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1.
Preprint in English | EuropePMC | ID: ppcovidwho-295673

ABSTRACT

Objective: Oxidative stress conditions may be responsible for an up-regulation of the expression of heme oxygenase (HO), the enzyme synthesizing carbon monoxide (CO) in cells. Elevated levels of arterial carboxyhemoglogin (aCOHb) have been found in critically ill patients, including those suffering from acute lung injury. We aimed to investigate the changes of aCOHb levels in COVID-19 critically ill patients. Design: Single center retrospective cohort study between March 1 and December 31, 2020. Setting: University teaching hospital with 900 beds including 48 ICU beds. Patients : Consecutive adults requiring ICU admission for severe COVID-19 infection. Measurements and main results : After exclusion of 23 patients who required extracorporeal membranous oxygenation (ECMO), a total of 135 patients was considered, from whom 76 required mechanical ventilation (MV) that was prolonged for more than 20 days in 28 patients. Demographics, laboratory values, treatment and outcomes were recorded. The evolution of aCOHb over time was investigated among survivors and non-survivors and among patients with or without MV. The admission and peak aCOHb values did not differ among survivors or non-survivors. In the patients with MV, there was a significant increase of aCOHb with time, with a biphasic evolution for the patients ventilated for more than 20 days: a parallel increase of aCOHb and PaCO 2 followed by a trend to a plateau of aCOHb during PaCO 2 recovery. Conclusions: Progressive increase in aCOHb from endogenous source is observed in COVID-19 patients requiring prolonged mechanical ventilation. Decrease of aCOHb appears slower than PaCO 2 recovery.

2.
Preprint in English | EuropePMC | ID: ppcovidwho-293398

ABSTRACT

Objective: Oxidative stress conditions may be responsible for an up-regulation of the expression of heme oxygenase (HO), the enzyme synthesizing carbon monoxide (CO) in cells. Elevated levels of arterial carboxyhemoglogin (aCOHb) have been found in critically ill patients, including those suffering from acute lung injury. We aimed to investigate the changes of aCOHb levels in COVID-19 critically ill patients. Design: Single center retrospective cohort study between March 1 and December 31, 2020. Setting: University teaching hospital with 900 beds including 48 ICU beds. Patients : Consecutive adults requiring ICU admission for severe COVID-19 infection. Measurements and main results : After exclusion of 23 patients who required extracorporeal membranous oxygenation (ECMO), a total of 135 patients was considered, from whom 76 required mechanical ventilation (MV) that was prolonged for more than 20 days in 28 patients. Demographics, laboratory values, treatment and outcomes were recorded. The evolution of aCOHb over time was investigated among survivors and non-survivors and among patients with or without MV. The admission and peak aCOHb values did not differ among survivors or non-survivors. In the patients with MV, there was a significant increase of aCOHb with time, with a biphasic evolution for the patients ventilated for more than 20 days: a parallel increase of aCOHb and PaCO 2 followed by a trend to a plateau of aCOHb during PaCO 2 recovery. Conclusions: Progressive increase in aCOHb from endogenous source is observed in COVID-19 patients requiring prolonged mechanical ventilation. Decrease of aCOHb appears slower than PaCO 2 recovery.

3.
Am J Respir Crit Care Med ; 204(9): 1024-1034, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1495777

ABSTRACT

Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/physiopathology , Case-Control Studies , Female , Humans , Immunohistochemistry , Logistic Models , Male , Middle Aged , Proportional Hazards Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/virology , Retrospective Studies , Severity of Illness Index , Up-Regulation
4.
J Med Virol ; 93(9): 5416-5424, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363679

ABSTRACT

The kinetics of IgG antibodies after coronavirus disease 2019 (COVID-19) remain poorly understood. We investigated factors influencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibody levels and time to seronegativation during the follow-up of severe and critically ill patients. We retrospectively reviewed serological evaluations drawn during the follow-up of severe or critical laboratory-proven COVID-19 patients hospitalized at a large academic hospital. Specific IgG titers were measured using a chemiluminescent assay targeting anti-spike and anti-nucleocapsid protein IgG. The influence of time, demographic factors, clinical and paraclinical characteristics, and COVID-19 therapeutics on IgG levels were assessed through linear regression using a mixed-effect model, and delay until IgG negativation through a Weibull regression model. The cohort included 116 patients with a total of 154 IgG measurements drawn at a median of 79 days after diagnosis. IgG antibodies were increased with age (p = 0.005) and decreased significantly over time (p = 0.0002). Using elapsed time and age as covariates, we demonstrated higher IgG levels in patients with a higher body mass index (BMI) (p = 0.0026) and lower IgG levels in immunocompromised patients (p = 0.032). A high BMI was further found to delay and immunodeficiency to hasten significantly seronegativation, whereas no significant effect was observed with corticosteroids. These data highlight the waning over time of IgG antibodies after severe or critical COVID-19. Age, BMI, and immunosuppression also appear to influence the IgG kinetics, while short-term corticotherapy does not. Those data improve the understanding of SARS-CoV-2 serology while further research should determine the determinants of long-term seroprotection.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Immunocompromised Host , Immunoglobulin G/blood , Respiratory Insufficiency/immunology , SARS-CoV-2/immunology , Adrenal Cortex Hormones/therapeutic use , Aged , Body Mass Index , COVID-19/blood , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19 Serological Testing , Convalescence , Female , Humans , Hydroxychloroquine/therapeutic use , Male , Middle Aged , Respiratory Insufficiency/blood , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/drug therapy , Retrospective Studies , Sensitivity and Specificity , Severity of Illness Index , Time Factors
5.
Crit Care ; 25(1): 212, 2021 06 14.
Article in English | MEDLINE | ID: covidwho-1269885

ABSTRACT

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) is highly variable between individuals, ranging from asymptomatic infection to critical disease with acute respiratory distress syndrome requiring mechanical ventilation. Such variability stresses the need for novel biomarkers associated with disease outcome. As SARS-CoV-2 infection causes a kidney proximal tubule dysfunction with urinary loss of uric acid, we hypothesized that low serum levels of uric acid (hypouricemia) may be associated with severity and outcome of COVID-19. METHODS: In a retrospective study using two independent cohorts, we investigated and validated the prevalence, kinetics and clinical correlates of hypouricemia among patients hospitalized with COVID-19 to a large academic hospital in Brussels, Belgium. Survival analyses using Cox regression and a competing risk approach assessed the time to mechanical ventilation and/or death. Confocal microscopy assessed the expression of urate transporter URAT1 in kidney proximal tubule cells from patients who died from COVID-19. RESULTS: The discovery and validation cohorts included 192 and 325 patients hospitalized with COVID-19, respectively. Out of the 517 patients, 274 (53%) had severe and 92 (18%) critical COVID-19. In both cohorts, the prevalence of hypouricemia increased from 6% upon admission to 20% within the first days of hospitalization for COVID-19, contrasting with a very rare occurrence (< 1%) before hospitalization for COVID-19. During a median (interquartile range) follow-up of 148 days (50-168), 61 (12%) patients required mechanical ventilation and 93 (18%) died. In both cohorts considered separately and in pooled analyses, low serum levels of uric acid were strongly associated with disease severity (linear trend, P < 0.001) and with progression to death and respiratory failure requiring mechanical ventilation in Cox (adjusted hazard ratio 5.3, 95% confidence interval 3.6-7.8, P < 0.001) or competing risks (adjusted hazard ratio 20.8, 95% confidence interval 10.4-41.4, P < 0.001) models. At the structural level, kidneys from patients with COVID-19 showed a major reduction in urate transporter URAT1 expression in the brush border of proximal tubules. CONCLUSIONS: Among patients with COVID-19 requiring hospitalization, low serum levels of uric acid are common and associate with disease severity and with progression to respiratory failure requiring invasive mechanical ventilation.


Subject(s)
COVID-19/metabolism , COVID-19/physiopathology , Kidney Tubules, Proximal/metabolism , Severity of Illness Index , Uric Acid/blood , Aged , Belgium , COVID-19/complications , Cohort Studies , Critical Illness/epidemiology , Humans , Male , Middle Aged , Organic Anion Transporters/metabolism , Organic Cation Transport Proteins/metabolism , Outcome Assessment, Health Care , Retrospective Studies
6.
Respir Med ; 181: 106383, 2021 05.
Article in English | MEDLINE | ID: covidwho-1174487

ABSTRACT

BACKGROUND: COVID-19 pandemic resulted in an unprecedented number of hospitalizations in general wards and intensive care units (ICU). Severe and critical COVID-19 patients suffer from extensive pneumonia; therefore, long-term respiratory sequelae may be expected. RESEARCH QUESTION: We conducted a cohort study to determine respiratory sequelae in patients with severe and critical COVID-19. We aimed at evaluating the proportion of patients with persisting respiratory symptoms and/or abnormalities in pulmonary function tests (PFT) or in lung imaging. STUDY DESIGN: and methods: This is a single center cohort study including COVID-19 survivors who underwent a three-month follow-up with clinical evaluation, PFT and lung high-resolution computed tomography (HRCT). All clinical, functional, and radiological data were centrally reviewed. Multiple linear regression analysis was performed to identify factors associated with residual lesions on HRCT. RESULTS: Full clinical evaluation, PFT and lung HRCT were available for central review in 126, 122 and 107 patients, respectively. At follow-up, 25% of patients complained from dyspnea and 35% from fatigue, lung diffusion capacity (DLCO) was decreased in 45%, 17% had HRCT abnormalities affecting more than 5% of their lung parenchyma while signs of fibrosis were found in 21%. In multiple linear regression model, number of days in ICU were related to the extent of persisting lesions on HRCT, while intubation was associated with signs of fibrosis at follow-up (P = 0.0005, Fisher's exact test). In contrast, the severity of lung imaging or PFT changes were not predictive of fatigue and dyspnea. INTERPRETATION: Although most hospitalized COVID-19 patients recover, a substantial proportion complains from persisting dyspnea and fatigue. Impairment of DLCO and signs suggestive of fibrosis are common but are not strictly related to long-lasting symptoms.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/physiopathology , Lung/diagnostic imaging , Lung/physiopathology , Aged , COVID-19/complications , Cohort Studies , Dyspnea/etiology , Fatigue/etiology , Female , Follow-Up Studies , Humans , Linear Models , Male , Middle Aged , Positron-Emission Tomography , Radiographic Image Enhancement , Respiratory Function Tests , Severity of Illness Index , Tomography, X-Ray Computed
7.
Respir Care ; 66(5): 724-732, 2021 05.
Article in English | MEDLINE | ID: covidwho-1115488

ABSTRACT

BACKGROUND: Prone positioning (PP) during invasive mechanical ventilation improves outcomes of patients with severe ARDS. Recent studies suggest that PP in spontaneously breathing, nonintubated patients with acute respiratory failure is well tolerated and improves oxygenation. However, little is known regarding patient triggered ventilation in intubated patients with ARDS undergoing PP. We conducted a retrospective review of our experience with placing patients in the prone position in 2 cohorts of subjects with moderate and severe ARDS (ie, one cohort with ARDS related to COVID-19, the other with ARDS unrelated to COVID-19), many of whom were receiving pressure support ventilation (PSV). METHODS: We conducted a retrospective analysis in a single 22-bed mixed ICU. The subjects included in the analysis were ≥ 18 y old, met the Berlin definition for moderate or severe ARDS (whether related COVID-19 or not), and underwent PP during invasive ventilation. RESULTS: 39 subjects were included in the analysis: 20 subjects had ARDS related to COVID-19, while 19 had ARDS related to other etiologies. A total of 113 PP episodes were analyzed: 84 during PSV and 29 during volume control continuous mandatory ventilation. PP during PSV was well tolerated and was effective in improving arterial oxygenation (ie, an increase of median [Formula: see text] from 100 mm Hg [interquartile range 75-120] before PP to 135 mm Hg [interquartile range 111-161] at the end of the PP session, P < .0001). No significant difference between continuous mandatory ventilation and PSV was noted regarding arterial oxygenation during PP. Compared with continuous mandatory ventilation mode, PP during PSV was associated with a significant decrease in the use of neuromuscular blocking agents (4% vs 69% of subjects, P < .001), while sedative requirements remained unchanged. CONCLUSIONS: In a retrospective analysis of consecutive intubated subjects with moderate or severe ARDS, related or not to COVID-19, spontaneous breathing during PP was well tolerated and achieved significant improvement in arterial oxygenation.


Subject(s)
COVID-19 , Noninvasive Ventilation , Respiratory Distress Syndrome , Humans , Prone Position , Respiration, Artificial , Respiratory Distress Syndrome/therapy , Retrospective Studies , SARS-CoV-2
9.
Acta Haematol ; 144(3): 319-321, 2021.
Article in English | MEDLINE | ID: covidwho-802601

ABSTRACT

A 54-year-old man with a long history of severe haemophilia A treated prophylactically with efmoroctocog alpha (3,000 IU twice weekly) was diagnosed with COVID-19 infection. He had multiple risk factors for COVID-19 severity including obesity, diabetes mellitus and hypertension. He required prolonged intensive care unit (ICU) stay due to the severity of respiratory failure until his death on day 24. During his ICU stay, he received a continuous infusion of efmoroctocog alpha in order to maintain factor VIII activity between 80 and 100%, together with therapeutic doses of low-molecular-weight heparin targeting anti-Xa activity above 0.5 IU/mol. He tolerated numerous invasive procedures without bleeding. At post-mortem examination, there was no evidence for thrombosis or haemorrhage in the different organs.


Subject(s)
COVID-19/diagnosis , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Heparin, Low-Molecular-Weight/therapeutic use , Immunoglobulin Fc Fragments/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Blood Coagulation Tests , COVID-19/complications , COVID-19/virology , Hemophilia A/complications , Hemophilia A/pathology , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index
10.
Kidney Int ; 98(5): 1296-1307, 2020 11.
Article in English | MEDLINE | ID: covidwho-704001

ABSTRACT

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome.


Subject(s)
Coronavirus Infections/physiopathology , Kidney Tubules, Proximal/physiopathology , Pneumonia, Viral/physiopathology , Aged , Aged, 80 and over , Belgium/epidemiology , Betacoronavirus , COVID-19 , Case-Control Studies , Coronavirus Infections/mortality , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Humans , Kidney Tubules, Proximal/ultrastructure , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , SARS-CoV-2
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