Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial.

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p < 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273.

D-dimer Thresholds to Exclude Pulmonary Embolism among COVID-19 Patients in the Emergency Department: Derivation with Independent Validation.

OBJECTIVE: To derive and validate a D-dimer cutoff for ruling out pulmonary embolism (PE) in COVID-19 patients presenting to the emergency department (ED). METHODS: A retrospective cohort study was performed in an integrated healthcare system including 22 adult ED's between March 1, 2020, and January 31, 2021. Results were validated among patients enrolled in the RECOVER Registry, representing data from 154 ED's from 26 US states. Consecutive ED patients with laboratory confirmed COVID-19, a D-dimer performed within 48 h of ED arrival, and with objectively confirmed PE were compared to those without PE. After identifying a D-dimer threshold at which the 95% confidence lower bound of the negative predictive value for PE was higher than 98% in the derivation cohort, it was validated using RECOVER registry data. RESULTS: Among 3978 patients with a D-dimer result, 3583 with confirmed COVID-19 infection were included in the derivation cohort. Overall, PE incidence was 4.1% and a D-dimer cutoff of <2 µ/mL (2000 ng/mL) was associated with a NPV of 98.5% (95% CI = 98.0%-98.9%). In the validation cohort of 13,091 patients with a D-dimer, 7748 had confirmed COVID-19 infection, and the PE incidence was 1.14%. A D-dimer cutoff of <2 µ/mL was associated with a NPV of 99.5% (95% CI = 99.3%-99.7%). CONCLUSION: A D-dimer cutoff of <2 µ/ml was associated with a high negative predictive value for PE among patients with COVID-19. However, the resultant sensitivity for PE result at that threshold without pre-test probability assessment would be considered clinically unsafe.

Age-Adjusted D-Dimer Levels May Improve Diagnostic Assessment for Pulmonary Embolism in COVID-19 Patients.

INTRODUCTION: SARS-CoV-2 infection leads to a hypercoagulable state. The prevalence of pulmonary embolism (PE) seems to be higher in this subgroup of patients. PATIENTS AND METHODS: We combined data from two tertiary referral centers specialized in the management of PE. The aims of this study were as follows: (1) to evaluate the prevalence of PE among a large population of consecutive patients admitted for COVID-19 pneumonia in two centers, (2) to identify a plasma D-dimer threshold that may be useful in PE diagnostic assessment, (3) to characterize the abnormalities associated with PE and mortality in COVID-19 patients. RESULTS: The incidence of symptomatic acute PE was 19.3%. For diagnosing PE in COVID-19 patients, based on ROC curve analysis, we identified a D-dimer concentration/patient's age ratio of 70, which improved D-dimer diagnostic capacity for PE and led to a reclassification improvement of 14% (NRI 0.14, p = 0.03) when compared to a cut-off level of 1000 ng/mL. Especially in severe COVID-19 lung involvement, D-dimer/age ratio cut-off equal to 70 was characterized by high diagnostic feasibility (sensitivity, specificity, negative predictive value, positive predictive value of 83%, 94%, 96%, and 73%, respectively). Apart from PE status, lung involvement and troponin T concentration were also independent predictors of in-hospital mortality. In the subgroup of PE patients, mortality was comparable with non-PE patients (19/88 (21.5%) vs. 101/368 (27.4%) for non-PE, p = 0.26) and was associated with older age, higher Bova scores, and higher troponin T concentrations. Age was the sole independent predictor for mortality in this subgroup. CONCLUSIONS: PE in COVID-19 patients is common, but it may not influence mortality when managed at a specialized center. In suspected PE, age-adjusted D-dimer levels (upper limit of normal obtained from the formula patient's age × 70) may still be a useful tool to start the diagnostic workup. In COVID-19 patients without PE, older age, more extensive parenchymal involvement, or higher D-dimer levels are factors predicting mortality.

Thromboembolic Risk in COVID-19 Patients: Is There a Hidden Link?

Background Although evidence has emerged indicating that patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia present a high risk of venous thromboembolism (VTE), its real incidence and best diagnosis course remain unclear. In this study, we aimed to determine the incidence of pulmonary embolism in these patients and the role of D-dimer serum level as a predictive factor of a new VTE event. Methodology This was a single-center retrospective observational cohort study conducted in a tertiary hospital. All patients admitted to the infectious diseases ward with SARS-CoV-2 pneumonia with clinical or laboratory criteria for suspected VTE events were eligible for inclusion in the study. The t-test or Mann-Whitney U test was used to analyze the differences between the with-VTE group and the without-VTE group. Results Overall, VTE incidence was registered to be 30%. Chest computed tomography angiography data revealed thrombus mainly in segmental (five patients, 71%) and subsegmental pulmonary artery branches (four patients, 57%). No thrombus on major branches was documented. D-dimer serum levels (collected at hospital admission, 48 hours before the suspected VTE event date and at suspected VTE event date) were analyzed, and, despite a consistent tendency of higher values in the with-VTE group, no statistical difference was observed. Moreover, no statistical difference was observed between the two groups in mortality rates. Conclusions A clear higher risk of VTE events in SARS-CoV-2 pneumonia patients was not documented, and a link between the impact of VTE occurrence and a worse prognosis was not demonstrated. Therefore, we suggest that the use of D-dimer serum level should not be used as a predictor of VTE in SARS-CoV-2 pneumonia patients.

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19.

Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19.

A proposal for the management of COVID-19-induced coagulopathy in adults.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the cause of the coronavirus disease 2019 (COVID-19) pandemic, which has a high case fatality rate. Most severely ill patients develop a special type of coagulopathy that had not been described before and that is now considered the main cause of death. For this reason, anticoagulant treatment has become one of the cornerstones of the treatment of this infection. However, the rate at which the evidence regarding the use of anticoagulants is generated is quite fast, and sometimes it is difficult to interpret and conflicting. After having performed an extensive review of the published literature, this proposal for the use of anticoagulant treatment is made, taking into account available resources in Mexico.

La infección por coronavirus 2 del síndrome respiratorio agudo grave (SARS-CoV-2) es la causante de la pandemia de enfermedad por coronavirus 2019 (COVID-19), con un índice de letalidad alto. La mayoría de los pacientes graves desarrollan un tipo especial de coagulopatía no descrito hasta ahora y la cual se considera ahora la principal causa de muerte. Por esta razón, el tratamiento anticoagulante se ha convertido en una de las piedras angulares del tratamiento de esta infección. Sin embargo, la velocidad con la que se genera la evidencia respecto al uso de anticoagulantes es muy rápida y, en ocasiones difícil de interpretar y contradictoria. Luego de hacer una revisión extensa de la literatura publicada, se hace esta propuesta para el uso del tratamiento anticoagulante tomando en cuenta los recursos disponibles en México.

Acute pulmonary embolism in a patient with mild COVID-19 symptoms: a case report.

BACKGROUND: The venous thromboembolism (VTE) is a frequent condition, which may worsen the prognosis of hospitalized COVID-19 patients. Nevertheless, the incidence of this complication is unknown in patients with mild COVID-19 symptoms. CASE SUMMARY: A 26-year-old female nurse, who had been taking oral contraceptive pills (OCPs) treatment for the last 2 years, developed mild COVID-19 symptoms (rhinitis and anosmia). She underwent isolation at home and was subsequently followed up with telehealth visits. Fifteen days after her initial presentation, she developed acute onset sudden dyspnoea. On physical examination, she was found to be tachycardic with normal pulse oximetry. The initial risk score for VTE was moderate and laboratory results showed increased D-dimer level without other relevant findings. Computed tomography pulmonary angiography was performed, which confirmed low-risk subsegmental pulmonary embolism. DISCUSSION: Venous thromboembolism in patients who present with severe COVID-19 symptoms has already been described in the literature; its incidence is greater in patients hospitalized in intensive care units. Efforts to prevent VTE based on risk scores are widely recognized. However, the relationship in patients who present with mild COVID-19 symptoms and VTE is still unknown. Recently, experts on this field have introduced thromboprophylaxis guidelines including ambulatory patients based on the severity of COVID-19 symptoms and pro-thrombotic risk. Our patient showed no major risk for developing VTE; therefore, the VTE could be associated with SARS-CoV-2 infection or the eventual pro-thrombotic association with the concomitant use of OCPs.

Combined hormonal contraception and COVID-19.

Aim: This article reviews the possibility of using combined hormonal contraception during the COVID-19 pandemic. Methods: narrative reviewResults: The factors that protect women from the severity of the disease are analysed, as well as the risk factors for the use of this type of contraception, especially related to the increased risk of a thrombotic event in patients affected by the disease. Finally, the information available on the guidelines for action in patients with COVID-19 using combined hormonal contraception is collected.Conclusions: We can continue to prescribe and use hormonal methods with EE.

Extensive DVT and Pulmonary Embolism Leading to the Diagnosis of Coronavirus Disease 2019 in the Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia.

There is growing evidence that coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. To date, all patients reported with venous thromboembolic disease and COVID-19 have shown evidence of viral pneumonia. Here, we report the case of a 31-year-old patient with unexplained extensive DVT and bilateral pulmonary embolism in the absence of COVID-19 pneumonia, leading to the diagnosis of otherwise asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the context of the COVID-19 pandemic, given the high rates of otherwise asymptomatic patients, testing for SARS-CoV-2 should be performed in all patients with unexplained VTE occurring in COVID-19-endemic areas, even in the absence of other disease manifestations suggestive of SARS-CoV-2 infection.

Proposal for the management of COVID-19-associated coagulopathy in children.

SARS-CoV-2 infection (COVID-19) has become a pandemic with a high case fatality rate that mainly affects adults. Most severely ill adult patients develop a coagulopathy that was not described until recently, and which is currently considered a main cause of death. Everything indicates that a similar phenomenon also occurs in children with COVID-19. Anticoagulant treatment has become one of the therapeutic foundations for this infection; however, its implementation in children can be difficult since, until recently, it was not considered in the pediatric population. Evidence regarding the use of anticoagulants in COVID-19 is rapidly generated, changes constantly, it is often difficult to interpret, and can be contradictory. After an extensive review of the published literature, a proposal was generated that offers suggestions for anticoagulant treatment, considering available resources in Mexico.

La infección por SARS-CoV-2 (COVID-19) se ha constituido en una pandemia con alto índice de letalidad que afecta principalmente a los adultos. La mayor parte de los pacientes adultos graves desarrolla una coagulopatía que no estaba descrita, la cual actualmente se considera la principal causa de muerte. Todo indica que un fenómeno parecido ocurre también en el niño con COVID-19. El tratamiento anticoagulante se ha convertido en uno de los fundamentos terapéuticos de esta infección; sin embargo, su establecimiento en el niño puede ser difícil ya que, hasta hace poco, no estaba considerado en la población pediátrica. La evidencia respecto al uso de anticoagulantes en COVID-19 se genera con rapidez, cambia constantemente, con frecuencia es difícil de interpretar y puede ser contradictoria. Después de una extensa revisión de la literatura publicada, se generó una propuesta que ofrece sugerencias para el tratamiento anticoagulante en la que se consideran los recursos disponibles en México.

Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany.

Autopsies of deceased with a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can provide important insights into the novel disease and its course. Furthermore, autopsies are essential for the correct statistical recording of the coronavirus disease 2019 (COVID-19) deaths. In the northern German Federal State of Hamburg, all deaths of Hamburg citizens with ante- or postmortem PCR-confirmed SARS-CoV-2 infection have been autopsied since the outbreak of the pandemic in Germany. Our evaluation provides a systematic overview of the first 80 consecutive full autopsies. A proposal for the categorisation of deaths with SARS-CoV-2 infection is presented (category 1: definite COVID-19 death; category 2: probable COVID-19 death; category 3: possible COVID-19 death with an equal alternative cause of death; category 4: SARS-CoV-2 detection with cause of death not associated to COVID-19). In six cases, SARS-CoV-2 infection was diagnosed postmortem by a positive PCR test in a nasopharyngeal or lung tissue swab. In the other 74 cases, SARS-CoV-2 infection had already been known antemortem. The deceased were aged between 52 and 96 years (average 79.2 years, median 82.4 years). In the study cohort, 34 deceased were female (38%) and 46 male (62%). Overall, 38% of the deceased were overweight or obese. All deceased, except for two women, in whom no significant pre-existing conditions were found autoptically, had relevant comorbidities (in descending order of frequency): (1) diseases of the cardiovascular system, (2) lung diseases, (3) central nervous system diseases, (4) kidney diseases, and (5) diabetes mellitus. A total of 76 cases (95%) were classified as COVID-19 deaths, corresponding to categories 1-3. Four deaths (5%) were defined as non-COVID-19 deaths with virus-independent causes of death. In eight cases, pneumonia was combined with a fulminant pulmonary artery embolism. Peripheral pulmonary artery embolisms were found in nine other cases. Overall, deep vein thrombosis has been found in 40% of the cases. This study provides the largest overview of autopsies of SARS-CoV-2-infected patients presented so far.