmatic mice. In addition, a subdued T helper 2 (Th2) response was observed, characterized by the downregulation of IL-4 and the upregulation of IFN-γ. Furthermore, the expression of the DC surface molecules, CD80, CD86 and major histocompatibility complex class II, as well as the proportion of lung CD103+ DCs, decreased in the OVA-sensitized and challenged mice. The proportion of lung CD103+ DCs also exhibited a positive correlation with the levels of plasma NGF in the mice. These results may provide an explanation for the role of NGF in amplifying the Th2 response in allergic diseases. Therefore, NGF may promote the maturation and polarization towards a Th2-stimulating phenotype of activated DCs, contributing to an amplification of the Th2 response in asthma.

Exercise is one of the most common triggers of bronchoconstriction in patients with asthma. The low levels of circulating epinephrine produced by the adrenal medullary chromaffin cells (AMCCs) are associated with exercise-induced bronchoconstriction (EIB) in asthmatics. In the present study, we tested the hypothesis that low-intensity aerobic exercise may ameliorate EIB using a rat model of asthma. Male Sprague-Dawley rats at 7 weeks of age, sensitized with ovalbumin or treated with saline, were subjected to low or moderate exercise training (50 or 75% of maximum velocity) for one hour in a treadmill 30 min after ovalbumin or saline inhalation. The exercise capacity, airway responsiveness, lung morphology, the morphological changes and endocrine function of AMCCs were measured in both groups of rats after exercise training for 6 weeks. Either low-intensity or moderate-intensity exercise mitigated EIB and increased exercise capacity in ovalbumin-sensitized (asthmatic) rats. Low-intensity aerobic exercise reduced the vacuolar degeneration degrees, lipid contents, neuronal peripherin and neurofilament-68 expression, demolished neurites, but increased the chromaffin granule density, endocrine chromogranin A and phenylethanolamine N-methyltransferase expression in the adrenal medullary tissues, accompanied by increased levels of circulating epinephrine and corticosterone, but decreased nerve growth factor in asthmatic rats. Finally, low-intensity aerobic exercise significantly reduced the relative levels of phosphorylated extracellular signal-regulated kinase and phosphorylated cAMP responsive element-binding protein and the relative mRNA expression levels of downstream molecules, including c-FOS and c-JUN in the adrenal medullary of asthmatic rats. We suggest that low-intensity aerobic exercise improves the endocrine dysfunction of AMCCs and mitigates EIB.

A high prevalence of exercise-induced bronchoconstriction (EIB) can be found in elite athletes, but the underlying mechanisms remain elusive. Airway responsiveness, NGF and epinephrine (EPI) levels, and chromaffin cell structure in high- (HiTr) and moderate-intensity training (MoTr) rats with or without ovalbumin (OVA) sensitization were measured in a total of 120 male Sprague-Dawley rats. The expression of NGF-associated genes in rat adrenal medulla was tested. Both HiTr and OVA intervention significantly increased airway resistance to aerosolized methacholine measured by whole body plethysmography. HiTr significantly increased inflammatory reaction in the lung with a major increase in peribronchial lymphocyte infiltration, whereas OVA significantly increased the infiltration of various inflammatory cells with an over 10-fold increase in eosinophil level in bronchoalveolar lavage. Both HiTr and OVA intervention upregulated circulating NGF level and peripherin level in adrenal medulla, but downregulated phenylethanolamine N-methyl transferase level in adrenal medulla and circulating EPI level. HiTr + OVA and HiTr + ExhEx (exhaustive exercise) interventions significantly enhanced most of the HiTr effects. The elevated NGF level was significantly associated with neuronal conversion of adrenal medulla chromaffin cells (AMCC). The levels of p-Erk1/2, JMJD3, and Mash1 were significantly increased, but the levels of p-p38 and p-JNK were significantly decreased in adrenal medulla in HiTr and OVA rats. Injection of NGF antiserum and moderate-intensity training reversed these changes observed in HiTr and/or OVA rats. Our study suggests that NGF may play a vital role in the pathogenesis of EIB by inducing neuron transdifferentiation of AMCC via MAPK pathways and subsequently decreasing circulating EPI.

Previously, we demonstrated that pyroptosis in alveolar macrophages (AMs) plays an essential role in lipopolysaccharide (LPS)-induced acute lung injury. However, the underlying mechanism remains largely unclear. Here, we show that the absence of interferon regulatory factor 1 (IRF-1) in genetic knock-out mice strongly abrogates pyroptosis in AMs and alleviates the LPS-induced lung injury and systemic inflammation. Our study demonstrates that IRF-1 contributes to caspase-1 activation and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain pyroptosome formation in AMs and leads to downstream inflammatory cytokine release, including that of IL-1β, IL-18, and HMGB1. The nuclear translocation of IRF-1 is linked to the presence of toll-like receptor 4 (TLR4). Our findings suggest that pyroptosis and the downstream inflammatory response in AMs induced by LPS is a process that is dependent on TLR4-mediated up-regulation of IRF-1. In summary, IRF-1 plays a key role in controlling caspase-1-dependent pyroptosis and inflammation.

To elucidate intracellular transcription factor activation of C(7) approximately T(5) dorsal root ganglia in rats recurrently infected with respiratory syncytial virus (RSV).Eighty 1 approximately 2 weeks old Sprague-Dawley rats were randomly divided into 2 groups: a control group and a RSV-infection group. The rats in the RSV-infection group were infected with 5 x 10(5) U/mL RSV once a week and the rats in the control group were treated with culture medium without RSV. Airway response was measured after 8 weeks. Lung tissue was submitted for HE staining and in situ hybridization. The C(7) approximately T(5) dorsal root ganglia were obtained for the preliminary screening of the intracellular transcription factors by TranSignal protein/DNA combo array. Nuclear protein of C(7) approximately T(5) dorsal root ganglia were extracted and submitted to Western blot.Airway response in the RSV-infection group was higher than that in the control group (P0.05). HE staining showed inflammatory cell infiltration, and in situ hybridization demonstrated positive RSV RNA in the RSV-infection rat lung which was not present in the control group, thus validating the efficacy of our model. TranSignal protein/DNA combo array screening showed that 55 transcription factors increased by at least 2 folds in the C(7) approximately T(5) DRG cells of the RSV-infection group. The transcription factors Smad and interferon regulatory factor (1 or 2) were the 2 most upregulated transcription factors identified by combo array screening (59 and 43 fold increase compared with the control, respectively). Western blot confirmed Smad(1/2/3) and IRF-1 upregulate while IRF-2 remained unchanged.Respiratory syncytial virus infection results in airway hyperresponsiveness and transcription factor activation in C(7) approximately T(5) spinal adorsal root ganglia in rats, which may contribute to airway nerve network dysfunction and airway hyperresponsiveness.