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1.
West J Emerg Med ; 23(4): 497-504, 2022 Jun 05.
Article in English | MEDLINE | ID: covidwho-20242018

ABSTRACT

Point-of-care lung ultrasonography is an evidence-based application that may play a vital role in the care of critically ill pediatric patients. Lung ultrasonography has the advantage of being available at the patient's bedside with results superior to chest radiography and comparable to chest computed tomography for most lung pathologies. It has a steep learning curve. It can be readily performed in both advanced healthcare systems and resource-scarce settings. The purpose of this review is to discuss the basic principles of lung ultrasonography and its applications in the evaluation and treatment of critically ill pediatric patients.


Subject(s)
Critical Illness , Point-of-Care Systems , Child , Humans , Lung/diagnostic imaging , Tomography, X-Ray Computed , Ultrasonography/methods
2.
Nat Commun ; 14(1): 3500, 2023 06 13.
Article in English | MEDLINE | ID: covidwho-20236856

ABSTRACT

The SARS-CoV-2 Omicron subvariants BA.1 and BA.2 exhibit reduced lung cell infection relative to previously circulating SARS-CoV-2 variants, which may account for their reduced pathogenicity. However, it is unclear whether lung cell infection by BA.5, which displaced these variants, remains attenuated. Here, we show that the spike (S) protein of BA.5 exhibits increased cleavage at the S1/S2 site and drives cell-cell fusion and lung cell entry with higher efficiency than its counterparts from BA.1 and BA.2. Increased lung cell entry depends on mutation H69Δ/V70Δ and is associated with efficient replication of BA.5 in cultured lung cells. Further, BA.5 replicates in the lungs of female Balb/c mice and the nasal cavity of female ferrets with much higher efficiency than BA.1. These results suggest that BA.5 has acquired the ability to efficiently infect lung cells, a prerequisite for causing severe disease, suggesting that evolution of Omicron subvariants can result in partial loss of attenuation.


Subject(s)
COVID-19 , Animals , Female , Mice , Ferrets , SARS-CoV-2 , Mice, Inbred BALB C , Lung
3.
Front Immunol ; 14: 1117760, 2023.
Article in English | MEDLINE | ID: covidwho-20236664

ABSTRACT

Cytoplasmic DNA is emerging as a pivotal contributor to the pathogenesis of inflammatory diseases and cancer, such as COVID-19 and lung carcinoma. However, the complexity of various cytoplasmic DNA-related pathways and their crosstalk remains challenging to distinguish their specific roles in many distinct inflammatory diseases, especially for the underlying mechanisms. Here, we reviewed the latest findings on cytoplasmic DNA and its signaling pathways in inflammatory lung conditions and lung cancer progression. We found that sustained activation of cytoplasmic DNA sensing pathways contributes to the development of common lung diseases, which may result from external factors or mutations of key genes in the organism. We further discussed the interplays between cytoplasmic DNA and anti-inflammatory or anti-tumor effects for potential immunotherapy. In sum, this review aids in understanding the roles of cytoplasmic DNAs and exploring more therapeutic strategies.


Subject(s)
COVID-19 , Neoplasms , Humans , Immunity, Innate , DNA , Neoplasms/genetics , Neoplasms/therapy , Lung
4.
Viruses ; 15(5)2023 05 06.
Article in English | MEDLINE | ID: covidwho-20236421

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo. Using human lung epithelial cells and pseudoviral particles carrying spike proteins from different SARS-CoV-2 variants, we found that YUM70 was equally effective at blocking viral entry mediated by original and variant spike proteins. Furthermore, YUM70 reduced SARS-CoV-2 infection without impacting cell viability in vitro and suppressed viral protein production following SARS-CoV-2 infection. Additionally, YUM70 rescued the cell viability of multi-cellular human lung and liver 3D organoids transfected with a SARS-CoV-2 replicon. Importantly, YUM70 treatment ameliorated lung damage in transgenic mice infected with SARS-CoV-2, which correlated with reduced weight loss and longer survival. Thus, GRP78 inhibition may be a promising approach to augment existing therapies to block SARS-CoV-2, its variants, and other viruses that utilize GRP78 for entry and infection.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Mice , Humans , SARS-CoV-2/physiology , Endoplasmic Reticulum Chaperone BiP , Virus Internalization , Spike Glycoprotein, Coronavirus , Pandemics , Lung
5.
Elife ; 122023 04 20.
Article in English | MEDLINE | ID: covidwho-20236082

ABSTRACT

We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.


Subject(s)
Acute Lung Injury , Transcriptome , Mice , Animals , Humans , Apelin/metabolism , Apelin Receptors/metabolism , Lung , Mice, Transgenic , Endothelial Cells/metabolism
6.
Ter Arkh ; 94(11): 1333-1339, 2022 Dec 26.
Article in Russian | MEDLINE | ID: covidwho-20234221

ABSTRACT

The viral infectious disease pandemic caused by SARS-CoV-2 has affected over 500 million people and killed over 6 million. This is the official data provided by the WHO as of the end of May 2022. Among people who have recovered from COVID-19, post-COVID syndrome is quite common. Scattered epidemiological studies on post-COVID syndrome, however, indicate its high relevance. One of the manifestations of post-COVID syndrome is the development of pulmonary fibrosis (PF). This article is devoted to the analysis of literature data on epidemiology, immunomorphology, as well as X-ray morphological and functional characteristics of PF in patients with post-COVID syndrome. Attention is drawn to the various phenotypes of the post-COVID syndrome and the incidence of PF, which, as clinical practice shows, is most common in people who have had severe COVID-19. This article discusses in detail the molecular biological and immunological mechanisms of PF development. The fibrotic process of the lung parenchyma is not an early manifestation of the disease; as a rule, radiomorphological signs of this pathological process develop after four weeks from the onset of acute manifestations of a viral infection. The characteristic signs of PF include those that indicate the process of remodulation of the lung tissue: volumetric decrease in the lungs, "cellular" degeneration of the lung parenchyma, bronchiectasis and traction bronchiolectasis. The process of remodulating the lung tissue, in the process of fibrosis, is accompanied by a violation of the lung function; a particularly sensitive test of functional disorders is a decrease in the diffusion capacity of the lung tissue. Therefore, in the process of monitoring patients with post-COVID syndrome, a dynamic study of the ventilation function of the lungs is recommended. The main clinical manifestation of PF is dyspnea that occurs with minimal exertion. Shortness of breath also reflects another important aspect of fibrous remodulation of the lung parenchyma - oxygen dissociation is disturbed, which reflects a violation of the gas exchange function of the lungs. There are no generally accepted treatments for PF in post-COVID syndrome. The literature considers such approaches as the possibility of prescribing antifibrotic therapy, hyaluronidase, and medical gases: thermal helium, nitric oxide, and atomic hydrogen. The article draws attention to the unresolved issues of post-covid PF in people who have had COVID-19.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Humans , COVID-19/complications , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/epidemiology , Pulmonary Fibrosis/etiology , SARS-CoV-2 , Lung/diagnostic imaging , Lung/pathology , Dyspnea
7.
Viruses ; 15(5)2023 05 14.
Article in English | MEDLINE | ID: covidwho-20234156

ABSTRACT

The respiratory epithelium, particularly the airway epithelium, is the primary infection site for respiratory pathogens. The apical surface of epithelial cells is constantly exposed to external stimuli including invading pathogens. Efforts have been made to establish organoid cultures to recapitulate the human respiratory tract. However, a robust and simple model with an easily accessible apical surface would benefit respiratory research. Here, we report the generation and characterization of apical-out airway organoids from the long-term expandable lung organoids that we previously established. The apical-out airway organoids morphologically and functionally recapitulated the human airway epithelium at a comparable level to the apical-in airway organoids. Moreover, apical-out airway organoids sustained productive and multicycle replication of SARS-CoV-2, and accurately recapitulated the higher infectivity and replicative fitness of the Omicron variants BA.5 and B.1.1.529 and an ancestral virus. In conclusion, we established a physiologically relevant and convenient apical-out airway organoid model for studying respiratory biology and diseases.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Lung , Organoids
8.
Crit Care ; 27(1): 226, 2023 06 08.
Article in English | MEDLINE | ID: covidwho-20232670

ABSTRACT

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).


Subject(s)
COVID-19 , Pulmonary Edema , Respiratory Distress Syndrome , Humans , COVID-19/complications , Imatinib Mesylate/adverse effects , Lung , Double-Blind Method
9.
PLoS One ; 18(6): e0286211, 2023.
Article in English | MEDLINE | ID: covidwho-20232587

ABSTRACT

BACKGROUND AND PURPOSE: Cytokine storm invoked during acute and chronic lung injury promotes alveolar damage and remodeling. The current study shows that degraded elastin-targeted nanoparticles releasing doxycycline (Doxy NPs) are potent in mitigating cytokines storm, migration of immune cells in the lungs, and inhibiting inflammasome pathways in the LPS mouse model. EXPERIMENTAL APPROACH: Cytokine storm and lung injury were induced using LPS and elastase in C57BL/6 mice (rodent model for emphysema). The mice were then treated with I.V. Doxy NPs, blank NPs, or Doxy a day before LPS administration. Cytokine levels, immune cell population, and MMP activity were analyzed in broncheo-alveolar lavage fluid (BALF) 4 hours after LPS administration. Additionally, gene expression of IL-6, IL-1beta, MCP-1, NLRP3, Caspase 1 and MMPs were investigated in alveolar cells on day 3 after LPS administration. KEY RESULTS: Doxycycline NPs but not Doxycycline significantly decreased IL-6, TNF-α, IL-23 and were significantly more effective in decreasing the percentage of immune cells in the BALF. This is the first in-vivo study to demonstrate that Doxycycline can effectively inhibit inflammasome pathways in the lungs. CONCLUSION AND IMPLICATIONS: IV administration of elastin antibody conjugated Doxycycline-loaded albumin NPs can effectively modulate the local immune environment in the lungs, which is not achieved by IV Doxycycline even at 100-fold higher dose. This novel method of drug delivery can effectively lead to the repurposing of traditional Doxycycline as a potential adjunct treatment for managing the cytokine storm in the lungs in COPD and viral infections.


Subject(s)
Lung Injury , Nanoparticles , Pneumonia , Mice , Animals , Lipopolysaccharides/pharmacology , Inflammasomes/metabolism , Interleukin-6/metabolism , Cytokine Release Syndrome , Elastin/metabolism , Mice, Inbred C57BL , Pneumonia/metabolism , Lung/metabolism , Cytokines/metabolism , Lung Injury/metabolism
10.
BMJ Case Rep ; 16(6)2023 Jun 05.
Article in English | MEDLINE | ID: covidwho-20238760

ABSTRACT

Anti-synthetase syndrome (ASS) is a rare inflammatory myopathy with a wide variety of clinical presentations. ASS-related interstitial lung disease (ASS-ILD) presents with rapid onset and progression, which could often be confused with other more common acute processes such as pneumonia, especially when ILD can be the sole manifestation. A woman in her 50s presented with recurrent dyspnoea for 2 months requiring multiple hospital admissions, and each time, she was diagnosed with multifocal pneumonia and treated with antibiotics. On admission, the evaluation revealed a markedly elevated creatine kinase level at 3258 U/L and a CT scan of the chest revealed worsening scattered ground-glass opacities. Given the concern for ILD as the cause of antibiotic failure, she underwent bronchoscopy with bronchoalveolar lavage which revealed non-specific interstitial pneumonia. A subsequent myositis panel revealed a positive anti-Jo-1 antibody, and she was diagnosed with ASS-ILD. She completed a course of intravenous immunoglobulin and methylprednisolone and experienced significant clinical improvement with the resolution of hypoxaemia and improved polyarthralgia.ASS could often be misdiagnosed as other more common acute lung processes, as a clinically subtle course can escape detection given its rarity, as well as its non-specific and highly variable presentations. This case highlights the importance of early suspicion and consideration of performing specific autoantibody testing when evaluating patients with a suspicion of undifferentiated autoimmune condition.


Subject(s)
Lung Diseases, Interstitial , Myositis , Pneumonia , Female , Humans , Animals , Ligases , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/etiology , Lung , Myositis/diagnosis , Myositis/drug therapy , Myositis/complications , Autoantibodies , Pneumonia/complications , Equidae
11.
Molecules ; 28(11)2023 May 30.
Article in English | MEDLINE | ID: covidwho-20238682

ABSTRACT

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) induces a severe cytokine storm that may cause acute lung injury/acute respiratory distress syndrome (ALI/ARDS) with high clinical morbidity and mortality in infected individuals. Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid isolated and extracted from Stephania cepharantha Hayata. It exhibits various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, anti-tumor, and antiviral activities. The low oral bioavailability of CEP can be attributed to its poor water solubility. In this study, we utilized the freeze-drying method to prepare dry powder inhalers (DPI) for the treatment of acute lung injury (ALI) in rats via pulmonary administration. According to the powder properties study, the aerodynamic median diameter (Da) of the DPIs was 3.2 µm, and the in vitro lung deposition rate was 30.26; thus, meeting the Chinese Pharmacopoeia standard for pulmonary inhalation administration. We established an ALI rat model by intratracheal injection of hydrochloric acid (1.2 mL/kg, pH = 1.25). At 1 h after the model's establishment, CEP dry powder inhalers (CEP DPIs) (30 mg/kg) were sprayed into the lungs of rats with ALI via the trachea. Compared with the model group, the treatment group exhibited a reduced pulmonary edema and hemorrhage, and significantly reduced content of inflammatory factors (TNF-α, IL-6 and total protein) in their lungs (p < 0.01), indicating that the main mechanism of CEP underlying the treatment of ALI is anti-inflammation. Overall, the dry powder inhaler can deliver the drug directly to the site of the disease, increasing the intrapulmonary utilization of CEP and improving its efficacy, making it a promising inhalable formulation for the treatment of ALI.


Subject(s)
Acute Lung Injury , Benzylisoquinolines , COVID-19 , Rats , Animals , Administration, Inhalation , Dry Powder Inhalers , COVID-19/metabolism , SARS-CoV-2 , Respiratory Aerosols and Droplets , Lung/metabolism , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Benzylisoquinolines/pharmacology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/analysis , Particle Size , Powders/analysis
12.
Zhongguo Zhong Yao Za Zhi ; 48(10): 2606-2612, 2023 May.
Article in Chinese | MEDLINE | ID: covidwho-20244902

ABSTRACT

Xiao Chaihu Decoction combined with Maxing Shigan Decoction is a classic herbal formula. All of them are derived from Treatise on Cold Damage(Shang Han Lun) by ZHANG Zhong-jing. This combination has the effects of harmonizing lesser yang, relieving exterior syndrome, clearing lung heat, and relieving panting. It is mainly used for treating the disease involving the triple-Yang combination of diseases and accumulation of pathogenic heat in the lung. Xiao Chaihu Decoction combined with Maxing Shigan Decoction is a classic combination for the treatment of exogenous diseases involving the triple-Yang combination. They are commonly used in exogenous diseases, especially in the north of China. This combination is also the main treatment strategy for coronavirus disease 2019(COVID-19) accompanied by fever and cough. Maxing Shigan Decoction is a classical herbal formula for treating the syndrome of phlegm-heat obstructing the lung. "Dyspnea after sweating" suggests the accumulation of pathogenic heat in the lung. Patients with mild symptoms may develop cough and asthma along with forehead sweating, and those in critical severe may develop whole-body sweating, especially the front chest. Modern medicine believes that the above situation is related to lung infection. "Mild fever" refers to syndromes rather than pathogenesis. It does not mean that the heat syndrome is not heavy, instead, it suggests that severe heat and inflammation have occurred. The indications of Xiao Chaihu Decoction combined with Maxing Shigan Decoction are as follows.(1) In terms of diseases, it is suitable for the treatment of viral pneumonia, bronchopneumonia, lobar pneumonia, mycoplasma pneumonia, COVID-19 infection, measles with pneumonia, severe acute respiratory syndrome(SARS), avian influenza, H1N1 influenza, chronic obstructive pulmonary disease with acute exacerbation, pertussis, and other influenza and pneumonia.(2) In terms of syndromes, it can be used for the syndromes of bitter mouth, dry pharynx, vertigo, loss of appetite, vexation, vomiting, and fullness and discomfort in the chest and hypochondrium. It can also be used to treat alternate attacks of chill and fever and different degrees of fever, as well as chest tightness, cough, asthma, expectoration, dry mouth, wanting cold drinks, feeling agitated, sweating, yellow urine, dry stool, red tongue, yellow or white fur, and floating, smooth, and powerful pulse, especially the right wrist pulse.


Subject(s)
Asthma , COVID-19 , Drugs, Chinese Herbal , Influenza A Virus, H1N1 Subtype , Influenza, Human , Pulmonary Disease, Chronic Obstructive , Animals , Humans , Cough , Syndrome , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/pharmacology , Lung , Pulmonary Disease, Chronic Obstructive/drug therapy , Critical Care , Medicine, Chinese Traditional
13.
Viruses ; 15(5)2023 04 25.
Article in English | MEDLINE | ID: covidwho-20244362

ABSTRACT

Several reports demonstrated the susceptibility of domestic cats to SARS-CoV-2 infection. Here, we describe a thorough investigation of the immune responses in cats after experimental SARS-CoV-2 inoculation, along with the characterization of infection kinetics and pathological lesions. Specific pathogen-free domestic cats (n = 12) were intranasally inoculated with SARS-CoV-2 and subsequently sacrificed on DPI (days post-inoculation) 2, 4, 7 and 14. None of the infected cats developed clinical signs. Only mild histopathologic lung changes associated with virus antigen expression were observed mainly on DPI 4 and 7. Viral RNA was present until DPI 7, predominantly in nasal and throat swabs. The infectious virus could be isolated from the nose, trachea and lungs until DPI 7. In the swab samples, no biologically relevant SARS-CoV-2 mutations were observed over time. From DPI 7 onwards, all cats developed a humoral immune response. The cellular immune responses were limited to DPI 7. Cats showed an increase in CD8+ cells, and the subsequent RNA sequence analysis of CD4+ and CD8+ subsets revealed a prominent upregulation of antiviral and inflammatory genes on DPI 2. In conclusion, infected domestic cats developed a strong antiviral response and cleared the virus within the first week after infection without overt clinical signs and relevant virus mutations.


Subject(s)
COVID-19 , Animals , Cats , COVID-19/pathology , SARS-CoV-2 , Lung , Immunity, Humoral
14.
Int J Mol Sci ; 24(1)2022 Dec 25.
Article in English | MEDLINE | ID: covidwho-20243838

ABSTRACT

Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress to fibrosis. Within this group of pneumonias, idiopathic pulmonary fibrosis (IPF) is considered the most common. This disease has no known cause, is devastating and has no cure. Chronic lesion of alveolar type II (ATII) cells represents a key mechanism for the development of IPF. ATII cells are specialized in the biosynthesis and secretion of pulmonary surfactant (PS), a lipid-protein complex that reduces surface tension and minimizes breathing effort. Some differences in PS composition have been reported between patients with idiopathic pulmonary disease and healthy individuals, especially regarding some specific proteins in the PS; however, few reports have been conducted on the lipid components. This review focuses on the mechanisms by which phospholipids (PLs) could be involved in the development of the fibroproliferative response.


Subject(s)
Idiopathic Pulmonary Fibrosis , Lung Diseases, Interstitial , Pulmonary Surfactants , Humans , Pulmonary Surfactants/therapeutic use , Pulmonary Surfactants/metabolism , Phospholipids , Lung/pathology , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/pathology , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/pathology
15.
J Transl Med ; 21(1): 374, 2023 Jun 08.
Article in English | MEDLINE | ID: covidwho-20243655

ABSTRACT

BACKGROUND: Although mRNA vaccines have overall efficacy preventing morbidity/mortality from SARS-CoV-2 infection, immunocompromised persons remain at risk. Antibodies mostly prevent early symptomatic infection, but cellular immunity, particularly the virus-specific CD8+ T cell response, is protective against disease. Defects in T cell responses to vaccination have not been well characterized in immunocompromised hosts; persons with lung transplantation are particularly vulnerable to vaccine failure with severe illness. METHODS: Comparison groups included persons with lung transplantation and no history of COVID-19 (21 and 19 persons after initial mRNA vaccination and a third booster vaccination respectively), 8 lung transplantation participants recovered from COVID-19, and 22 non-immunocompromised healthy control individuals after initial mRNA vaccination (without history of COVID-19). Anti-spike T cell responses were assayed by stimulating peripheral blood mononuclear cells (PBMCs) with pooled small overlapping peptides spanning the SARS-CoV-2 spike protein, followed by intracellular cytokine staining (ICS) and flow cytometry for release of cytokines in response to stimulation, including negative controls (no peptide stimulation) and positive controls (phorbol myristate acetate [PMA] and ionomycin stimulation). To evaluate for low frequency memory responses, PBMCs were cultured in the presence of the mRNA-1273 vaccine for 14 days before this evaluation. RESULTS: Ionophore stimulation of PBMCs revealed a less inflammatory milieu in terms of interleukin (IL)-2, IL-4, and IL-10 profiling in lung transplantation individuals, reflecting the effect of immunosuppressive treatments. Similar to what we previously reported in healthy vaccinees, spike-specific responses in lung transplantation recipients were undetectable (< 0.01%) when tested 2 weeks after vaccination or later, but were detectable after in vitro culture of PBMCs with mRNA-1273 vaccine to enrich memory T cell responses. This was also seen in COVID-19-recovered lung transplantation recipients. Comparison of their enriched memory responses to controls revealed relatively similar CD4+ T cell memory, but markedly reduced CD8+ T cell memory both after primary vaccination or a booster dose. These responses were not correlated to age or time after transplantation. The vaccine-induced CD4+ and CD8+ responses correlated well in the healthy control group, but poorly in the transplantation groups. CONCLUSIONS: These results reveal a specific defect in CD8+ T cells, which have key roles both in transplanted organ rejection but also antiviral effector responses. Overcoming this defect will require strategies to enhance vaccine immunogenicity in immunocompromised persons.


Subject(s)
COVID-19 , Transplant Recipients , Humans , CD8-Positive T-Lymphocytes , 2019-nCoV Vaccine mRNA-1273 , SARS-CoV-2 , Leukocytes, Mononuclear , COVID-19/prevention & control , Vaccination , Antibodies , Cytokines , Lung , Antibodies, Viral
16.
Orv Hetil ; 164(22): 864-870, 2023 Jun 04.
Article in Hungarian | MEDLINE | ID: covidwho-20243522

ABSTRACT

The use of ultrasound became an essential tool in the everyday practice of anesthesiology and intensive care as an indispensable prerequisite for the precise guidance of invasive procedures and also as a point-of-care diagnostic method. Despite the limitations of imaging the lung and thoracic structures, the COVID-19 pandemic and recent advances made this technology an evolving field. The intensive therapy applies these methods with important experience for differential diagnosis and assessment of disease severity or prognosis. Minor modifications of these results make the method beneficial for anesthesia and perioperative medicine. In the present review, the authors accentuate the most important imaging artefacts of lung ultrasonography and the principles of lung ultrasound diagnostic steps. Methods and artefacts of high importance supported by evidence for the assessment of airway management, attuning of intraoperative mechanical ventilation, respiratory disorders during surgery, and postoperative prognosis are articulated. This review intends to focus on evolving subfields in which technological or scientific novelties are expected. Orv Hetil. 2023; 164(22): 864-870.


Subject(s)
COVID-19 , Humans , COVID-19/diagnostic imaging , Pandemics , Ultrasonography , Lung/diagnostic imaging , Anesthesia, General
17.
Int J Environ Res Public Health ; 20(10)2023 05 22.
Article in English | MEDLINE | ID: covidwho-20243207

ABSTRACT

(1) Background: Between the beginning of the coronavirus pandemic and summer 2022, we distinguished four pandemic waves, with different characteristics of the affected patients. This study investigated the impact of patient characteristics on the outcome of inpatient pulmonary rehabilitation (PR). (2) Methods: Using a prospective approach, the characteristics of post-acute COVID-19 patients of the different waves who participated in inpatient PR were compared based on their assessments and results collected as part of PR (Cumulative Illness Rating Scale (CIRS), six-minute walk test (6-MWT), Pulmonary Function Testing (PFT), and Functional Independent Measurement (FIM). (3) Results: A total of 483 patients were included in the analysis (Wave 1 n = 51, Wave 2 n = 202, Wave 3 n = 84, Wave 4 n = 146). Compared to Wave 3 + 4, patients of Wave 1 + 2 were older (69 vs. 63 years; p < 0.001), had a significantly lower CIRS (13.0 vs. 14.7 points; p = 0.004), had significant better PFT (FVC: 73 vs. 68%pred; p = 0.009; DLCOSB: 58 ± 18 vs. 50 ± 17%pred; p = 0.001), and showed significantly more comorbidities (2.0 vs. 1.6 n/pers.; p = 0.009). Wave 3 + 4 showed significantly greater improvements according to the 6-MWT (147 vs. 188 m; p < 0.001) and the FIM (5.6 vs. 21.1 points; p < 0.001). (4) Conclusions: Patients of the COVID-19 infection waves differed significantly according to their anthropometric data, incidence of comorbidities, and impact of the infection. All cohorts achieved clinically relevant and significant functional improvements during PR, with significant higher improvements in Wave 3 + 4.


Subject(s)
COVID-19 , Pandemics , Humans , COVID-19/epidemiology , Lung , Treatment Outcome , Comorbidity
18.
Nat Med ; 29(6): 1563-1577, 2023 Jun.
Article in English | MEDLINE | ID: covidwho-20242944

ABSTRACT

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.


Subject(s)
COVID-19 , Lung Neoplasms , Pulmonary Fibrosis , Humans , Lung , Lung Neoplasms/genetics , Macrophages
19.
Ter Arkh ; 95(3): 217-222, 2023 Apr 26.
Article in Russian | MEDLINE | ID: covidwho-20242903

ABSTRACT

AIM: To establish symptoms, lung function and to evaluate subsequent exacerbations of chronic obstructive pulmonary disease (COPD) during a year after virus-induced COPD exacerbations. MATERIALS AND METHODS: Patients hospitalized with viral (n=60), bacterial (n=60) and viral-bacterial (n=60) COPD exacerbations were enrolled to single-center prospective observational study. COPD was diagnosed according spirography criteria. Viral infection was established in bronchoalveolar lavage fluid or sputum by real-time reverse transcription-polymerase chain reaction for RNA of influenza A and B virus, rhinovirus, respiratory syncytial virus and SARS-CoV-2. Symptoms, lung function, COPD exacerbations were assessed. Patients were investigated at the hospitalization onset and then 4 and 52 weeks following the discharge from the hospital. RESULTS: After 52 weeks in viral and viral-bacterial COPD exacerbations groups the rate of forced expiratory volume in one second (FEV1) decline were maximal - 71 (68; 73) ml/year and 69 (67; 72) ml/year versus 59 (55; 62) ml/year after bacterial exacerbations. Low levels of diffusion lung capacity for carbon monoxide (DLco/Va) - 52.5% (45.1%; 55.8%), 50.2% (44.9%; 56.0%) and 75.3% (72.2%; 80.1%) respectively, of 6-minute walk distance; p<0.001 in relation to bacterial exacerbations. In Cox proportional hazards regression analyses viral and viral-bacterial exacerbations were associated with increased risk of subsequent COPD exacerbations by 2.4 times independent of exacerbations rate before index event and FEV1. In linear regression models the relationships between airflow limitation and respiratory syncytial virus, rhinovirus and influenza virus infection, between low DLco/Va and rhinovirus, influenza virus and SARS-CoV-2 infection. CONCLUSION: COPD after virus-induced exacerbations were characterized by progression of airflow limitation, low DLco/Va, low 6-minute walking test distance, subsequent COPD exacerbations risk.


Subject(s)
COVID-19 , Influenza, Human , Pulmonary Disease, Chronic Obstructive , Humans , Influenza, Human/complications , Influenza, Human/diagnosis , COVID-19/complications , COVID-19/diagnosis , SARS-CoV-2 , Pulmonary Disease, Chronic Obstructive/complications , Lung , Disease Progression
20.
Sensors (Basel) ; 23(11)2023 Jun 03.
Article in English | MEDLINE | ID: covidwho-20242759

ABSTRACT

Coronavirus disease 2019 (COVID-19) has seen a crucial outburst for both females and males worldwide. Automatic lung infection detection from medical imaging modalities provides high potential for increasing the treatment for patients to tackle COVID-19 disease. COVID-19 detection from lung CT images is a rapid way of diagnosing patients. However, identifying the occurrence of infectious tissues and segmenting this from CT images implies several challenges. Therefore, efficient techniques termed as Remora Namib Beetle Optimization_ Deep Quantum Neural Network (RNBO_DQNN) and RNBO_Deep Neuro Fuzzy Network (RNBO_DNFN) are introduced for the identification as well as classification of COVID-19 lung infection. Here, the pre-processing of lung CT images is performed utilizing an adaptive Wiener filter, whereas lung lobe segmentation is performed employing the Pyramid Scene Parsing Network (PSP-Net). Afterwards, feature extraction is carried out wherein features are extracted for the classification phase. In the first level of classification, DQNN is utilized, tuned by RNBO. Furthermore, RNBO is designed by merging the Remora Optimization Algorithm (ROA) and Namib Beetle Optimization (NBO). If a classified output is COVID-19, then the second-level classification is executed using DNFN for further classification. Additionally, DNFN is also trained by employing the newly proposed RNBO. Furthermore, the devised RNBO_DNFN achieved maximum testing accuracy, with TNR and TPR obtaining values of 89.4%, 89.5% and 87.5%.


Subject(s)
COVID-19 , Coleoptera , Deep Learning , Perciformes , Pneumonia , Female , Male , Animals , COVID-19/diagnostic imaging , Fishes , Tomography, X-Ray Computed , Lung/diagnostic imaging
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