Modulation of alveolar macrophage and mitochondrial fitness by medicinal plant-derived nanovesicles to mitigate acute lung injury and viral pneumonia.

Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.

Integrated serum pharmacochemistry and investigation of the anti-influenza A virus pneumonia effect of Qingjin Huatan decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingjin Huatan Decoction (QJHTT) consists of 11 herbal medicines: Scutellaria baicalensis Georgi, Gardenia jasminoides J. Ellis, Platycodon grandiflorus (Jacq.) A. DC., Ophiopogon japonicus (Thunb.) Ker Gawl., Morus alba L., Fritillaria thunbergii Miq., Anemarrhena asphodeloides Bunge, Trichosanthes kirilowii Maxim., Citrus reticulata Blanco, Poria cocos (Schw.) Wolf, and Glycyrrhiza uralensis Fisch. As a traditional Chinese medicinal formula, QJHTT has been used for more than 400 years in China. It has shown promising results in treating influenza A virus (IAV) pneumonia. AIM OF THE STUDY: To elusive the specific pharmacological constituents and mechanisms underlying its anti-IAV pneumonia effects. MATERIALS AND METHODS: The components in QJHTT were analyzed through the use of a serum pharmacology-based ultra high-performance liquid chromatography Q- Exactive Orbitrap mass spectrometry (UHPLC-Q Exactive Orbitrap-MS) method. Simultaneously, the dynamic changes in IAV-infected mouse lung viral load, lung index, and expression of lung inflammation factors were monitored by qRT-PCR. RESULTS: We successfully identified 152 chemical components within QJHTT, along with 59 absorbed chemical prototype constituents found in the serum of mice treated with QJHTT. 43.45% of these chemical components and 43.10% of the prototype constituents were derived from the monarch drugs, namely Huangqin and Zhizi, aligning perfectly with traditional Chinese medicine theory. Notably, our analysis led to the discovery of 14 compounds within QJHTT for the first time, three of which were absorbed into the bloodstream. Simultaneously, we observed that QJHTT not only reduced the viral load but also modulated the expression of inflammation factors in the lung tissue including TNF-α, IL-1ß, IL-4, IL-6, IFN-γ, and IL17A. A time-effect analysis further revealed that QJHTT intervention effectively suppressed the peak of inflammatory responses, demonstrating a robust anti-IAV pneumonia effect. CONCLUSIONS: We comprehensively analyzed the pharmacological material basis of QJHTT by a highly sensitive and high-resolution UHPLC-Q Exactive Orbitrap-MS method, and demonstrated its efficacy in combating IAV pneumonia by reducing lung viral load and inflammatory factors. This study has significant importance for elucidating the pharmacological basis and pharmacological mechanism of QJHTT in combating IAV pneumonia.

Therapeutic high-dose vitamin D for vitamin D-deficient severe COVID-19 disease: randomized, double-blind, placebo-controlled study (SHADE-S).

BACKGROUND: efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied. OBJECTIVE: effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19. METHODS: participants with moderate to severe COVID-19 with PaO2/FiO2 ratio < 200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo. OUTCOMES: primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality. RESULTS: in all, 90 patients (45 each group) were included for intention-to-treat analysis. 25(OH)D3 levels were 12 (10-16) and 13 (12-18) ng/ml (P = 0.06) at baseline; and 60 (55-65) ng/ml and 4 (1-7) ng/ml by Day 7 in vitamin D and placebo groups, respectively. The SOFA score on Day 7 was better in the vitamin D group [3 (95% CI, 2-5) versus 5 (95% CI, 3-7), P = 0.01, intergroup difference - 2 (95% CI, -4 to -0.01); r = 0.4]. A lower all-cause 28-day mortality [24% compared to 44% (P = 0.046)] was observed with vitamin D. CONCLUSIONS: single high-dose oral cholecalciferol supplementation on ICU admission can improve SOFA score at Day 7 and reduce in-hospital mortality in vitamin D-deficient COVID-19. ClinicalTrials.gov  id: NCT04952857 registered dated 7 July 2021. What is already known on this topic-vitamin D has immunomodulatory role. Observational and isolated intervention studies show some benefit in COVID-19. Targeted therapeutic vitamin D supplementation improve outcomes in severe COVID-19 is not studied in RCTs. What this study adds-high-dose vitamin D supplementation (0.6 Million IU) to increase 25(OH)D > 50 ng/ml is safe and reduces sequential organ failure assessment score, in-hospital mortality in moderate to severe COVID-19. How this study might affect research, practice or policy-vitamin D supplementation in vitamin D-deficient patients with severe COVID-19 is useful may be practiced.

Prediction of viral pneumonia based on machine learning models analyzing pulmonary inflammation index scores.

OBJECT: To obtain Pulmonary Inflammation Index scores from imaging chest CT and combine it with clinical correlates of viral pneumonia to predict the risk and severity of viral pneumonia using a computer learning model. METHODS: All patients with suspected viral pneumonia on CT examination admitted to The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University from December 2022 to March 2023 were retrospectively selected. The respiratory viruses were monitored by RT-PCR and categorized into patients with viral pneumonia and those with non-viral pneumonia. The extent of lung inflammation was quantified according to the Pulmonary Inflammation Index score (PII). Information on patient demographics, comorbidities, laboratory tests, pathogenetic testing, and radiological data were collected. Five machine learning models containing Random Forest(RF), Radial Basis Function Neural Network (RBFNN), Support Vector Machine (SVM), K Nearest Neighbour Algorithm (KNN), and Kernel Ridge Regression (KRR) were used to predict the risk of onset and severity of viral pneumonia based on the clinically relevant factors or PII. RESULTS: Among the five models, the SVM model performed best in ACC (76.75 %), SN (73.99 %), and F1 (72.42 %) and achieved a better area under the receiver operating characteristic curve (ROC) (0.8409) when predicting the risk of developing viral pneumonia. RF had the best overall classification accuracy in predicting the severity of viral pneumonia, especially in predicting pneumonia with a PII classification of grade I, the RF model achieved an accuracy of 98.89%. CONCLUSION: Machine learning models are valuable in assessing the risk of viral pneumonia. Meanwhile, machine learning models confirm the importance in predicting the severity of viral pneumonia through PII. The establishment of machine learning models for predicting the risk and severity of viral pneumonia promotes the further development of machine learning in the medical field.

Flavonoid substituted polysaccharides from Tamarix chinensis Lour. alleviate H1N1-induced acute lung injury via inhibiting complement system.

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is a highly pathogenic respiratory infectious disease associated with excessive activation of the complement system. Our previous studies found that the anticomplement polysaccharides from some medicinal plants could significantly alleviate H1N1-induced acute lung injury (H1N1-ALI). The leaves and twigs of Tamarix chinensis Lour. are traditionally used as a Chinese medicine Xiheliu for treating inflammatory disorders. Interestingly, its crude polysaccharides (MBAP90) showed potent anticomplement activity in vitro. AIM OF THE STUDY: To evaluate the therapeutic effects and possible mechanism of MBAP90 on viral pneumonia and further isolate and characterize the key active substance of MBAP90. MATERIALS AND METHODS: The protective effects of MBAP90 were evaluated by survival tests and pharmacodynamic experiments on H1N1-ALI mice. Histopathological changes, viral load, inflammatory markers, and complement deposition in lungs were analyzed by H&E staining, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. An anticomplement homogenous polysaccharide (MBAP-3) was obtained from MBAP90 by bio-guided separation, and its structure was further characterized by methylation analysis and NMR spectroscopy. RESULTS: Oral administration of MBAP90 at a dose of 400 mg/kg significantly increased the survival rate of mice infected with the lethal H1N1 virus. In H1N1-induced ALI, mice treated with MBAP90 (200 and 400 mg/kg) could decrease the lung index, lung pathological injury, the levels of excessive proinflammatory cytokines (IL-6, TNF-α, MCP-1, IL-18, and IL-1ß), and complement levels (C3c and C5b-9). In addition, MBAP-3 was characterized as a novel homogenous polysaccharide with potent in vitro anticomplement activity (CH50: 0.126 ± 0.002 mg/mL), containing 10.51% uronic acids and 9.67% flavonoids, which were similar to the composition of MBAP90. The backbone of MBAP-3 consisted of →4)-α-D-Glcp-(1→, →3,4,6)-α-D-Glcp-(1→, and →3,4)-α-D-Glcp-(1→, with branches comprising α-L-Araf-(1→, α-D-GlcpA-(1→, →4,6)-α-D-Manp-(1→ and →4)-ß-D-Galp-(1 â†’ . Particularly, O-6 of →4)-ß-D-Galp-(1→ was conjugated with a flavonoid, myricetin. CONCLUSIONS: MBAP90 could ameliorate H1N1-ALI by inhibiting inflammation and over-activation of the complement system. These polysaccharides (MBAP90 and MBAP-3) with relative high contents of uronic acid and flavonoid substituent might be vital components of T. chinensis for treating viral pneumonia.

Phillyrin ameliorates influenza a virus-induced pulmonary inflammation by antagonizing CXCR2 and inhibiting NLRP3 inflammasome activation.

Influenza is an acute viral respiratory illness with high morbidity rates worldwide. Excessive pulmonary inflammation is the main characteristic of lethal influenza A virus (IAV) infections. Therapeutic options for managing influenza are limited to vaccines and some antiviral medications. Phillyrin is one of the major bioactive components of the Chinese herbal medicine Forsythia suspensa, which has the functions of sterilization, heat clearing and detoxification. In this work, the effect and mechanism of phillyrin on H1N1 influenza (PR8)-induced pneumonia were investigated. We reported that phillyrin (15 mg/kg) treatment after viral challenge significantly improved the weight loss, ameliorated pulmonary inflammation and inhibited the accumulation of multiple cytokines and chemokines in bronchoalveolar lavage fluid on 7 days post infection (dpi). In vitro, phillyrin suppressed influenza viral replication (Matrixprotein and nucleoprotein messenger RNA level) and reduced influenza virus-induced cytopathic effect (CPE). Furthermore,chemokine receptor CXCR2 was confirmed to be markedly inhibited by phillyrin. Surface plasmon resonance results reveal that phillyrin exhibits binding affinity to CXCR2, having a binding affinity constant (KD) value of 1.858e-5 M, suggesting that CXCR2 is a potential therapeutic target for phillyrin. Moreover, phillyrin inhibited the mRNA and protein expression levels of Caspase1, ASC and NLRP3 in the lungs of mice with H1N1-induced pneumonia.This study reveals that phillyrin ameliorates IAV-induced pulmonary inflammation by antagonizing CXCR2 and inhibiting NLRP3 inflammasome activation partly.

Qingjin Huatan decoction protects mice against influenza a virus pneumonia via the chemokine signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingjin Huatan Decoction (QJHTT) consists of 11 herbal medicines: Scutellaria baicalensis Georgi, Gardenia jasminoides J.Ellis, Platycodon grandiflorus (Jacq.) A.DC., Ophiopogon japonicus (Thunb.) Ker Gawl., Morus alba L., Fritillaria thunbergii Miq., Anemarrhena asphodeloides Bunge, Trichosanthes kirilowii Maxim., Citrus reticulata Blanco, Poria cocos (Schw.) Wolf, and Glycyrrhiza uralensis Fisch. As a traditional compound Chinese medicinal formula, QJHTT has been used for more than 400 years in China. Historically, it was used to treat respiratory diseases and had shown beneficial clinical results for diseases related to lung inflammation. AIM OF THE STUDY: To investigate the therapeutic effect of QJHTT on influenza A virus (IAV) pneumonia in mice and explore its possible mechanism of action. MATERIALS AND METHODS: The components in QJHTT were analyzed by UPLC-Q-TOF-MS and some antiviral active components reported in the literature were determined and quantified by HPLC. The protective effects of QJHTT were investigated using lethal and sublethal doses (2 LD50 or 0.8 LD50 viral suspension, separately) of H1N1-infected mice. Mortality and lung lesions in H1N1-infected mice were used to evaluate the efficacy of QJHTT. The potential mechanism of QJHTT in the treatment of viral pneumonia was determined at the gene level by RNA sequencing and validated by qRT-PCR. Following this, the changes in protein levels of JAK2/STAT3 were analyzed since it is a key downstream target of the chemokine signaling pathways. Preliminary elucidation of the mechanism of QJHTT to protect mice against IAV pneumonia through this pathway was conducted. RESULTS: In this study, 12 antiviral active constituents including baicalin, geniposide, and mangiferin were identified from QJHTT. In vivo treatment of QJHTT reduced the virus titers of lung tissue significantly and improved the survival rate, lung index, and pulmonary histopathological changes; additionally, a reduction in the serum levels of TNF-α, IL-1ß, IL-6, and IFN-γ inflammatory factors in H1N1-infected mice was observed. RNA-seq analysis and qRT-PCR showed that QJHTT primarily reversed the activities CCL2, CCL7, CCR1, and other chemokines and their reception-related genes, suggesting that QJHTT may produce disease-resistant pneumonia by inhibiting the downstream JAK2/STAT3 pathway. Western blot analysis confirmed that QJHTT effectively reduced the protein levels of JAK2, STAT3, and related phosphorylated products in the lung tissue of H1N1-infected mice. CONCLUSIONS: Our results indicated that QJHTT alleviated IAV pneumonia in mice by regulating related chemokines and their receptor-related genes in lung tissue, thereby inhibiting JAK2/STAT3 pathway. This could pave way for the design of novel therapeutic strategies to treat viral pneumonia.

Integrating metabolomics and network pharmacology to assess the effects of quercetin on lung inflammatory injury induced by human respiratory syncytial virus.

Quercetin (QR) has significant anti-respiratory syncytial virus (RSV) effects. However, its therapeutic mechanism has not been thoroughly explored. In this study, a lung inflammatory injury model caused by RSV was established in mice. Untargeted lung tissue metabolomics was used to identify differential metabolites and metabolic pathways. Network pharmacology was used to predict potential therapeutic targets of QR and analyze biological functions and pathways modulated by QR. By overlapping the results of the metabolomics and the network pharmacology analyses, the common targets of QR that were likely to be involved in the amelioration of RSV-induced lung inflammatory injury by QR were identified. Metabolomics analysis identified 52 differential metabolites and 244 corresponding targets, while network pharmacology analysis identified 126 potential targets of QR. By intersecting these 244 targets with the 126 targets, hypoxanthine-guanine phosphoribosyltransferase (HPRT1), thymidine phosphorylase (TYMP), lactoperoxidase (LPO), myeloperoxidase (MPO), and cytochrome P450 19A1 (CYP19A1) were identified as the common targets. The key targets, HPRT1, TYMP, LPO, and MPO, were components of purine metabolic pathways. The present study demonstrated that QR effectively ameliorated RSV-induced lung inflammatory injury in the established mouse model. Combining metabolomics and network pharmacology showed that the anti-RSV effect of QR was closely associated with purine metabolism pathways.

Contribution of Chinese herbal medicine in the treatment of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis of randomized controlled trials.

Coronavirus disease 2019 (COVID-19) has become a global epidemic, and there is no specific treatment for anti-COVID-19 drugs. However, treatment of COVID-19 using Chinese herbal medicine (CHM) has been widely practiced in China. PubMed, Embase, Cochrane Library, CNKI, Wanfang and VIP databases were searched to evaluate the efficacy and safety of CHM in the treatment of COVID-19. Twenty-six studies were included in this meta-analysis. The included cases were all patients diagnosed with COVID-19 according to the "New Coronary Virus Pneumonia Diagnosis and Treatment Program," with a total of 2,407 cases. Patients were treated with CHM, including 36 prescriptions, and 105 flavors of CHM were included. The results of the meta-analysis showed that the CHM group improved in lung CT, clinical cure rate, clinical symptom score and time to negative for viral nucleic acid. However, this study still has many limitations due to the limited number of included studies. Therefore, high-quality RCT studies are needed to provide more reliable evidence for CHM treatment of COVID-19. In conclusion, CHM may significantly improve the clinical manifestations and laboratory indicators of patients with COVID-19. In addition, no serious adverse reactions were found after CHM treatment. Therefore, CHM may be used as a potential candidate for COVID-19. HIGHLIGHTS: COVID-19 has become a global epidemic, and there is no specific treatment for anti-COVID-19 drugs. CHM has made a new breakthrough in the treatment of COVID-19. CHM may relieve lung CT images of COVID-19 patients. CHM may improve clinical symptoms of COVID-19 patients. CHM may inhibit the expression of inflammatory factors in patients with COVID-19.

The synergistic effect and mechanisms of flavonoids and polysaccharides from Houttuynia cordata on H1N1-induced pneumonia in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Houttuynia cordata Thunb. (HC, Saururaceae family) is a classical Traditional Chinese Medicine used to treat pneumonia clinically. The total flavonoids (HCF) and polysaccharides (HCP) are key medicinal components of H. cordata involved in its beneficial effect on viral pneumonia. AIM OF THE STUDY: The purpose of the study is to investigate the synergistic or complementary effects of combination of HCF and HCP on viral pneumonia as well as the mechanisms underlying. MATERIALS AND METHODS: HCF or HCP were administrated separately or combined in different proportions on influenza virus H1N1 - infected mice. The survival and lung weight of mice were recorded. The synergistic effect on HCF and HCP combination was calculated by Chou-Talalay method. H&E staining was performed to detect lung histomorphology. Western blot, immunohistochemistry and enzyme linked immunosorbent assay were done to analyze the representative protein expression in lung and intestine tissues. AB - PAS staining on intestine tissue sections was performed to evaluate the histopathology of intestines. Bacterial genomic DNA was extracted and sequenced for gut microbiota analysis. RESULTS: In H1N1 lethally infected mice, the combined administration of HCF and HCP significantly increased the survival rate and prolonged the life span of mice, compared with mono-drug therapy. The viral pneumonia was remarkably improved by HCF and HCP combination reflected by lower lung index, more intact lung morphology, and less inflammatory cells and mediators. Furthermore, the combination of HCF and HCP regulated intestinal microbiota, significantly reduced the proportion of pathogenic Proteobacteria and the secretion of proinflammatory cytokine in gut. The combined HCF and HCP showed synergistic effect on reducing lung and intestine injury. The complementary interaction was also found in HCF and HCP combined therapy, as HCF provided the significant antiviral activity and HCP markedly improved intestinal physical barrier and increased the protein expression involving removal of edema. CONCLUSIONS: Our findings indicated that combination of HCF and HCP from H. cordata synergistically alleviated H1N1-induced viral pneumonia in mice via multimodal regulation of both pulmonary and intestinal homeostasis, which might imply novel therapeutic strategy for treating viral pneumonia.

Therapeutic Potential of 2-Methylquinazolin-4(3H)-one as an Antiviral Agent against Influenza A Virus-Induced Acute Lung Injury in Mice.

Qingdai-Mabo (QM), a traditional Chinese herbal formula composed of medicinal herb and fungus, has been used for treatment of cough and viral pneumonia. However, the underlying mechanism and bioactive components against anti-influenza A virus remain unclear. In the present study, ethyl acetate (EA) extract of QM decoctions was tested for its biological activity against acute lung injury (ALI) and its main components were identified using UPLC-MS/MS. In total, 18 bioactive components were identified, including 2-Methylquinaozlin-4(3H)-one (C1), which showed significant antiviral activity in vitro with an IC50 of 23.8 µg/mL. Furthermore, we validated the efficacy of C1 in ameliorating ALI lesions and inflammation in influenza A virus-infected mice. The results showed that C1 significantly reduced the lung index, downregulated neuraminidase (NA) and nucleoprotein (NP), and decreased the expression of pro-inflammatory molecules IFN-α, TNF-α, MCP-1, IL-6, and IL-8; however, they enhanced levels of IL-10 and IFN-γ in lung homogenate from mice infected by influenza A virus. In addition, C1 inhibited the recruitment of macrophages. These in vitro and in vivo studies suggested that the significant anti-influenza A virus activity contributed to its curative effect on lesions and inflammation of viral pneumonia in mice. Given its potential antiviral activity against influenza A virus, C1 is determined to be a main active component in the EA extract of QM. Taken together, the antiviral activity of C1 suggests its potential as an effective treatment against viral pneumonia via the inhibition of virus replication, but the mechanism C1 on antiviral research needs to be explored further.

Comparative efficacy and safety of antiviral traditional Chinese medicine injections for viral pneumonia: a systematic review and network meta-analysis.

BACKGROUND: Viral pneumonia (VP) is becoming a persistent and pervasive burden of disease. Traditional Chinese medicine Injections (TCMIs) have been proved effective in the treatment of patients with VP, which are now widely used in China. The evidence of TCMIs for VP is evolving rapidly. This study aims to assess the comparative efficacy and safety of TCMIs to provide more evidence and sights for the treatment selection of VP. RESEARCH DESIGN AND METHODS: Seven databases were searched from their inception up to 16 March 2022. Only randomized controlled trials (RCTs) are included to compare the efficacy and safety of antiviral TCMIs for the treatment of viral pneumonia. Clinical efficacy and rate of adverse events were considered as primary outcomes. RESULTS: A total of 76 RCTs with eight TCMIs comprising 7925 patients were included in the NMA. According to NMA, Reduning Injection combined with conventional antiviral drugs (CAD) produced superior effects in the effective outcomes and reduced the adverse event incidence rate of VP. CONCLUSIONS: This study indicated that TCMIs combined with CAD was more effective and safer than CAD monotherapy and compared different TCMIs therapies, which provided guidance and reference for the selection of clinical treatment medication.

Comparative efficacy and safety of pharmacological interventions for severe COVID-19 patients: An updated network meta-analysis of 48 randomized controlled trials.

BACKGROUND: To date, there has been little agreement on what drug is the "best" drug for treating severe COVID-19 patients. This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19. METHODS: We searched databases for randomized controlled trials (RCTs) published up to February 28, 2022, with no language restrictions, of medications recommended for patients (aged 16 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). RESULTS: We identified 4021 abstracts and of these included 48 RCTs comprising 9147 participants through database searches and other sources. For decrease in ACM, we found that ivermectin/doxycycline, C-IVIG (i.e., a hyperimmune anti-COVID-19 intravenous immunoglobulin), methylprednisolone, interferon-beta/standard-of-care (SOC), interferon-beta-1b, convalescent plasma, remdesivir, lopinavir/ritonavir, immunoglobulin gamma, high dosage sarilumab (HS), auxora, and imatinib were effective when compared with placebo or SOC group. We found that colchicine and interferon-beta/SOC were only associated with the TEAEs of severe COVID-19 patients. CONCLUSION: This study suggested that ivermectin/doxycycline, C-IVIG, methylprednisolone, interferon-beta/SOC, interferon-beta-1b, convalescent plasma (CP), remdesivir, lopinavir/ritonavir, immunoglobulin gamma, HS, auxora, and imatinib were efficacious for treating severe COVID-19 patients. We found that most medications were safe in treating severe COVID-19. More large-scale RCTs are still needed to confirm the results of this study.

[Influence of therapeutic exercises and hardware massage in electrostatic field on lung damage in patients with novel coronavirus pneumonia]. / Otsenka vliyaniya lechebnoi gimnastiki i apparatnogo massazha v elektrostaticheskom pole na stepen' porazheniya legkikh u patsientov s pnevmoniei pri novoi koronavirusnoi infektsii.

OBJECTIVE: To analyze the efficacy and safety of therapeutic exercises and chest hardware massage in electrostatic field in patients with COVID-associated viral pneumonia. MATERIAL AND METHODS: We retrospectively analyzed 1551 patients admitted to the Clinical Hospital No. 1 (MEDSI Group JSC) with COVID-associated pneumonia between April 01, 2020 and June 15, 2021 (ICD-10 U07.1 and U07.2). Considering inclusion and exclusion criteria, we enrolled 153 patients. All patients were divided into comparable groups and subgroups depending on the methods of rehabilitation treatment and CT stage of viral pneumonia. Lung damage was assessed semi-automatically using Philips Portal v11 COPD software. Rehabilitation measures included therapeutic exercises and chest hardware massage in electrostatic field. therapeutic exercises. RESULTS: Therapeutic exercises significantly reduced severity of lung damage in patients with viral pneumonia CT-2 and no oxygen support (from 28.05% [28; 29.5] at admission to 15.3% [14.2; 19.3] at discharge). It was not observed in patients without rehabilitation treatment and in patients undergoing therapeutic exercises and massage in electrostatic field. CONCLUSION: Therapeutic exercises in patients with COVID-19 and baseline lung damage > 25% and < 50% (CT-2 stage) significantly reduce severity of lung damage at discharge compared to the control group.

Clinical management of COVID-19: living guideline - 15 September 2022

The WHO COVID-19 Clinical management: living guidance contains the Organization's most up-to-date recommendations for the clinical management of people with COVID-19. Providing guidance that is comprehensive and holistic for the optimal care of COVID-19 patients throughout their entire illness is important. The latest version of this living guideline is available in pdf format (via the 'Download' button) and via an online platform, and is updated regularly as new evidence emerges. No further updates to the previous existing recommendations were made in this latest version. This updated (fifth) version contains 16 new recommendations for the rehabilitation of adults with post COVID-19 condition (see Chapter 24), which includes: strong recommendation that exertional desaturation and cardiac impairment following COVID-19 should be ruled out and managed before consideration of physical exercise training

What are the long-term holistic health consequences of COVID-19 among survivors? An umbrella systematic review.

Many people who have survived COVID-19 have experienced negative persistent impacts on health. Impacts on health have included persistent respiratory symptoms, decreased quality of life, fatigue, impaired functional capacity, memory deficits, psychological impacts, and difficulties in returning to paid employment. Evidence is yet to be pooled to inform future directions in research and practice, to determine the physical, psychological, social, and spiritual impacts of the illness which extend beyond the acute phase of COVID-19 survivors. This umbrella review (review of systematic reviews) critically synthesized physical (including abnormal laboratory parameters), psychological, social, and spiritual impacts which extended beyond the acute phase of COVID-19 survivors. The search strategy was based on the sample, phenomena of interest, design, evaluation, research model and all publications were double screened independently by four review authors for the eligibility criteria. Data extraction and quality assessment were conducted in parallel independently. Eighteen systematic reviews were included, which represented a total of 493 publications. Sample sizes ranged from n = 15 to n = 44 799 with a total of n = 295 455 participants. There was incomplete reporting of several significant data points including the description of the severe acute respiratory syndrome coronavirus 2 variant, COVID-19 treatments, and key clinical and demographic data. A number of physical, psychological, and social impacts were identified for individuals grappling with post-COVID condition. The long term sequalae of acute COVID-19 and size of the problem is only beginning to emerge. Further investigation is needed to ensure that those affected by post-COVID condition have their informational, spiritual, psychological, social, and physical needs met in the future.

Clinical features of adverse events associated with Xiyanping-Ribavirin combination: A systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, Xiyanping (XYP) has been widely used in combination with Ribavirin (RB) for the treatment of infectious diseases. It has been found that this combination may change the severity of XYP-associated adverse events (AEs). AIM: To provide a comprehensive review about the clinal features of AEs of XYP-RB combination from randomized controlled trials, cohort studies, case-control studies, case reports, case series, and data from the National Adverse Drug Reaction Monitoring Information System (NADRMIS). MATERIALS AND METHODS: Seven electronic databases were searched in March 2021. Articles on AEs associated with XYP published from January 2004 to December 2020 in the NADRMIS were included. Data on the incidence of AEs, distribution of AEs, occurrence time of AEs, type and possible signal of AEs, primary diseases, allergic history, family history of allergies, dosage, and combination interval were extracted. RESULTS: We included 228 cases of AEs with XYP-RB combination (63 cases from randomized controlled trials, 1 from a cohort study, and 164 from the NADRMIS). The most common primary disease was hand-foot-and-mouth disease. The main age distribution was 0-6 years (118 cases, 72%) and 8 cases (6.8%) experienced serious AEs. The combination group showed a significant reduction than the RB group in the incidence of AEs in those with hand-foot-and-mouth disease (risk ratio = 0.54, 95% confidence interval = 0.38-0.78, P = 0.0008) and children with viral pneumonia (risk ratio = 0.36, 95% confidence interval = 0.14-0.95, P = 0.04). Allergic history and infusion interval were not described in the randomized controlled trials. AEs were reported in 57.9% of cases in the first combination (XYP-RB were combined for the first time) (NADRMIS), 56.4% of which were skin and appendage reactions, and the risk signal of skin and appendage reactions was a maximum (Information Component = 6.21). CONCLUSION: The major AE associated with XYP-RB combination was skin and appendage reactions. Most of the combination AEs were pseudo-allergic reactions. These findings suggest that we should increase awareness about the safety of XYP-RB combination treatment and standardize medication protocol, especially for children. Unless absolutely necessary, children should avoid combination therapy. More rigorous high-quality studies are needed to obtain more evidence.

Targeting ectromelia virus and TNF/NF-κB or STAT3 signaling for effective treatment of viral pneumonia.

Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1ß, IL-12p40, TGF-ß, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.

[Application of the ICF in assessing the effectiveness of magnetotherapy in patients with viral pneumonia associated with COVID-19]. / Primenenie MKF v otsenke effektivnosti magnitoterapii u patsientov s virusnoi pnevmoniei, assotsiirovannoi s COVID-19.

The number of patients who have had pneumonia caused by COVID-19 is increasing every month. However, despite the ongoing treatment, the consequences of this disease are possible, which may appear in the short term or after a while. Pneumonia associated by the new coronavirus infection COVID-19 is characterized by the presence of such complications as cough, shortness of breath, fatigue, sleep disturbances, appetite disorders, etc. Often, pneumonia leads to dysfunctions of the respiratory system, higher mental functions, functions of the cardiovascular system and, unfortunately, possible disability. The search and implementation of new methods of physical rehabilitation is an urgent task of modern medicine. Low-frequency magnetotherapy is one of the safest and most commonly recommended treatments for pneumonia. The development of new methods of medical rehabilitation for patients with pneumonia associated with COVID-19, using physical factors such as low-frequency magnetotherapy, laser therapy is one of the leading fields. Magnetotherapy is included in the recommendations of the Ministry of Health of the Russian Federation for the purpose of anti-inflammatory, decongestant, reparative-regenerative action; improvement of microcirculation, acceleration of the resorption of infiltrative changes (Temporary methodological recommendations «Medical rehabilitation for a new coronavirus infection (COVID-19)¼, version 2 of 31.07.2020). International rehabilitation practice of using the International Classification of Functioning, Disability and Health (ICF) advises to use it as a tool that allows you to objectively determine the state of health of patients, determine the prognosis of impaired functions and evaluate the effectiveness of ongoing rehabilitation measures. OBJECTIVE: To assess the effectiveness of the use of low-frequency magnetotherapy in the complex medical rehabilitation of patients who have had pneumonia in the phase of convalescence according to the International Classification of Functioning, Disability and Health. MATERIAL AND METHODS: The study included 200 patients who had suffered from pneumonia associating by COVID-19 and whose average age was 54.3±5.8 years. 1st (main) group (n=100), against the background of standard therapy on the 16th day after discharge from the hospital, received low-frequency magnetotherapy on the ALMAG-02 apparatus («Elamed¼, Russia) daily for 10-20 minutes, a course of 15 procedures. The 2nd group(control) included 100 patients who underwent low-frequency placebo-magnetotherapy on the ALMAG-02 apparatus («Elamed¼, Russia). In order to assess the dynamics of clinical and laboratory data and the effectiveness of treatment, control methods were used in this study in accordance with the Temporary Clinical Recommendations of the Ministry of Health of the Russian Federation. Each patient was evaluated for the severity of the initial manifestations of respiratory failure using the mMRC scale (Degree of Shortness of breath) and the Borg scale, and the quality of life of patients was assessed on the EQ-5D scale. Also, at the time of inclusion in the study and during the control examination after the completion of prospective follow-up, the Individual profile of patients was determined in accordance with the international classification of functioning (ICF) with the data of the «Individual Registration Card of the clinical trial participant¼. RESULTS AND DISCUSSION: In 43% (43 people) of patients of the 1th group, an improvement in respiration functions was noted with lung auscultation and with spirometry, an increase in the vital capacity of the lungs by 28.2% (p=0.0021), an increase in chest excursion by 53.1% (p=0.0019) a decrease in the level of shortness of breath by 50% and Borg by 33.3% (p=0.0016). According to the data of the quality of life questionnaire (EQ-5D), the patients of the main group showed an improvement in the quality of life by 23% (p=0.0019). In the 1st group of patients, there was a decrease in moderate disorders in the domains «b152 - emotion functions¼ in 45% of patients; «b440 - respiratory functions¼ in 87% of patients; «b455 - exercise tolerance functions¼ in 74% of patients; «b134 - sleep functions¼ in 30% of patients; «d450 - walking¼ in 100% of patients. In the general blood analysis of patients of the 1st (main) group, there was a relief of leukocytosis, normalization of the erythrocyte sedimentation rate (ESR). In the 1st group a decrease in the duration of being on the sick list was observed for 3.4±0.2 days. CONCLUSION: The inclusion of low-frequency magnetic therapy in the complex rehabilitation of patients who have suffered pneumonia associated by COVID-19 contributes to improving the function of external respiration of patients, regression of residual infiltrative changes in the lungs after pneumonia, relief of residual manifestations of the inflammatory process, reducing the duration of the rehabilitation period and the duration of disability, improving the general well-being of patients, increasing tolerance to physical exertion, normalization of the psycho-emotional state and, as a result,, restoring activity in everyday life and improving the quality of life of patients. The researchers did not register any side effects and side effects of magnetic therapy from ALMAG-02 apparatus (Elamed, Russia).

GeGen QinLian decoction alleviate influenza virus infectious pneumonia through intestinal flora.

Influenza in humans is often accompanied by gastroenteritis-like symptoms. GeGen QinLian decoction (GQD), a Chinese herb formula, has been widely used to treat infectious diarrhea for centuries and has the effect of restoring intestinal flora. Studies have also reported that GQD were used to treat patients with influenza. However, whether regulating the intestinal flora is one of the ways GQD treats influenza has not been confirmed. In present research, we conducted a systemic pharmacological study, and the results showed that GQD may acts through multiple targets and pathways. In influenza-infected mice, GQD treatment reduced mortality and lung inflammation. Most importantly, the mortality and lung inflammation were also reduced in influenza-infected mice that have undergone fecal microbiota transplantation (FMT) from GQD (FMT-GQD) treated mice. GQD treatment or FMT-GQD treatment restores the intestinal flora, resulting in an increase in Akkermansia_muciniphila, Desulfovibrio_C21_c20 and Lactobacillus_salivarius, and a decrease in Escherichia_coli. FMT-GQD treatment inhibited the NOD/RIP2/NF-κB signaling pathway in the intestine and affected the expression of downstream related inflammatory cytokines in mesenteric lymph nodes (mLNs) and serum. In addition, FMT-GQD treatment showed systemic protection by restraining the inflammatory differentiation of CD4+ T cells. In conclusion, our study shows that GQD can affect systemic immunity, at least in part, through the intestinal flora, thereby protect the mice against influenza virus infectious pneumonia.