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1.
Crit Care Med ; 50(2): 212-223, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1735675

ABSTRACT

OBJECTIVES: Body temperature trajectories of infected patients are associated with specific immune profiles and survival. We determined the association between temperature trajectories and distinct manifestations of coronavirus disease 2019. DESIGN: Retrospective observational study. SETTING: Four hospitals within an academic healthcare system from March 2020 to February 2021. PATIENTS: All adult patients hospitalized with coronavirus disease 2019. INTERVENTIONS: Using a validated group-based trajectory model, we classified patients into four previously defined temperature trajectory subphenotypes using oral temperature measurements from the first 72 hours of hospitalization. Clinical characteristics, biomarkers, and outcomes were compared between subphenotypes. MEASUREMENTS AND MAIN RESULTS: The 5,903 hospitalized coronavirus disease 2019 patients were classified into four subphenotypes: hyperthermic slow resolvers (n = 1,452, 25%), hyperthermic fast resolvers (1,469, 25%), normothermics (2,126, 36%), and hypothermics (856, 15%). Hypothermics had abnormal coagulation markers, with the highest d-dimer and fibrin monomers (p < 0.001) and the highest prevalence of cerebrovascular accidents (10%, p = 0.001). The prevalence of venous thromboembolism was significantly different between subphenotypes (p = 0.005), with the highest rate in hypothermics (8.5%) and lowest in hyperthermic slow resolvers (5.1%). Hyperthermic slow resolvers had abnormal inflammatory markers, with the highest C-reactive protein, ferritin, and interleukin-6 (p < 0.001). Hyperthermic slow resolvers had increased odds of mechanical ventilation, vasopressors, and 30-day inpatient mortality (odds ratio, 1.58; 95% CI, 1.13-2.19) compared with hyperthermic fast resolvers. Over the course of the pandemic, we observed a drastic decrease in the prevalence of hyperthermic slow resolvers, from representing 53% of admissions in March 2020 to less than 15% by 2021. We found that dexamethasone use was associated with significant reduction in probability of hyperthermic slow resolvers membership (27% reduction; 95% CI, 23-31%; p < 0.001). CONCLUSIONS: Hypothermics had abnormal coagulation markers, suggesting a hypercoagulable subphenotype. Hyperthermic slow resolvers had elevated inflammatory markers and the highest odds of mortality, suggesting a hyperinflammatory subphenotype. Future work should investigate whether temperature subphenotypes benefit from targeted antithrombotic and anti-inflammatory strategies.


Subject(s)
Body Temperature , COVID-19/pathology , Hyperthermia/pathology , Hypothermia/pathology , Phenotype , Academic Medical Centers , Aged , Anti-Inflammatory Agents/therapeutic use , Biomarkers/blood , Blood Coagulation , Cohort Studies , Dexamethasone/therapeutic use , Female , Humans , Inflammation , Male , Middle Aged , Organ Dysfunction Scores , Retrospective Studies , SARS-CoV-2
2.
Ocul Immunol Inflamm ; 29(4): 743-750, 2021 May 19.
Article in English | MEDLINE | ID: covidwho-1379400

ABSTRACT

PURPOSE: To assess the prevalence of retinopathy and its association with systemic morbidity and laboratory indices of coagulation and inflammatory dysfunction in severe COVID-19. DESIGN: Retrospective, observational cohort study. METHODS: Adult patients hospitalized with severe COVID-19 who underwent ophthalmic examination from April to July 2020 were reviewed. Retinopathy was defined as one of the following: 1) Retinal hemorrhage; 2) Cotton wool spots; 3) Retinal vascular occlusion. We analyzed medical comorbidities, sequential organ failure assessment (SOFA) scores, clinical outcomes, and laboratory values for their association with retinopathy. RESULTS: Thirty-seven patients with severe COVID-19 were reviewed, the majority of whom were female (n = 23, 62%), Black (n = 26, 69%), and admitted to the intensive care unit (n = 35, 95%). Fourteen patients had retinopathy (38%) with retinal hemorrhage in 7 (19%), cotton wool spots in 8 (22%), and a branch retinal artery occlusion in 1 (3%) patient. Patients with retinopathy had higher SOFA scores than those without retinopathy (8.0 vs. 5.3, p = .03), higher rates of respiratory failure requiring invasive mechanical ventilation and shock requiring vasopressors (p < .01). Peak D-dimer levels were 28,971 ng/mL in patients with retinopathy compared to 12,575 ng/mL in those without retinopathy (p = .03). Peak CRP was higher in patients with cotton wool spots versus those without cotton wool spots (354 mg/dL vs. 268 mg/dL, p = .03). Multivariate logistic regression modeling showed an increased risk of retinopathy with higher peak D-dimers (aOR 1.32, 95% CI 1.01-1.73, p = .04) and male sex (aOR 9.6, 95% CI 1.2-75.5, p = .04). CONCLUSION: Retinopathy in severe COVID-19 was associated with greater systemic disease morbidity involving multiple organs. Given its association with coagulopathy and inflammation, retinopathy may offer insight into disease pathogenesis in patients with severe COVID-19.


Subject(s)
COVID-19/epidemiology , Retinal Diseases/epidemiology , SARS-CoV-2 , COVID-19/diagnosis , Follow-Up Studies , Hospitalization/trends , Morbidity , Retrospective Studies , Severity of Illness Index , United States/epidemiology
3.
Shock ; 55(3): 316-320, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1304005

ABSTRACT

ABSTRACT: The coronavirus disease (COVID-19) pandemic has threatened millions of lives worldwide with severe systemic inflammation, organ dysfunction, and thromboembolic disease. Within our institution, many critically ill COVID-19-positive patients suffered major thrombotic events, prompting our clinicians to evaluate hypercoagulability outside of traditional coagulation testing.We determined the prevalence of fibrinolysis shutdown via rotational thromboelastometry (ROTEM, Instrumentation Laboratories, Bedford, Mass) in patients admitted to the intensive care unit over a period of 3 weeks. In 25 patients who had a ROTEM test, we found that 11 (44%) met criteria for fibrinolysis shutdown. Eight of 9 (73%) of the VTE patients met criteria for fibrinolysis shutdown.Given the high rate of fibrinolysis shutdown in these patients, our data support using viscoelastic testing to evaluate for the presence of impaired fibrinolysis. This may help identify patient subsets who might benefit from the administration of fibrinolytics.


Subject(s)
COVID-19/complications , Fibrinolysis , Intensive Care Units , Thrombelastography , Thrombophilia/diagnosis , Thrombosis/diagnosis , Venous Thromboembolism/diagnosis , Adult , Aged , COVID-19/blood , COVID-19/diagnosis , Clinical Decision-Making , Female , Fibrinolysis/drug effects , Fibrinolytic Agents/therapeutic use , Humans , Male , Middle Aged , Patient Selection , Predictive Value of Tests , Retrospective Studies , Thrombophilia/blood , Thrombophilia/drug therapy , Thrombophilia/etiology , Thrombosis/blood , Thrombosis/drug therapy , Thrombosis/etiology , Venous Thromboembolism/blood , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology
4.
Cell Rep Med ; 2(6): 100321, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1253745

ABSTRACT

The pathogenesis of severe coronavirus disease 2019 (COVID-19) remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (93%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM) and less frequently auto-reactive IgG or IgA. Importantly, these auto-IgMs preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, analytical proteome microarray technology, and lactose dehydrogenase (LDH)-release cytotoxicity assays, we identify high-affinity, complement-fixing, auto-reactive IgM directed against 260 candidate autoantigens, including numerous molecules preferentially expressed on the cellular membranes of pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for therapeutic interventions.


Subject(s)
Autoantibodies/immunology , COVID-19/pathology , Immunoglobulin M/immunology , Autoantibodies/blood , COVID-19/immunology , COVID-19/virology , Cell Line , Complement C4/metabolism , Critical Illness , Humans , Immunoglobulin M/blood , Intensive Care Units , Lung/metabolism , Protein Array Analysis , Proteome/analysis , SARS-CoV-2/isolation & purification
5.
Transfusion ; 61(6): 1740-1748, 2021 06.
Article in English | MEDLINE | ID: covidwho-1243668

ABSTRACT

BACKGROUND: While convalescent plasma (CP) may benefit patients with COVID-19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG-specific anti-SARS-CoV-2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP. STUDY DESIGN AND METHODS: Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti-SARS-CoV-2 antibody titers against the receptor-binding domain responsible for viral entry. Symptom onset was obtained by chart review. RESULTS: Increased IgA anti-SARS-CoV-2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID-19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation. CONCLUSIONS: IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID-19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Convalescence , Immunoglobulin A/blood , SARS-CoV-2/immunology , Antibodies, Viral/blood , Blood Donors , Down Syndrome/complications , Down Syndrome/immunology , Down Syndrome/therapy , Female , Heart Septal Defects/complications , Heart Septal Defects/immunology , Heart Septal Defects/therapy , Humans , Immunity, Humoral/immunology , Immunization, Passive/methods , Immunoglobulin A/analysis , Immunoglobulin G/blood , Immunoglobulin M/blood , Infant , Retrospective Studies , Serologic Tests , United States
6.
JCO Oncol Pract ; 17(9): 517-521, 2021 09.
Article in English | MEDLINE | ID: covidwho-1238743

ABSTRACT

There is an increasing recognition of association of COVID-19 with a distinct coagulopathy and increased risk of thrombosis. Unfortunately, effective strategies to prevent and treat thrombosis in this patient population remain uncertain. In the setting of a worsening pandemic, there is an urgent need to provide practical guidance to the clinicians on management of the coagulopathy, while waiting for the results from large systematic trials to establish best practices. At our institution, we convened an interdisciplinary group of 25 experts in the field of thrombosis from different medical specialties to review available literature and brainstorm management strategies. The group provided a 3-tiered anticoagulation algorithm for patients with COVID-19 along with a pathway for multidisciplinary review of difficult or refractory cases, which are described in this manuscript. In these unprecedented times where medical decision making is made difficult by both the novelty of the disease and paucity of robust data, clinical algorithms such as the one presented here may prove to be helpful for frontline providers caring for individual patients.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Thrombosis , Humans , Pandemics , SARS-CoV-2 , Thrombosis/prevention & control
8.
J Thromb Thrombolysis ; 52(3): 766-771, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1172396

ABSTRACT

Patients critically ill with COVID-19 are at risk for thrombotic events despite prophylactic anticoagulation. Impaired fibrinolysis has been proposed as an underlying mechanism. Our objective was to determine if fibrinolysis stimulated by tissue plasminogen activator (tPA) differed between COVID patients and controls. Plasma from 14 COVID patients on prophylactic heparin therapy was obtained and compared with heparinized plasma from 14 different healthy donors to act as controls. Kaolin activated thromboelastography with heparinase was utilized to obtain baseline measurements and then repeated with the addition of 4 nM tPA. Baseline fibrinogen levels were higher in COVID plasma as measured by maximum clot amplitude (43.6 ± 6.9 mm vs. 23.2 ± 5.5 mm, p < 0.0001) and Clauss assay (595 ± 135 mg/dL vs. 278 ± 44 mg/dL, p < 0.0001). With the addition of tPA, fibrinolysis at 30 min after MA (LY30%) was lower (37.9 ± 16.5% vs. 58.9 ± 18.3%, p = 0.0035) and time to 50% lysis was longer (48.8 ± 16.3 vs. 30.5 ± 15.4 min, p = 0.0053) in the COVID-19 samples. Clotting times and rate of fibrin polymerization ('R' or 'α' parameters) were largely the same in both groups. Clot from COVID patients contains a higher fibrin content compared to standard controls and shows resistance to fibrinolysis induced by tPA. These findings suggest the clinical efficacy of thrombolytics may be reduced in COVID-19 patients.


Subject(s)
COVID-19/blood , Fibrinolysis/drug effects , Fibrinolytic Agents/pharmacology , Thrombelastography , Tissue Plasminogen Activator/pharmacology , COVID-19/diagnosis , Case-Control Studies , Critical Illness , Humans , Kinetics
9.
PLoS One ; 16(3): e0248230, 2021.
Article in English | MEDLINE | ID: covidwho-1143293

ABSTRACT

BACKGROUND: There is limited data on the markers of coagulation and hemostatic activation (MOCHA) profile in Coronavirus disease 2019 (COVID-19) and its ability to identify COVID-19 patients at risk for thrombotic events and other complications. METHODS: Hospitalized patients with confirmed SARS-COV-2 from four Atlanta hospitals were included in this observational cohort study and underwent admission testing of MOCHA parameters (plasma d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrin monomer). Clinical outcomes included deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, access line thrombosis, ICU admission, intubation and mortality. MAIN RESULTS: Of 276 patients (mean age 59 ± 6.4 years, 47% female, 62% African American), 45 (16%) had a thrombotic endpoint. Each MOCHA parameter was independently associated with a thrombotic event (p<0.05) and ≥ 2 abnormalities was associated with thrombotic endpoints (OR 3.3, 95% CI 1.2-8.8) as were admission D-dimer ≥ 2000 ng/mL (OR 3.1, 95% CI 1.5-6.6) and ≥ 3000 ng/mL (OR 3.6, 95% CI 1.6-7.9). However, only ≥ 2 MOCHA abnormalities were associated with ICU admission (OR 3.0, 95% CI 1.7-5.2) and intubation (OR 3.2, 95% CI 1.6-6.4). MOCHA and D-dimer cutoffs were not associated with mortality. MOCHA with <2 abnormalities (26% of the cohort) had 89% sensitivity and 93% negative predictive value for a thrombotic endpoint. CONCLUSIONS: An admission MOCHA profile is useful to risk-stratify COVID-19 patients for thrombotic complications and more effective than isolated d-dimer for predicting risk of ICU admission and intubation.


Subject(s)
Antithrombin III/analysis , COVID-19/pathology , Fibrin Fibrinogen Degradation Products/analysis , Peptide Fragments/analysis , Peptide Hydrolases/analysis , Prothrombin/analysis , Thrombosis/diagnosis , Aged , Area Under Curve , COVID-19/complications , COVID-19/mortality , COVID-19/virology , Cohort Studies , Female , Humans , Intensive Care Units , Male , Middle Aged , Odds Ratio , Patient Admission , ROC Curve , Risk Factors , SARS-CoV-2/isolation & purification , Survival Rate , Thrombosis/complications
10.
J Racial Ethn Health Disparities ; 9(2): 385-389, 2022 04.
Article in English | MEDLINE | ID: covidwho-1064659

ABSTRACT

BACKGROUND: Studies of COVID-19 have shown that African Americans have been affected by the virus at a higher rate compared to other races. This cohort study investigated comorbidities and clinical outcomes by race among COVID-19 patients admitted to the intensive care unit. METHODS: This is a case series of critically ill patients admitted with COVID-19 to an academic healthcare system in Atlanta, Georgia. The study included all critically ill hospitalized patients between March 6, 2020, and May 5, 2020. Clinical outcomes during hospitalization included mechanical ventilation, renal replacement therapy, and mortality stratified by race. RESULTS: Of 288 patients included (mean age, 63 ± 16 years; 45% female), 210 (73%) were African American. African Americans had significantly higher rates of comorbidities compared to other races, including hypertension (80% vs 59%, P = 0.001), diabetes (49% vs 34%, P = 0.026), and mean BMI (33 kg/m2 vs 28 kg/m2, P < 0.001). Despite African Americans requiring continuous renal replacement therapy during hospitalization at higher rates than other races (27% vs 13%, P = 0.011), rates of intubation, intensive care unit length of stay, and overall mortality (30% vs 24%, P = 0.307) were similar. CONCLUSION: This racially diverse series of critically ill COVID-19 patients shows that despite higher rates of comorbidities at hospital admission in African Americans compared with other races, there was no significant difference in mortality.


Subject(s)
African Americans , COVID-19 , Critical Illness , Academic Medical Centers/statistics & numerical data , African Americans/statistics & numerical data , Aged , COVID-19/epidemiology , COVID-19/mortality , COVID-19/therapy , Cohort Studies , Comorbidity , Critical Illness/epidemiology , Critical Illness/mortality , Critical Illness/therapy , Female , Georgia , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Race Factors , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
11.
Transfusion ; 61(4): 1029-1034, 2021 04.
Article in English | MEDLINE | ID: covidwho-969728

ABSTRACT

BACKGROUND: Recent data suggests an association between blood hyperviscosity and both propensity for thrombosis and disease severity in patients with COVID-19. This raises the possibility that increased viscosity may contribute to endothelial damage and multiorgan failure in COVID-19, and that therapeutic plasma exchange (TPE) to decrease viscosity may improve patient outcomes. Here we sought to share our experience using TPE in the first 6 patients treated for COVID-19-associated hyperviscosity. STUDY DESIGN AND METHODS: Six critically ill COVID-19 patients with plasma viscosity levels ranging from 2.6 to 4.2 centipoise (cP; normal range, 1.4-1.8 cP) underwent daily TPE for 2-3 treatments. RESULTS: TPE decreased plasma viscosity in all six patients (Pre-TPE median 3.75 cP, range 2.6-4.2 cP; Post-TPE median 1.6 cP, range 1.5-1.9 cP). TPE also decreased fibrinogen levels in all five patients for whom results were available (Pre-TPE median 739 mg/dL, range 601-1188 mg/dL; Post-TPE median 359 mg/dL, range 235-461 mg/dL); D-dimer levels in all six patients (Pre-TPE median 5921 ng/mL, range 1134-60 000 ng/mL; Post-TPE median 4893 ng/mL, range 620-7518 ng/mL); and CRP levels in five of six patients (Pre-TPE median 292 mg/L, range 136-329 mg/L; Post-TPE median 84 mg/L, range 31-211 mg/L). While the two sickest patients died, significant improvement in clinical status was observed in four of six patients shortly after TPE. CONCLUSIONS: This series demonstrates the utility of TPE to rapidly correct increased blood viscosity in patients with COVID-19-associated hyperviscosity. Large randomized trials are needed to determine whether TPE may improve clinical outcomes for patients with COVID-19.


Subject(s)
Blood Viscosity , COVID-19 , Plasma Exchange , SARS-CoV-2/metabolism , Adult , Aged , COVID-19/blood , COVID-19/therapy , Humans , Male , Middle Aged
12.
Medicine (Baltimore) ; 99(46): e23186, 2020 Nov 13.
Article in English | MEDLINE | ID: covidwho-922437

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been associated with increased incidence of venous thromboembolic events (VTE) as well as mortality. D-dimer is a marker of fibrinolysis and has been used as a diagnostic and prognostic marker in VTE among other diseases. The purpose of our study is to describe outcomes from out center and to examine trends in D-dimer levels as it relates to VTE and mortality.Patients admitted with confirmed COVID-19 cases to Emory Healthcare from March 12, 2020 through April 6, 2020 with measured plasma D-dimer levels were included in our retrospective analysis. Relevant data about comorbidities, hospitalization course, laboratory results, and outcomes were analyzed.One hundred fifteen patients were included in our study. Mean age was 64 ±â€Š15 years, 47 (41%) females and 84 (73%) African-American. Hypertension was present in 83 (72%) and diabetes in 60 (52%). Mean duration of hospitalization was 19 ±â€Š11 days with 62 (54%) patients intubated (mean duration of 13 ±â€Š8 days). VTE was diagnosed in 27 (23%) patients (mean time to diagnosis 14 ±â€Š9 days). Median D-dimer within the first 7 days of hospitalization was higher (6450 vs. 1596 ng/mL, p < 0.001) in VTE cases compared to non-VTE cases, and was predictive of VTE (area under the curve [AUC] = 0.72, optimal threshold 2500 ng/mL) although not of mortality (AUC 0.55, P = .34). Change in D-dimer level (AUC = 0.72 P = .004) and rate of D-dimer rise (AUC = 0.75 P = .001) were also predictive of VTE, though neither predicted death (P > .05 for all). Within the first 7 days of hospitalization, peak D-dimer level of >2500 ng/mL and a rate of change exceeding 150 ng/mL/d were predictive of future diagnosis of VTE. Rise in D-dimer >2000 ng/mL within any 24 hour period through hospital day 10 had 75% sensitivity and 74% specificity for diagnosis of VTE.We found that both magnitude and rate of rise in d-dimer within the first 10 days of hospitalization are predictive of diagnosis of VTE but not mortality. These parameters may aid in identifying individuals with possible underlying VTE or at high risk for VTE, thereby guiding risk stratification and anticoagulation policies in COVID-19 patients.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/complications , Fibrin Fibrinogen Degradation Products/analysis , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Venous Thromboembolism/etiology , Aged , Aged, 80 and over , Betacoronavirus , Biomarkers , COVID-19 , Comorbidity , Female , Humans , Intubation, Intratracheal , Length of Stay , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2 , Sensitivity and Specificity
13.
EClinicalMedicine ; 26: 100545, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-778780
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