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1.
Respir Res ; 22(1): 255, 2021 Sep 27.
Article in English | MEDLINE | ID: covidwho-1440932

ABSTRACT

INTRODUCTION: There is relatively little published on the effects of COVID-19 on respiratory physiology, particularly breathing patterns. We sought to determine if there were lasting detrimental effect following hospital discharge and if these related to the severity of COVID-19. METHODS: We reviewed lung function and breathing patterns in COVID-19 survivors > 3 months after discharge, comparing patients who had been admitted to the intensive therapy unit (ITU) (n = 47) to those who just received ward treatments (n = 45). Lung function included spirometry and gas transfer and breathing patterns were measured with structured light plethysmography. Continuous data were compared with an independent t-test or Mann Whitney-U test (depending on distribution) and nominal data were compared using a Fisher's exact test (for 2 categories in 2 groups) or a chi-squared test (for > 2 categories in 2 groups). A p-value of < 0.05 was taken to be statistically significant. RESULTS: We found evidence of pulmonary restriction (reduced vital capacity and/or alveolar volume) in 65.4% of all patients. 36.1% of all patients has a reduced transfer factor (TLCO) but the majority of these (78.1%) had a preserved/increased transfer coefficient (KCO), suggesting an extrapulmonary cause. There were no major differences between ITU and ward lung function, although KCO alone was higher in the ITU patients (p = 0.03). This could be explained partly by obesity, respiratory muscle fatigue, localised microvascular changes, or haemosiderosis from lung damage. Abnormal breathing patterns were observed in 18.8% of subjects, although no consistent pattern of breathing pattern abnormalities was evident. CONCLUSIONS: An "extrapulmonary restrictive" like pattern appears to be a common phenomenon in previously admitted COVID-19 survivors. Whilst the cause of this is not clear, the effects seem to be similar on patients whether or not they received mechanical ventilation or had ward based respiratory support/supplemental oxygen.


Subject(s)
COVID-19/physiopathology , Hospitalization/trends , Lung/physiology , Respiratory Mechanics/physiology , Spirometry/trends , Survivors , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/therapy , Female , Humans , Lung Diseases/diagnosis , Lung Diseases/physiopathology , Lung Diseases/therapy , Male , Middle Aged , Patient Discharge/trends , Respiratory Function Tests/methods , Respiratory Function Tests/trends , Spirometry/methods , Young Adult
2.
Int J Mol Sci ; 22(5)2021 Mar 04.
Article in English | MEDLINE | ID: covidwho-1389392

ABSTRACT

Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air-liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery.


Subject(s)
Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/physiology , Lung Diseases/physiopathology , Lung/physiology , Alveolar Epithelial Cells/cytology , Animals , COVID-19/physiopathology , Humans , Immunity, Innate , Ions/metabolism , Lung/anatomy & histology , Lung Diseases/etiology , Lung Diseases/pathology , Pulmonary Surfactant-Associated Proteins/metabolism , Regeneration
3.
Cells ; 10(7)2021 06 26.
Article in English | MEDLINE | ID: covidwho-1389304

ABSTRACT

The lungs are affected by illnesses including asthma, chronic obstructive pulmonary disease, and infections such as influenza and SARS-CoV-2. Physiologically relevant models for respiratory conditions will be essential for new drug development. The composition and structure of the lung extracellular matrix (ECM) plays a major role in the function of the lung tissue and cells. Lung-on-chip models have been developed to address some of the limitations of current two-dimensional in vitro models. In this review, we describe various ECM substitutes utilized for modeling the respiratory system. We explore the application of lung-on-chip models to the study of cigarette smoke and electronic cigarette vapor. We discuss the challenges and opportunities related to model characterization with an emphasis on in situ characterization methods, both established and emerging. We discuss how further advancements in the field, through the incorporation of interstitial cells and ECM, have the potential to provide an effective tool for interrogating lung biology and disease, especially the mechanisms that involve the interstitial elements.


Subject(s)
Lab-On-A-Chip Devices , Lung Diseases/pathology , Lung/physiology , Regeneration/physiology , Respiratory Mucosa/cytology , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , Cells, Cultured , Extracellular Matrix/physiology , Humans , Lung/cytology , Lung/pathology , Lung Diseases/physiopathology , Lung Diseases/therapy , Models, Biological , Respiratory Mucosa/pathology , Respiratory Mucosa/physiology , SARS-CoV-2/pathogenicity , Tissue Culture Techniques/instrumentation , Tissue Culture Techniques/methods
4.
G Ital Cardiol (Rome) ; 22(8): 638-647, 2021 Aug.
Article in Italian | MEDLINE | ID: covidwho-1365476

ABSTRACT

In recent years, lung ultrasonography has acquired an important role as a valuable diagnostic tool in clinical practice. The lung is usually poorly explorable, but it provides more acoustic information in pathological conditions that modify the relationship between air, water and tissues. The different acoustic impedance of all these components makes the chest wall a powerful ultrasound reflector: this is responsible for the creation of several artifacts providing valuable information about lung pathophysiology. Lung ultrasonography helps in the diagnostic process of parenchymal and pleural pathologies, in the differential diagnosis of dyspnea and in the clinical and prognostic evaluation of the SARS-CoV-2 infection.


Subject(s)
COVID-19/diagnostic imaging , Lung/diagnostic imaging , Ultrasonography/methods , Cardiologists , Diagnosis, Differential , Dyspnea/diagnostic imaging , Humans , Lung/virology , Lung Diseases/diagnostic imaging , Lung Diseases/physiopathology , Prognosis
5.
Pediatr Rheumatol Online J ; 19(1): 104, 2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1292002

ABSTRACT

BACKGROUND: H syndrome (HS) is a rare autoinflammatory disease caused by a mutation in the solute carrier family 29, member 3 (SCL29A3) gene. It has a variable clinical presentation and little phenotype-genotype correlation. The pathognomonic sign of HS is cutaneous hyperpigmentation located mainly in the inner thighs and often accompanied by other systemic manifestations. Improvement after tocilizumab treatment has been reported in a few patients with HS. We report the first patient with HS who presented cardiogenic shock, multiorgan infiltration, and digital ischemia. CASE PRESENTATION: 8-year-old boy born to consanguineous parents of Moroccan origin who was admitted to the intensive care unit during the Coronavirus Disease-2019 (COVID-19) pandemic with tachypnoea, tachycardia, and oliguria. Echocardiography showed dilated cardiomyopathy and severe systolic dysfunction compatible with cardiogenic shock. Additionally, he presented with multiple organ dysfunction syndrome. SARS-CoV-2 polymerase chain reaction (PCR) and antibody detection by chromatographic immunoassay were negative. A previously ordered gene panel for pre-existing sensorineural hearing loss showed a pathological mutation in the SCL29A3 gene compatible with H syndrome. Computed tomography scan revealed extensive alveolar infiltrates in the lungs and multiple poor defined hypodense lesions in liver, spleen, and kidneys; adenopathy; and cardiomegaly with left ventricle subendocardial nodules. Invasive mechanical ventilation, broad antibiotic and antifungal coverage showed no significant response. Therefore, Tocilizumab as compassionate use together with pulsed intravenous methylprednisolone was initiated. Improvement was impressive leading to normalization of inflammation markers, liver and kidney function, and stabilising heart function. Two weeks later, he was discharged and has been clinically well since then on two weekly administration of Tocilizumab. CONCLUSIONS: We report the most severe disease course produced by HS described so far in the literature. Our patient's manifestations included uncommon, new complications such as acute heart failure with severe systolic dysfunction, multi-organ cell infiltrate, and digital ischemia. Most of the clinical symptoms of our patient could have been explained by SARS-CoV-2, demonstrating the importance of a detailed differential diagnosis to ensure optimal treatment. Although the mechanism of autoinflammation of HS remains uncertain, the good response of our patient to Tocilizumab makes a case for the important role of IL-6 in this syndrome and for considering Tocilizumab as a first-line treatment, at least in severely affected patients.


Subject(s)
Cardiomyopathy, Dilated/physiopathology , Hereditary Autoinflammatory Diseases/physiopathology , Ischemia/physiopathology , Multiple Organ Failure/physiopathology , Shock, Cardiogenic/physiopathology , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Cardiomyopathy, Dilated/diagnostic imaging , Cardiomyopathy, Dilated/therapy , Child , Glucocorticoids/therapeutic use , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/therapy , Humans , Ischemia/therapy , Kidney Diseases/diagnostic imaging , Kidney Diseases/physiopathology , Kidney Diseases/therapy , Liver Diseases/diagnostic imaging , Liver Diseases/physiopathology , Liver Diseases/therapy , Lung Diseases/diagnostic imaging , Lung Diseases/physiopathology , Lung Diseases/therapy , Lymphadenopathy/diagnostic imaging , Lymphadenopathy/physiopathology , Lymphadenopathy/therapy , Male , Methylprednisolone/therapeutic use , Multiple Organ Failure/therapy , Nucleoside Transport Proteins/genetics , Pulse Therapy, Drug , Respiration, Artificial , SARS-CoV-2 , Shock, Cardiogenic/therapy , Splenic Diseases/diagnostic imaging , Splenic Diseases/physiopathology , Splenic Diseases/therapy , Toes/blood supply , Tomography, X-Ray Computed , Treatment Outcome
6.
J Thorac Imaging ; 35(6): 344-345, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-1219915

ABSTRACT

In this hypothesis paper, we suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce intravascular pulmonary thrombosis, which may result in the rapid worsening of clinical conditions and, eventually, exitus. Previously published papers have demonstrated that increased levels of D-dimer at hospital admission correlate with a more severe disease (0.5 mg/L) or occurrence of death (1 mg/L). The potential prothrombotic action of the SARS-CoV-2 is supported by the topographical involvement of the lung regions with a predilection for the lower lobe with peripheral involvement. If this hypothesis is demonstrated, this could suggest the benefit of using antithrombotic/coagulation regimens for SARS-CoV-2 and, at the same time, the urgency to identify drugs that could alter the inflammatory storm, thus protecting the vessel wall.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Thrombosis/etiology , Thrombosis/physiopathology , COVID-19/blood , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Lung/physiopathology , Lung Diseases/blood , Lung Diseases/etiology , Lung Diseases/physiopathology , SARS-CoV-2 , Thrombosis/blood
7.
Elife ; 102021 03 15.
Article in English | MEDLINE | ID: covidwho-1196112

ABSTRACT

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.


Chronic respiratory disorders like asthma affect around 600 million people worldwide. Although these illnesses are widespread, they can have several different underlying causes, making them difficult to treat. Drugs that work well on one type of respiratory disorder may be completely ineffective on another. Understanding the biological and environmental factors that cause these illnesses will allow them to be treated more effectively by tailoring therapies to each patient. Reduced lung function is a factor in respiratory disorders and it can have many genetic causes. Studying the genes of patients with reduced lung function can reveal the genes involved, some of which may already be targets of existing drugs for other illnesses. So, could a patient's genetics be used to repurpose existing drugs to treat their respiratory disorders? Reay et al. combined three methods to link genetics and biological processes to the causes of reduced lung function. The results reveal several factors that could lead to new treatments. In one example, reduced lung function showed a link to genes associated with high blood sugar. As such, treatments used in diabetes might help improve lung function in some patients. Reay et al. also developed a scoring system that could predict the efficacy of a treatment based on a patient's genetics. The study suggests that COVID-19 infection could be affected by blood sugar levels too. Chronic respiratory disorders are a critical issue worldwide and have proven difficult to treat, but these results suggest a way to identify new therapies and target them to the right patients. The findings also support a connection between lung function and blood sugar levels. This implies that perhaps existing diabetes treatments ­ including diet and lifestyle changes aimed at reducing or limiting blood sugar ­ could be repurposed to treat respiratory disorders in some patients. The next step will be to perform clinical trials to test whether these therapies are in fact effective.


Subject(s)
Drug Repositioning/methods , Hyperglycemia/genetics , Lung Diseases/drug therapy , Lung Diseases/genetics , Blood Glucose/metabolism , Causality , Databases, Genetic , Genome-Wide Association Study/methods , Humans , Hyperglycemia/metabolism , Hyperglycemia/physiopathology , Lung/drug effects , Lung/physiology , Lung/physiopathology , Lung Diseases/metabolism , Lung Diseases/physiopathology , Multifactorial Inheritance , Phenotype , Polymorphism, Single Nucleotide , Respiratory Function Tests/methods , Transcriptome
8.
Respiration ; 100(7): 594-599, 2021.
Article in English | MEDLINE | ID: covidwho-1194385

ABSTRACT

BACKGROUND AND OBJECTIVES: The 6-minute walk test (6MWT), as a clinical assessment tool for functional exercise capacity, is an integral component of lung allocation scores (LASs). In times of the coronavirus disease (COVID-19) pandemic, patients underwent 6MWTs wearing a surgical mask in ambulatory care. We investigated the impact of wearing a mask on 6-minute walk distances (6MWDs). METHOD: 6MWDs of 64 patients with end-stage lung diseases wearing an oronasal surgical mask were retrospectively compared to previously investigated 6MWDs of the same cohort, in a pre-COVID-19 pandemic era, without wearing a mask. Four patients were excluded due to a primary vascular disease, 29 patients due to clinically unstable pulmonary functions, and 1 patient due to a psychiatric disorder. RESULTS: The median age of the patients included was 55 (46-58) years; 15 (48%) were male. Ten (32.2%) were on the Eurotransplant lung transplant waiting list with a median LAS of 34.3 (31.9-36.2). Twenty (64.5%) patients had chronic obstructive pulmonary diseases, 7 (22.6%) had interstitial lung diseases, and 4 (12.9%) had other end-stage lung diseases. The mean 6MWD without versus with wearing a mask was 306.9 (101.9) versus 305.7 (103.8) m, with a mean difference of -1.19 m (95% confidence interval -13.4 to 11.03). The observed difference is statistically equivalent to zero (p < 0.001). No significant differences in 6MWDs were observed between the clinical groups. CONCLUSION: Wearing an oronasal surgical mask did not affect the 6MWDs of patients with advanced lung diseases. Therefore, a masked 6MWT appears to provide a reliable examination of functional exercise capacity in this cohort.


Subject(s)
COVID-19/prevention & control , Lung Diseases, Interstitial/physiopathology , Masks , Pulmonary Disease, Chronic Obstructive/physiopathology , Respiratory Insufficiency/physiopathology , Walk Test/methods , Blood Gas Analysis , Chronic Disease , Exercise Tolerance , Female , Forced Expiratory Volume , Humans , Lung Diseases/physiopathology , Lung Diseases/surgery , Lung Diseases, Interstitial/surgery , Lung Transplantation , Male , Middle Aged , Minimal Clinically Important Difference , Plethysmography, Whole Body , Pulmonary Disease, Chronic Obstructive/surgery , Reproducibility of Results , Respiratory Insufficiency/surgery , Retrospective Studies , SARS-CoV-2 , Vital Capacity
9.
Pharmacol Ther ; 225: 107839, 2021 09.
Article in English | MEDLINE | ID: covidwho-1152612

ABSTRACT

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-ß induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.


Subject(s)
Lung Diseases/drug therapy , Lung Diseases/physiopathology , Airway Remodeling/physiology , Asthma/drug therapy , Asthma/physiopathology , Calcium-Binding Proteins/metabolism , Extracellular Matrix/metabolism , Fibroblasts , Fibrosis/physiopathology , Glycoproteins/metabolism , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/physiopathology , Matrix Metalloproteinases/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/physiopathology , Transforming Growth Factor beta
10.
Hepatology ; 74(3): 1674-1686, 2021 09.
Article in English | MEDLINE | ID: covidwho-1103301

ABSTRACT

Pulmonary disease in liver cirrhosis and portal hypertension (PH) constitutes a challenging clinical scenario and may have important implications with regard to prognosis, liver transplantation (LT) candidacy, and post-LT outcome. Pre-LT evaluation should include adequate screening for pulmonary diseases that may occur concomitantly with liver disease as well as for those that may arise as a complication of end-stage liver disease and PH, given that either may jeopardize safe LT and successful outcome. It is key to discriminate those patients who would benefit from LT, especially pulmonary disorders that have been reported to resolve post-LT and are considered "pulmonary indications" for transplant, from those who are at increased mortality risk and in whom LT is contraindicated. In conclusion, in this article, we review the impact of several pulmonary disorders, including cystic fibrosis, alpha 1-antitrypsin deficiency, hereditary hemorrhagic telangiectasia, sarcoidosis, coronavirus disease 2019, asthma, chronic obstructive pulmonary disease, pulmonary nodules, interstitial lung disease, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension, on post-LT survival, as well as the reciprocal impact of LT on the evolution of lung function.


Subject(s)
Hypertension, Portal/complications , Liver Cirrhosis/complications , Liver Transplantation/mortality , Lung Diseases/complications , Adult , Asthma/diagnosis , Asthma/epidemiology , Asthma/mortality , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/mortality , COVID-19/virology , Child , Cystic Fibrosis , End Stage Liver Disease/complications , Hepatopulmonary Syndrome/diagnosis , Hepatopulmonary Syndrome/epidemiology , Hepatopulmonary Syndrome/mortality , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , Liver Transplantation/methods , Lung Diseases/epidemiology , Lung Diseases/pathology , Lung Diseases/physiopathology , Mass Screening , Patient Selection/ethics , Prognosis , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/mortality , Respiratory Function Tests/methods , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Sarcoidosis/diagnosis , Sarcoidosis/epidemiology , Sarcoidosis/mortality , Survival Rate/trends , Telangiectasia, Hereditary Hemorrhagic/diagnosis , Telangiectasia, Hereditary Hemorrhagic/epidemiology , Telangiectasia, Hereditary Hemorrhagic/mortality , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/epidemiology , alpha 1-Antitrypsin Deficiency/mortality
11.
Crit Care ; 25(1): 53, 2021 02 08.
Article in English | MEDLINE | ID: covidwho-1069578

ABSTRACT

The current pandemic of COVID-19 caused thousands of deaths and healthcare professionals struggle to properly manage infected patients. This review summarizes information about SARS-CoV-2 receptor binding dynamics and intricacies, lung autopsy findings, immune response patterns, evidence-based explanations for the immune response, and COVID-19-associated hypercoagulability.


Subject(s)
COVID-19/physiopathology , Carrier Proteins/physiology , Lung Diseases/physiopathology , Pneumonia, Viral/physiopathology , SARS-CoV-2/pathogenicity , COVID-19/immunology , Carrier Proteins/immunology , Humans , Lung Diseases/immunology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2/immunology
12.
Nature ; 591(7849): 293-299, 2021 03.
Article in English | MEDLINE | ID: covidwho-1046014

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic1-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses2. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.


Subject(s)
COVID-19/virology , Furin/metabolism , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Animals , Antibodies, Neutralizing/immunology , COVID-19/pathology , COVID-19/physiopathology , Cell Line , Chlorocebus aethiops , Cricetinae , Female , Humans , Lung Diseases/pathology , Lung Diseases/physiopathology , Lung Diseases/virology , Male , Mice , Mice, Transgenic , Models, Molecular , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Proteolysis , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Replication/genetics
13.
J Mol Cell Cardiol ; 153: 72-85, 2021 04.
Article in English | MEDLINE | ID: covidwho-989435

ABSTRACT

The first confirmed case of novel Coronavirus Disease 2019 (COVID-19) in the United States was reported on January 20, 2020. As of November 24, 2020, close to 12.2 million cases of COVID-19 was confirmed in the US, with over 255,958 deaths. The rapid transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), its unusual and divergent presentation has strengthened the status of COVID-19 as a major public health threat. In this review, we aim to 1- discuss the epidemiological data from various COVID-19 patient cohorts around the world and the USA as well the associated risk factors; 2- summarize the pathophysiology of SARS-CoV-2 infection and the underlying molecular mechanisms for the respiratory and cardiovascular manifestations; 3- highlight the potential treatments and vaccines as well as current clinical trials for COVID-19.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/drug therapy , Lung Diseases/drug therapy , SARS-CoV-2/isolation & purification , COVID-19/transmission , COVID-19/virology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/virology , Disease Management , Global Health , Humans , Lung Diseases/epidemiology , Lung Diseases/physiopathology , Lung Diseases/virology , United States/epidemiology
14.
Chest ; 158(6): 2502-2510, 2020 12.
Article in English | MEDLINE | ID: covidwho-956971

ABSTRACT

To reduce the spread of the severe acute respiratory syndrome coronavirus 2, many pulmonary function testing (PFT) laboratories have been closed or have significantly reduced their testing capacity. Because these mitigation strategies may be necessary for the next 6 to 18 months to prevent recurrent peaks in disease prevalence, fewer objective measurements of lung function will alter the diagnosis and care of patients with chronic respiratory diseases. PFT, which includes spirometry, lung volume, and diffusion capacity measurement, is essential to the diagnosis and management of patients with asthma, COPD, and other chronic lung conditions. Both traditional and innovative alternatives to conventional testing must now be explored. These may include peak expiratory flow devices, electronic portable spirometers, portable exhaled nitric oxide measurement, airwave oscillometry devices, and novel digital health tools such as smartphone microphone spirometers and mobile health technologies along with integration of machine learning approaches. The adoption of some novel approaches may not merely replace but could improve existing management strategies and alter common diagnostic paradigms. With these options comes important technical, privacy, ethical, financial, and medicolegal barriers that must be addressed. However, the coronavirus disease 19 pandemic also presents a unique opportunity to augment conventional testing by including innovative and emerging approaches to measuring lung function remotely in patients with respiratory disease. The benefits of such an approach have the potential to enhance respiratory care and empower patient self-management well beyond the current global pandemic.


Subject(s)
COVID-19 , Delivery of Health Care/methods , Lung Diseases/diagnosis , Lung Diseases/therapy , Respiratory Function Tests/instrumentation , Respiratory Function Tests/methods , Asthma/diagnosis , Asthma/physiopathology , Asthma/therapy , Breath Tests/instrumentation , Breath Tests/methods , Chronic Disease , Cystic Fibrosis/diagnosis , Cystic Fibrosis/therapy , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/therapy , Inventions , Lung Diseases/physiopathology , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/therapy , Lung Volume Measurements , Machine Learning , Oscillometry/instrumentation , Oscillometry/methods , Peak Expiratory Flow Rate , Pulmonary Diffusing Capacity/instrumentation , Pulmonary Diffusing Capacity/methods , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Disease, Chronic Obstructive/therapy , Self-Management , Smartphone , Spirometry/instrumentation , Spirometry/methods
15.
Respir Res ; 21(1): 276, 2020 Oct 21.
Article in English | MEDLINE | ID: covidwho-883579

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology. METHODS: We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing. RESULTS: We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia. DISCUSSION: Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04416100.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/metabolism , Homeostasis , Iron/metabolism , Lung Diseases/etiology , Lung Diseases/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , Adult , Aged , Anemia/etiology , C-Reactive Protein/analysis , COVID-19 , Cohort Studies , Coronavirus Infections/physiopathology , Female , Ferritins/blood , Follow-Up Studies , Humans , Inflammation/etiology , Inflammation/metabolism , Interleukin-6/blood , Lung Diseases/physiopathology , Male , Middle Aged , Monocytes/metabolism , Pandemics , Pneumonia, Viral/physiopathology , Prospective Studies , Tomography, X-Ray Computed
16.
Respir Med ; 174: 106197, 2020.
Article in English | MEDLINE | ID: covidwho-880602

ABSTRACT

BACKGROUND: Since December 2019 the novel coronavirus disease 2019 (COVID-19) has been burdening all health systems worldwide. However, pulmonary and extrapulmonary sequelae of COVID-19 after recovery from the acute disease are unknown. MATERIAL AND METHODS: Hospitalized COVID-19 patients not requiring mechanical ventilation were included and followed 6 weeks after discharge. Body plethysmography, lung diffusion capacity (DLco), blood gas analysis (ABG), 6-min walk test (6MWT), echocardiography, and laboratory tests were performed. Quality of life (QoL), depression, and anxiety were assessed using validated questionnaires. RESULTS: 33 patients with severe disease were included. Patients were discharged without prophylactic anticoagulation. At follow-up there were no thromboembolic complications in any patient. 11 patients (33%) had dyspnea, 11 (33%) had cough, and 15 (45%) suffered from symptoms of fatigue. Pulmonary function tests including ABG did not reveal any limitations (TLC: median=94% of predicted {IQR:85-105}; VC: 93% {78-101}; FEV1: 95% {72-103}; FEV1/FVC 79% {76-85}; PaO2: 72 mmHg {67-79}; PaCO2: 38 mmHg {35-38}), except for slightly reduced DLco (77% {69-95}). There were no echocardiographic impairments. 6MWT distance was reduced in most patients without oxygen desaturation. According to standardized questionnaires, patients suffered from reduced QoL, mainly due to decreased mobility (SGRQ activity score: 54 {19-78}). There were no indicators for depression or anxiety (PHQ-9: 7 {4-11}, GAD-7: 4 {1-9}, respectively). CONCLUSIONS: Hospitalized patients with severe COVID-19, who did not require mechanical ventilation, are unlikely to develop pulmonary long-term impairments, thromboembolic complications or cardiac impairments after discharge but frequently suffer from symptoms of fatigue.


Subject(s)
COVID-19/complications , Lung Diseases/etiology , SARS-CoV-2/genetics , Aged , Anxiety/epidemiology , Anxiety/etiology , Blood Gas Analysis/methods , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19/virology , Cough/epidemiology , Depression/epidemiology , Depression/etiology , Dyspnea/epidemiology , Echocardiography/methods , Fatigue/epidemiology , Female , Follow-Up Studies , Heart Diseases/epidemiology , Heart Diseases/etiology , Humans , Lung Diseases/epidemiology , Lung Diseases/physiopathology , Male , Middle Aged , Patient Discharge , Plethysmography, Whole Body/methods , Prospective Studies , Pulmonary Diffusing Capacity/methods , Quality of Life , Respiratory Function Tests/methods , Severity of Illness Index , Thromboembolism/epidemiology , Thromboembolism/etiology , Walk Test/methods
17.
Infection ; 49(1): 63-73, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-812468

ABSTRACT

PURPOSE: Knowledge regarding patients' clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19. METHODS: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models. RESULTS: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66-85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46-65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25-2.42, p = 0.001; 66-85 years: aOR 1.93, 95% CI 1.36-2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49-3.81, p < 0.001 vs. individuals aged 26-45 years], male sex (aOR 1.23, 95% CI 1.01-1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09-1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04-1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis. CONCLUSION: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.


Subject(s)
COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Diabetes Mellitus/epidemiology , Kidney Diseases/epidemiology , Lung Diseases/epidemiology , Pandemics , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Body Mass Index , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/virology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/virology , Cohort Studies , Comorbidity , Diabetes Mellitus/diagnosis , Diabetes Mellitus/physiopathology , Diabetes Mellitus/virology , Europe/epidemiology , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Kidney Diseases/diagnosis , Kidney Diseases/physiopathology , Kidney Diseases/virology , Logistic Models , Lung Diseases/diagnosis , Lung Diseases/physiopathology , Lung Diseases/virology , Male , Middle Aged , SARS-CoV-2/pathogenicity , Severity of Illness Index , Sex Factors
18.
Food Chem Toxicol ; 146: 111769, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-803143

ABSTRACT

Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/etiology , Digestive System Diseases/etiology , Kidney Diseases/etiology , Lung Diseases/etiology , Neoplasms/epidemiology , Nervous System Diseases/etiology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/physiopathology , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/virology , Comorbidity , Digestive System Diseases/physiopathology , Digestive System Diseases/virology , Female , Humans , Kidney Diseases/physiopathology , Kidney Diseases/virology , Lung Diseases/physiopathology , Lung Diseases/virology , Male , Nervous System Diseases/physiopathology , Nervous System Diseases/virology , Pandemics , SARS-CoV-2
19.
Nat Commun ; 11(1): 4883, 2020 09 28.
Article in English | MEDLINE | ID: covidwho-801570

ABSTRACT

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/physiopathology , Hypoxia/etiology , Hypoxia/physiopathology , Lung Diseases/etiology , Lung Diseases/physiopathology , Lung/blood supply , Lung/physiopathology , Models, Biological , Pneumonia, Viral/complications , Pneumonia, Viral/physiopathology , Pulmonary Circulation/physiology , COVID-19 , Computer Simulation , Coronavirus Infections/epidemiology , Humans , Hypoxia/therapy , Lung Diseases/therapy , Mathematical Concepts , Models, Cardiovascular , Oxygen Inhalation Therapy , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Time Factors , Vasoconstriction/physiology , Vasodilation/physiology , Ventilation-Perfusion Ratio/physiology
20.
Echocardiography ; 37(9): 1353-1361, 2020 09.
Article in English | MEDLINE | ID: covidwho-733238

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is characterized by severe lung involvement and hemodynamic alterations. Critical care ultrasonography is vital because it provides real time information for diagnosis and treatment. Suggested protocols for image acquisition and measurements have not yet been evaluated. METHODS: This cross-sectional study was conducted at two centers from 1 April 2020 to 30 May 2020 in adult patients with confirmed COVID-19 infection admitted to the critical care unit. Cardiac and pulmonary evaluations were performed using the ORACLE protocol, specifically designed for this study, to ensure a structured process of image acquisition and limit staff exposure to the infection. RESULTS: Eighty-two consecutively admitted patients were evaluated. Most of the patients were males, with a median age of 56 years, and the most frequent comorbidities were hypertension and type 2 diabetes, and 25% of the patients had severe acute respiratory distress syndrome. The most frequent ultrasonographic findings were elevated pulmonary artery systolic pressure (69.5%), E/e' ratio > 14 (29.3%), and right ventricular dilatation (28%) and dysfunction (26.8%). A high rate of fluid responsiveness (82.9%) was observed. The median score (19 points) on pulmonary ultrasound did not reveal any variation between the groups. Elevated pulmonary artery systolic pressure was associated with higher in-hospital mortality. CONCLUSION: The ORACLE protocol was a feasible, rapid, and safe bedside tool for hemodynamic and respiratory evaluation of patients with COVID-19. Further studies should be performed on the alteration in pulmonary hemodynamics and right ventricular function and its relationship with outcomes.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Critical Care/methods , Heart Diseases/diagnostic imaging , Lung Diseases/diagnostic imaging , Ultrasonography/methods , Aged , Clinical Protocols , Cross-Sectional Studies , Feasibility Studies , Female , Heart/diagnostic imaging , Heart/physiopathology , Heart Diseases/etiology , Heart Diseases/physiopathology , Hemodynamics/physiology , Humans , Lung/diagnostic imaging , Lung/physiopathology , Lung Diseases/etiology , Lung Diseases/physiopathology , Male , Middle Aged , Pandemics , Point-of-Care Systems , Ultrasonography/instrumentation
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