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1.
Arch Pathol Lab Med ; 146(6): 660-676, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1876076

ABSTRACT

CONTEXT.­: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. OBJECTIVE.­: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN.­: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. RESULTS.­: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. CONCLUSIONS.­: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.


Subject(s)
COVID-19 , Perinatal Death , Placenta , Pregnancy Complications, Infectious , COVID-19/complications , Female , Fibrin , Humans , Hypoxia/pathology , Hypoxia/virology , Infant, Newborn , Infectious Disease Transmission, Vertical , Perinatal Death/etiology , Placenta/pathology , Pregnancy , Pregnancy Complications, Infectious/mortality , Pregnancy Complications, Infectious/pathology , Pregnancy Complications, Infectious/virology , Retrospective Studies , SARS-CoV-2 , Stillbirth
2.
BMC Pulm Med ; 22(1): 51, 2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1666648

ABSTRACT

BACKGROUND: Understanding heterogeneity seen in patients with COVIDARDS and comparing to non-COVIDARDS may inform tailored treatments. METHODS: A multidisciplinary team of frontline clinicians and data scientists worked to create the Northwell COVIDARDS dataset (NorthCARDS) leveraging over 11,542 COVID-19 hospital admissions. The data was then summarized to examine descriptive differences based on clinically meaningful categories of lung compliance, and to examine trends in oxygenation. FINDINGS: Of the 1536 COVIDARDS patients in the NorthCARDS dataset, there were 531 (34.6%) who had very low lung compliance (< 20 ml/cmH2O), 970 (63.2%) with low-normal compliance (20-50 ml/cmH2O), and 35 (2.2%) with high lung compliance (> 50 ml/cmH2O). The very low compliance group had double the median time to intubation compared to the low-normal group (107.3 h (IQR 25.8, 239.2) vs. 39.5 h (IQR 5.4, 91.6)). Overall, 68.8% (n = 1057) of the patients died during hospitalization. In comparison to non-COVIDARDS reports, there were less patients in the high compliance category (2.2% vs. 12%, compliance ≥ 50 mL/cmH20), and more patients with P/F ≤ 150 (59.8% vs. 45.6%). There is a statistically significant correlation between compliance and P/F ratio. The Oxygenation Index is the highest in the very low compliance group (12.51, SD(6.15)), and lowest in high compliance group (8.78, SD(4.93)). CONCLUSIONS: The respiratory system compliance distribution of COVIDARDS is similar to non-COVIDARDS. In some patients, there may be a relation between time to intubation and duration of high levels of supplemental oxygen treatment on trajectory of lung compliance.


Subject(s)
COVID-19/physiopathology , Hypoxia/virology , Lung/physiopathology , Respiratory Distress Syndrome/virology , Adult , Aged , Aged, 80 and over , Biomechanical Phenomena , COVID-19/therapy , Case-Control Studies , Disease Progression , Female , Humans , Hypoxia/physiopathology , Hypoxia/therapy , Male , Middle Aged , Respiration, Artificial , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , Respiratory Function Tests , Retrospective Studies , Treatment Outcome
3.
Lancet ; 397(10285): 1637-1645, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1655260

ABSTRACT

BACKGROUND: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg-800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76-0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77-0·92; p<0·0001). INTERPRETATION: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , COVID-19/therapy , Hypoxia/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , Female , Hospital Mortality , Hospitalization , Humans , Hypoxia/diagnosis , Hypoxia/virology , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , SARS-CoV-2/isolation & purification , Severity of Illness Index , Treatment Outcome , Young Adult
4.
Am J Respir Crit Care Med ; 205(4): 431-439, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1551111

ABSTRACT

Rationale: The "Berlin definition" of acute respiratory distress syndrome (ARDS) does not allow inclusion of patients receiving high-flow nasal oxygen (HFNO). However, several articles have proposed that criteria for defining ARDS should be broadened to allow inclusion of patients receiving HFNO. Objectives: To compare the proportion of patients fulfilling ARDS criteria during HFNO and soon after intubation, and 28-day mortality between patients treated exclusively with HFNO and patients transitioned from HFNO to invasive mechanical ventilation (IMV). Methods: From previously published studies, we analyzed patients with coronavirus disease (COVID-19) who had PaO2/FiO2 of ⩽300 while treated with ⩾40 L/min HFNO, or noninvasive ventilation (NIV) with positive end-expiratory pressure of ⩾5 cm H2O (comparator). In patients transitioned from HFNO/NIV to invasive mechanical ventilation (IMV), we compared ARDS severity during HFNO/NIV and soon after IMV. We compared 28-day mortality in patients treated exclusively with HFNO/NIV versus patients transitioned to IMV. Measurements and Main Results: We analyzed 184 and 131 patients receiving HFNO or NIV, respectively. A total of 112 HFNO and 69 NIV patients transitioned to IMV. Of those, 104 (92.9%) patients on HFNO and 66 (95.7%) on NIV continued to have PaO2/FiO2 ⩽300 under IMV. Twenty-eight-day mortality in patients who remained on HFNO was 4.2% (3/72), whereas in patients transitioned from HFNO to IMV, it was 28.6% (32/112) (P < 0.001). Twenty-eight-day mortality in patients who remained on NIV was 1.6% (1/62), whereas in patients who transitioned from NIV to IMV, it was 44.9% (31/69) (P < 0.001). Overall mortality was 19.0% (35/184) and 24.4% (32/131) for HFNO and NIV, respectively (P = 0.2479). Conclusions: Broadening the ARDS definition to include patients on HFNO with PaO2/FiO2 ⩽300 may identify patients at earlier stages of disease but with lower mortality.


Subject(s)
COVID-19/therapy , Hypoxia/therapy , Oxygen Inhalation Therapy/methods , Respiratory Distress Syndrome/therapy , Aged , COVID-19/mortality , COVID-19/physiopathology , Female , Humans , Hypoxia/diagnosis , Hypoxia/mortality , Hypoxia/virology , Italy/epidemiology , Male , Middle Aged , Oxygen Inhalation Therapy/mortality , Patient Acuity , Respiration, Artificial/methods , Respiration, Artificial/mortality , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/virology , Treatment Outcome
5.
Placenta ; 117: 187-193, 2022 01.
Article in English | MEDLINE | ID: covidwho-1550030

ABSTRACT

INTRODUCTION: Recent evidence supports the - rare - occurrence of vertical transplacental SARS-CoV-2 transmission. We previously determined that placental expression of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, and associated viral cell entry regulators is upregulated by hypoxia. In the present study, we utilized a clinically relevant model of SARS-CoV-2-associated chronic histiocytic intervillositis/massive perivillous fibrin deposition (CHIV/MPFVD) to test the hypothesis that placental hypoxia may facilitate placental SARS-CoV-2 infection. METHODS: We performed a comparative immunohistochemical and/or RNAscope in-situ hybridization analysis of carbonic anhydrase IX (CAIX, hypoxia marker), ACE2 and SARS-CoV-2 expression in free-floating versus fibrin-encased chorionic villi in a 20-weeks' gestation placenta with SARS-CoV-2-associated CHIV/MPVFD. RESULTS: The levels of CAIX and ACE2 immunoreactivity were significantly higher in trophoblastic cells of fibrin-encased villi than in those of free-floating villi, consistent with hypoxia-induced ACE2 upregulation. SARS-CoV-2 showed a similar preferential localization to trophoblastic cells of fibrin-encased villi. DISCUSSION: The localization of SARS-CoV-2 to hypoxic, fibrin-encased villi in this placenta with CHIV/MPVFD suggests placental infection and, therefore, transplacental SARS-CoV-2 transmission may be promoted by hypoxic conditions, mediated by ACE2 and similar hypoxia-sensitive viral cell entry mechanisms. Understanding of a causative link between placental hypoxia and SARS-CoV-2 transmittability may potentially lead to the development of alternative strategies for prevention of intrauterine COVID-19 transmission.


Subject(s)
COVID-19/complications , Fibrin/analysis , Hypoxia/virology , Placenta/virology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/isolation & purification , Adult , Angiotensin-Converting Enzyme 2/analysis , COVID-19/pathology , COVID-19/virology , Carbonic Anhydrase IX/analysis , Chorionic Villi/enzymology , Chorionic Villi/virology , Female , Gestational Age , Histiocytes/pathology , Humans , Hypoxia/pathology , Infectious Disease Transmission, Vertical , Necrosis/virology , Placenta/chemistry , Placenta/pathology , Pregnancy , Stillbirth , Trophoblasts/enzymology , Trophoblasts/virology
6.
Placenta ; 117: 72-77, 2022 01.
Article in English | MEDLINE | ID: covidwho-1525920

ABSTRACT

Coronavirus disease 2019 (COVID-19) pneumonia rarely occurs in pregnant women. Case reports indicate that fibrin and lymphohistiocytic lesions in placentas may be typical. However, a meta-analysis to clarify whether there is a COVID-19-associated pattern of placental lesions has not yet been conducted. Systematic literature search with meta-analysis of publications on 10 or more cases of pregnancy with SARS-CoV-2 infection and placenta examination (30 publications from 2019 to 2021; 1452 placenta cases) was performed. The meta-analysis did not reveal any COVID-19-specific placenta changes. The incidence of both vascular and inflammatory lesions was mainly comparable to that of non-COVID-19 pregnancies. Transplacental viral transmission is very rare and there are no typical placental changes. The most important prognostic factor seems to be maternal-fetal hypoxia in the context of pneumonia.


Subject(s)
COVID-19/complications , Placenta/pathology , Pregnancy Complications, Infectious/virology , SARS-CoV-2 , Adult , COVID-19/pathology , COVID-19/transmission , Female , Fetal Hypoxia/virology , Humans , Hypoxia/virology , Infectious Disease Transmission, Vertical/statistics & numerical data , Pregnancy , Pregnancy Complications, Infectious/pathology
7.
Nat Commun ; 12(1): 6559, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1514414

ABSTRACT

SARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. Here we demonstrate in K18-hACE2 transgenic mice that B.1.1.7 and B.1.351 are 100-fold more lethal than the original SARS-CoV-2 bearing 614D. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. However, K18-hACE2 mice with prior infection of early SARS-CoV-2 strains or intramuscular immunization of viral spike or receptor binding domain are resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC than early strains. Our results thus distinguish pathogenic patterns in K18-hACE2 mice caused by B.1.1.7 and B.1.351 infection from those induced by early SARS-CoV-2 strains, and help inform potential medical interventions for combating COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Neutralizing/immunology , COVID-19/genetics , COVID-19/pathology , Cell Line , Chlorocebus aethiops , Cytokines/immunology , Disease Models, Animal , Female , Fibrin Fibrinogen Degradation Products/immunology , Hypoxia/virology , Lung/metabolism , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , SARS-CoV-2/classification , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
9.
Lipids Health Dis ; 20(1): 126, 2021 Oct 03.
Article in English | MEDLINE | ID: covidwho-1448237

ABSTRACT

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , Chemical and Drug Induced Liver Injury/complications , Hypoxia/complications , Liver/metabolism , Non-alcoholic Fatty Liver Disease/complications , SARS-CoV-2/pathogenicity , Age Factors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/virology , Cytokines/genetics , Cytokines/metabolism , Dipeptides/therapeutic use , Gene Expression Regulation , Glucose/metabolism , Glycyrrhizic Acid/therapeutic use , Humans , Hypoxia/drug therapy , Hypoxia/pathology , Hypoxia/virology , Liver/drug effects , Liver/pathology , Liver/virology , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/virology , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/virology , Receptors, Virus/genetics , Receptors, Virus/metabolism , Severity of Illness Index
10.
J Infect Dev Ctries ; 15(3): 353-359, 2021 Mar 31.
Article in English | MEDLINE | ID: covidwho-1444370

ABSTRACT

INTRODUCTION: The early identification of factors that predict the length of hospital stay (HS) in patients affected by coronavirus desease (COVID-19) might assist therapeutic decisions and patient flow management. METHODOLOGY: We collected, at the time of admission, routine clinical, laboratory, and imaging parameters of hypoxia, lung damage, inflammation, and organ dysfunction in a consecutive series of 50 COVID-19 patients admitted to the Respiratory Disease and Infectious Disease Units of the University Hospital of Sassari (North-Sardinia, Italy) and alive on discharge. RESULTS: Prolonged HS (PHS, >21 days) patients had significantly lower PaO2/FiO2 ratio and lymphocytes, and significantly higher Chest CT severity score, C-reactive protein (CRP) and lactic dehydrogenase (LDH) when compared to non-PHS patients. In univariate logistic regression, Chest CT severity score (OR = 1.1891, p = 0.007), intensity of care (OR = 2.1350, p = 0.022), PaO2/FiO2 ratio (OR = 0.9802, p = 0.007), CRP (OR = 1.0952, p = 0.042) and platelet to lymphocyte ratio (OR = 1.0039, p = 0.036) were significantly associated with PHS. However, in multivariate logistic regression, only the PaO2/FiO2 ratio remained significantly correlated with PHS (OR = 0.9164; 95% CI 0.8479-0.9904, p = 0.0275). In ROC curve analysis, using a threshold of 248, the PaO2/FiO2 ratio predicted PHS with sensitivity and specificity of 60% and 91%, respectively (AUC = 0.780, 95% CI 0.637-0.886 p = 0.002). CONCLUSIONS: The PaO2/FiO2 ratio on admission is independently associated with PHS in COVID-19 patients. Larger prospective studies are needed to confirm this finding.


Subject(s)
COVID-19/diagnosis , COVID-19/physiopathology , Hypoxia/diagnosis , Length of Stay/statistics & numerical data , Aged , Aged, 80 and over , COVID-19/epidemiology , Female , Humans , Hypoxia/virology , Italy/epidemiology , Male , Middle Aged , Prospective Studies , Retrospective Studies
11.
Mol Med ; 27(1): 120, 2021 09 26.
Article in English | MEDLINE | ID: covidwho-1440900

ABSTRACT

BACKGROUND: Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called 'long COVID' and 'neuroCOVID', becomes increasingly evident. Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term 'hypoxia paradox'. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this 'hypoxia paradox' caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues. SHORT CONCLUSION: Substitution of EPO may-among other beneficial EPO effects in severe COVID-19-circumvent downstream consequences of the 'hypoxia paradox'. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.


Subject(s)
COVID-19/complications , COVID-19/drug therapy , Erythropoietin/genetics , Hypoxia/drug therapy , Lung/drug effects , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Erythropoietin/analogs & derivatives , Erythropoietin/therapeutic use , Humans , Hypoxia/genetics , Hypoxia/pathology , Hypoxia/virology , Lung/pathology , Lung/virology , Pandemics , Recombinant Proteins/genetics , Recombinant Proteins/therapeutic use , SARS-CoV-2/drug effects
13.
Med Sci Monit ; 27: e930776, 2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1344551

ABSTRACT

During the coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients presented with COVID-19 pneumonia of varying severity. The phenomenon of severe hypoxemia without signs of respiratory distress is also known as silent or hidden hypoxemia. Although silent hypoxemia is not unique to pneumonia due to SARS-CoV-2 infection, this phenomenon is now recognized to be associated with severe COVID-19 pneumonia. Proper management of critically ill patients is the key to reducing mortality. Herein, we summarize the possible and rare factors contributing to silent hypoxemia in patients with COVID-19. Microvascular thrombosis causes dead space ventilation in the lungs, and the flow of pulmonary capillaries is reduced, which leads to an imbalance in the V/Q ratio. The dissociation curve of oxyhemoglobin shifts to the left and limits the release of oxygen to the tissue. SARS-CoV-2 interferes with the synthesis of hemoglobin and reduces the ability to carry oxygen. The accumulation of endogenous carbon monoxide and carboxyhemoglobin will reduce the total oxygen carrying capacity and interfere with pulse oxygen saturation readings. There are also some non-specific factors that cause the difference between pulse oximetry and oxygen partial pressure. We propose some potentially more effective clinical alternatives and recommendations for optimizing the clinical management processes of patients with COVID-19. This review aims to describe the prevalence of silent hypoxemia in COVID-19 pneumonia, to provide an update on what is known of the pathophysiology, and to highlight the importance of diagnosing silent hypoxemia in patients with COVID-19 pneumonia.


Subject(s)
COVID-19/metabolism , Hypoxia/virology , Pneumonia, Viral/virology , Asymptomatic Diseases/epidemiology , COVID-19/epidemiology , COVID-19/virology , Humans , Hypoxia/epidemiology , Hypoxia/metabolism , Lung/cytology , Lung/metabolism , Lung/virology , Microvessels/metabolism , Oximetry , Oxygen/metabolism , Pneumonia, Viral/metabolism , Prevalence , SARS-CoV-2/isolation & purification , Thrombosis/metabolism , Thrombosis/virology
15.
Crit Care ; 25(1): 224, 2021 06 30.
Article in English | MEDLINE | ID: covidwho-1286832

ABSTRACT

BACKGROUND: Previous studies reporting the causes of death in patients with severe COVID-19 have provided conflicting results. The objective of this study was to describe the causes and timing of death in patients with severe COVID-19 admitted to the intensive care unit (ICU). METHODS: We performed a retrospective study in eight ICUs across seven French hospitals. All consecutive adult patients (aged ≥ 18 years) admitted to the ICU with PCR-confirmed SARS-CoV-2 infection and acute respiratory failure were included in the analysis. The causes and timing of ICU deaths were reported based on medical records. RESULTS: From March 1, 2020, to April 28, 287 patients were admitted to the ICU for SARS-CoV-2 related acute respiratory failure. Among them, 93 patients died in the ICU (32%). COVID-19-related multiple organ dysfunction syndrome (MODS) was the leading cause of death (37%). Secondary infection-related MODS accounted for 26% of ICU deaths, with a majority of ventilator-associated pneumonia. Refractory hypoxemia/pulmonary fibrosis was responsible for death in 19% of the cases. Fatal ischemic events (venous or arterial) occurred in 13% of the cases. The median time from ICU admission to death was 15 days (25th-75th IQR, 7-27 days). COVID-19-related MODS had a median time from ICU admission to death of 14 days (25th-75th IQR: 7-19 days), while only one death had occurred during the first 3 days since ICU admission. CONCLUSIONS: In our multicenter observational study, COVID-19-related MODS and secondary infections were the two leading causes of death, among severe COVID-19 patients admitted to the ICU.


Subject(s)
COVID-19/mortality , Multiple Organ Failure/mortality , Pneumonia, Viral/mortality , Adult , Cause of Death , Female , Hospital Mortality , Humans , Hypoxia/mortality , Hypoxia/virology , Intensive Care Units , Ischemia/mortality , Ischemia/virology , Male , Multiple Organ Failure/virology , Pneumonia, Ventilator-Associated/mortality , Pneumonia, Ventilator-Associated/virology , Pneumonia, Viral/virology , Pulmonary Fibrosis/mortality , Pulmonary Fibrosis/virology , Retrospective Studies , SARS-CoV-2
16.
Ann Pharmacother ; 56(3): 237-244, 2022 03.
Article in English | MEDLINE | ID: covidwho-1285161

ABSTRACT

BACKGROUND: Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES: The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS: A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE: Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Respiratory Insufficiency , Adult , COVID-19/drug therapy , COVID-19/mortality , Hospital Mortality , Humans , Hypoxia/drug therapy , Hypoxia/virology , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , Retrospective Studies , Treatment Outcome
17.
J Aerosol Med Pulm Drug Deliv ; 34(4): 262-264, 2021 08.
Article in English | MEDLINE | ID: covidwho-1276115

ABSTRACT

Despite the various parenchymal presentation of coronavirus disease 2019 (COVID-19) pneumonia, the involvement of the vascular component, the reduction of perfusion in noninjured part of the lung and secondary right to left shunt play an important role in the genesis of the respiratory insufficiency. We present the case of a 72-year-old woman admitted to Livorno Hospital for severe respiratory insufficiency due to SARS-CoV-2 infection unresponsive to noninvasive in whom administration of nebulized phosphodiesterase 3 (PDE3) inhibitor enoximone was able to improve oxygenation avoiding tracheal intubation. Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension. This is the first case showing that inhaled route administration of PDE3 inhibitor enoximone could be important in the management of COVID-19 hypoxemia, to restore perfusion in noninjured part of the lung, improving oxygenation and avoiding risks of systemic infusion.


Subject(s)
COVID-19/drug therapy , Enoximone/administration & dosage , Hypoxia/drug therapy , Lung/blood supply , Phosphodiesterase 3 Inhibitors/administration & dosage , Pulmonary Circulation/drug effects , Administration, Inhalation , Aerosols , Aged , COVID-19/physiopathology , COVID-19/virology , Female , Humans , Hypoxia/physiopathology , Hypoxia/virology , Nebulizers and Vaporizers , Treatment Outcome
18.
Acta Pharmacol Sin ; 41(12): 1539-1546, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1269381

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19) and its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the greatest current threat to global public health. The highly infectious SARS-CoV-2 virus primarily attacks pulmonary tissues and impairs gas exchange leading to acute respiratory distress syndrome (ARDS) and systemic hypoxia. The current pharmacotherapies for COVID-19 largely rely on supportive and anti-thrombi treatment and the repurposing of antimalarial and antiviral drugs such as hydroxychloroquine and remdesivir. For a better mechanistic understanding of COVID-19, our present review focuses on its primary pathophysiologic features: hypoxia and cytokine storm, which are a prelude to multiple organ failure and lethality. We discussed a possible link between the activation of hypoxia inducible factor 1α (HIF-1α) and cell entry of SARS-CoV-2, since HIF-1α is shown to suppress the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) and upregulate disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). In addition, the protein targets of HIF-1α are involved with the activation of pro-inflammatory cytokine expression and the subsequent inflammatory process. Furthermore, we hypothesized a potential utility of so-called "hypoxic conditioning" to activate HIF-1α-induced cytoprotective signaling for reduction of illness severity and improvement of vital organ function in patients with COVID-19. Taken together, we would propose further investigations into the hypoxia-related molecular mechanisms, from which novel targeted therapies can be developed for the improved management of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Animals , COVID-19/physiopathology , COVID-19/virology , Cytokine Release Syndrome/virology , Drug Development , Drug Repositioning , Humans , Hypoxia/drug therapy , Hypoxia/virology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Molecular Targeted Therapy , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
19.
J Enzyme Inhib Med Chem ; 36(1): 1230-1235, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1254219

ABSTRACT

The ongoing Covid-19 is a contagious disease, and it is characterised by different symptoms such as fever, cough, and shortness of breath. Rising concerns about Covid-19 have severely affected the healthcare system in all countries as the Covid-19 outbreak has developed at a rapid rate all around the globe. Intriguing, a clinically used drug, acetazolamide (a specific inhibitor of carbonic anhydrase, CA, EC 4.2.1.1), is used to treat high-altitude pulmonary oedema (HAPE), showing a high degree of clinical similarities with the pulmonary disease caused by Covid-19. In this context, this preliminary study aims to provide insights into some factors affecting the Covid-19 patients, such as hypoxaemia, hypoxia as well as the blood CA activity. We hypothesise that patients with Covid-19 problems could show a dysregulated acid-base status influenced by CA activity. These preliminary results suggest that the use of CA inhibitors as a pharmacological treatment for Covid-19 may be beneficial.


Subject(s)
Acetazolamide/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Carbonic Anhydrase Inhibitors/therapeutic use , Carbonic Anhydrases/blood , Acid-Base Equilibrium/drug effects , Altitude Sickness/blood , Altitude Sickness/drug therapy , Anticonvulsants/therapeutic use , Bicarbonates/blood , COVID-19/blood , COVID-19/diagnostic imaging , COVID-19/virology , Carbon Dioxide/blood , Cough/blood , Cough/drug therapy , Cough/pathology , Cough/virology , Drug Repositioning , Dyspnea/blood , Dyspnea/drug therapy , Dyspnea/pathology , Dyspnea/virology , Fever/blood , Fever/drug therapy , Fever/pathology , Fever/virology , Humans , Hydrogen-Ion Concentration , Hypertension, Pulmonary/blood , Hypertension, Pulmonary/drug therapy , Hypoxia/blood , Hypoxia/drug therapy , Hypoxia/pathology , Hypoxia/virology , Oximetry , Research Design , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Severity of Illness Index , Tomography, X-Ray Computed
20.
Physiol Meas ; 42(6)2021 06 29.
Article in English | MEDLINE | ID: covidwho-1246679

ABSTRACT

Respiratory rate (RR) is routinely used to monitor patients with infectious, cardiac and respiratory diseases and is a component of early warning scores used to predict patient deterioration. However, it is often measured visually with considerable bias and inaccuracy.Objectives. Firstly, to compare distribution and accuracy of electronically measured RR (EMRR) and visually measured RR (VMRR). Secondly, to determine whether, and how far in advance, continuous electronic RR monitoring can predict oncoming hypoxic and pyrexic episodes in infectious respiratory disease.Approach.A retrospective cohort study analysing the difference between EMRR and VMRR was conducted using patient data from a large tertiary hospital. Cox proportional hazards models were used to determine whether continuous, EMRR measurements could predict oncoming hypoxic (SpO2 < 92%) and pyrexic (temperature >38 °C) episodes.Main results.Data were gathered from 34 COVID-19 patients, from which a total of 3445 observations of VMRR (independent of Hawthorne effect), peripheral oxygen saturation and temperature and 729 117 observations of EMRR were collected. VMRR had peaks in distribution at 18 and 20 breaths per minute. 70.9% of patients would have had a change of treatment during their admission based on the UK's National Early Warning System if EMRR was used in place of VMRR. An elevated EMRR was predictive of hypoxic (hazard ratio: 1.8 (1.05-3.07)) and pyrexic (hazard ratio: 9.7 (3.8-25)) episodes over the following 12 h.Significance.Continuous EMRR values are systematically different to VMRR values, and results suggest it is a better indicator of true RR as it has lower kurtosis, higher variance, a lack of peaks at expected values (18 and 20) and it measures a physiological component of breathing directly (abdominal movement). Results suggest EMRR is a strong marker of oncoming hypoxia and is highly predictive of oncoming pyrexic events in the following 12 h. In many diseases, this could provide an early window to escalate care prior to deterioration, potentially preventing morbidity and mortality.


Subject(s)
COVID-19 , Fever/diagnosis , Hypoxia/diagnosis , Monitoring, Physiologic , Respiratory Rate , COVID-19/diagnosis , Fever/virology , Humans , Hypoxia/virology , Retrospective Studies
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