Influence of obesity on incidence of thrombosis and disease severity in patients with COVID-19: From the CLOT-COVID study.

BACKGROUND: The influence of obesity on the development of thrombosis and severity of coronavirus disease 2019 (COVID-19) remains unclear. METHOD: The CLOT-COVID study was a retrospective multicenter cohort study enrolling 2894 consecutive hospitalized patients with COVID-19 between April 2021 and September 2021 among 16 centers in Japan. The present study consisted of 2690 patients aged over 18 years with available body mass index (BMI), who were divided into an obesity group (BMI ≥30) (N = 457) and a non-obesity group (BMI <30) (N = 2233). RESULTS: The obesity group showed more severe status of COVID-19 at admission compared with the non-obesity group. The incidence of thrombosis was not significantly different between the groups (obesity group: 2.6 % versus non-obesity group: 1.9 %, p = 0.39), while the incidence of a composite outcome of all-cause death, or requirement of mechanical ventilation or extracorporeal membrane oxygenation during hospitalization was significantly higher in the obesity group (20.1 % versus 15.0 %, p < 0.01). After adjusting confounders in the multivariable logistic regression model, the risk of obesity relative to non-obesity for thrombosis was not significant (adjusted OR, 1.39; 95 % CI, 0.68-2.84, p = 0.37), while the adjusted risk of obesity relative to non-obesity for the composite outcome was significant (adjusted OR, 1.85; 95 % CI, 1.39-2.47, p < 0.001). CONCLUSIONS: In the present large-scale observational study, obesity was not significantly associated with the development of thrombosis during hospitalization; however, it was associated with severity of COVID-19.

Fulminant Myocarditis and Acute Appendicitis after COVID-19 Vaccination: A Case Report.

A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the COVID-19 mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis.

Fulminant Myocarditis and Acute Appendicitis after COVID-19 Vaccination: A Case Report.

A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the COVID-19 mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis.

Real-World Management of Pharmacological Thromboprophylactic Strategies for COVID-19 Patients in Japan: From the CLOT-COVID Study.

Background: Data on prophylactic anticoagulation are important in understanding the current issues, unmet needs, and optimal management of Japanese COVID-19 patients. Objectives: This study aimed to investigate the clinical management strategies for prophylactic anticoagulation of COVID-19 patients in Japan. Methods: The CLOT-COVID study was a multicenter observational study that enrolled 2,894 consecutive hospitalized patients with COVID-19. The study population consisted of 2,889 patients (after excluding 5 patients with missing data); it was divided into 2 groups: patients with pharmacological thromboprophylaxis (n = 1,240) and those without (n = 1,649). Furthermore, we evaluated the 1,233 patients who received prophylactic anticoagulation-excluding 7 patients who could not be classified based on the intensity of their anticoagulants-who were then divided into 2 groups: patients receiving prophylactic anticoagulant doses (n = 889) and therapeutic anticoagulant doses (n = 344). Results: The most common pharmacological thromboprophylaxis anticoagulant was unfractionated heparin (68.2%). The severity of COVID-19 at admission was a predictor of the implementation of pharmacological thromboprophylaxis in the multivariable analysis (moderate vs mild: OR: 16.6; 95% CI:13.2-21.0; P < 0.001, severe vs mild: OR: 342.6, 95% CI: 107.7-1090.2; P < 0.001). It was also a predictor of the usage of anticoagulants of therapeutic doses in the multivariable analysis (moderate vs mild: OR: 2.10; 95% CI: 1.46-3.02; P < 0.001, severe vs mild: OR: 5.96; 95% CI: 3.91-9.09; P < 0.001). Conclusions: In the current real-world Japanese registry, pharmacological thromboprophylaxis, especially anticoagulants at therapeutic doses, was selectively implemented in COVID-19 patients with comorbidities and severe COVID-19 status at admission.

Fulminant Myocarditis and Acute Appendicitis after COVID-19 Vaccination: A Case Report.

A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the COVID-19 mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis.

Mortality-Associated Risk Factors in Hospitalized COVID-19 Patients in Japan: Findings of the CLOT-COVID Study.

BACKGROUND: Reports of mortality-associated risk factors in patients with coronavirus disease (COVID-19) are limited. METHODS: We evaluated the clinical features that were associated with mortality among patients who died during hospitalization (N=158) and those who were alive at discharge (N=2,736) from the large-scale, multicenter, retrospective, observational cohort CLOT-COVID study enrolled consecutively hospitalized COVID-19 patients from 16 centers in Japan from April to September 2021. Data from 2,894 hospitalized COVID-19 participants of the CLOT-COVID study were analyzed in this study. RESULTS: Patients who died were older (71.1 years versus 51.6 years, P<0.001), had higher median D-dimer values on admission (1.7 µg/mL versus 0.8 µg/mL, P<0.001), and had more comorbidities. On admission, the patients who died had more severe COVID-19 than did those who survived (mild: 16% versus 63%, moderate: 47% versus 31%, and severe: 37% versus 6.2%, P<0.001). In patients who died, the incidence of thrombosis and major bleeding during hospitalization was significantly higher than that in those who survived (thrombosis: 8.2% vs. 1.5%, P<0.001; major bleeding: 12.7% vs. 1.4%, P<0.001). Multivariable logistic regression analysis revealed that age >70 years, high D-dimer values on admission, heart disease, active cancer, higher COVID-19 severity on admission, and development of major bleeding during hospitalization were independently associated with a higher mortality risk. CONCLUSIONS: This large-scale observational study in Japan identified several independent risk factors for mortality in hospitalized patients with COVID-19 that could facilitate appropriate risk stratification of patients with COVID-19.

Incidence, risk factors, and clinical impact of major bleeding in hospitalized patients with COVID-19: a sub-analysis of the CLOT-COVID Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) causes extensive coagulopathy and a potential benefit of anticoagulation therapy has been documented for prevention of thromboembolic events. Bleeding events has also been reported as a notable complication; whereas, the incidence, risks, and clinical impact of bleeding remain unclear. METHOD: The CLOT-COVID Study was a nationwide, retrospective, multicenter cohort study on consecutive hospitalized patients with COVID-19 in Japan between April 2021 and September 2021. In this sub-analysis, we compared the characteristics of patients with and without major bleeding; moreover, we examined the risk factors for and clinical impact of bleeding events. RESULTS: Among 2882 patients with COVID-19, 57 (2.0%) had major bleeding. The incidence of major bleeding increased with COVID-19 severity as follows: 0.5%, 2.3%, and 12.3% in patients with mild, moderate, and severe COVID-19, respectively. COVID-19 severity, history of major bleeding, and anticoagulant type/dose were independently and additively associated with the bleeding incidence. Compared with patients without major bleeding, those with major bleeding exhibited a longer duration of hospitalization (9 [6-14] vs 28 [19-43] days, P < 0.001) and higher mortality during hospitalization (4.9% vs. 35.1%, P < 0.001). CONCLUSIONS: In the real-world clinical practice, the incidence of major bleeding was not uncommon, especially in patients with severe COVID-19. Independent risk factors for major bleeding included history of major bleeding, COVID-19 severity, and anticoagulant use, which could be associated with poor clinical outcomes including higher mortality. Precise recognition of the risks for bleeding may be helpful for an optimal use of anticoagulants and for better outcomes in patients with COVID-19.

Fulminant Myocarditis 24 Days after Coronavirus Disease Messenger Ribonucleic Acid Vaccination.

A 60-year-old Japanese woman was hospitalized for cardiogenic shock 24 days after receiving the second dose of the coronavirus disease 2019 BNT162b2 vaccine. Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were immediately initiated along with inotropic support and steroid pulse therapy, as an endomyocardial biopsy specimen showed myocarditis. Three weeks later, her cardiac function had recovered, and she was discharged. An immune response associated with the presence of spike protein in cardiac myocytes may be related to myocarditis in the present case because of positive immunostaining for severe acute respiratory syndrome coronavirus 2 spike protein and C4d in the myocardium.

Significant Impact of Age on Mortality and Non-significant Impact of Age on Thrombosis and Major Bleeding in Patients with COVID-19: From the CLOT-COVID Study.

AIM: There is scarce data on the impact of age on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). METHOD: The CLOT-COVID Study was a retrospective, multicenter cohort study enrolling 2894 consecutive hospitalized patients with COVID-19 among 16 centers in Japan from April 2021 to September 2021. We divided the entire cohort into five groups according to age strata; -19, 20-39, 40-59, 60-79, and 80- years. RESULTS: Most patients under 19 had mild COVID-19 on admission (99%), while older patients had more severe COVID-19. The incidence rates of clinical outcomes during hospitalization in patients aged ≤ 19, 20-39, 40-59, 60-79, and 80 ≥ years were 0.0%, 0.5%, 2.2%, 2.7%, and 1.5% for thrombosis; 0.0%, 1.2%, 1.5%, 3.4%, and 2.0% for major bleeding; and 0.0%, 0.4%, 2.0%, 12.1%, and 16.8% for all-cause death, respectively. In the stratified analysis according to COVID-19 severity on admission, the incidences of thrombosis were generally higher among patients with more severe status, although those were not significantly different among age strata in all sub-types of COVID-19 severity. However, the incidences of all-cause death were significantly higher with increasing age in all sub-types of COVID-19 severity. CONCLUSIONS: In the current large observational study of patients with COVID-19, the risk of mortality became markedly higher with increased age. However, the risks of thrombosis and major bleeding did not necessarily increase as age increases, which seemed to be consistent irrespective of COVID-19 severity on admission.

Delayed Acute Perimyocarditis and Bilateral Facial Nerve Palsy in a Patient with COVID-19.

A 41-year-old Japanese man was admitted to our hospital with acute perimyocarditis 4 weeks after coronavirus disease 2019 (COVID-19) infection. Ten days after admission, the patient showed bilateral facial nerve palsy in the course of improvement of perimyocarditis under treatment with aspirin and colchicine. After prednisolone therapy, perimyocarditis completely improved, and the facial nerve palsy gradually improved. Acute perimyocarditis and facial nerve palsy can occur even 4 weeks after contracting COVID-19.

D-Dimer Values and Venous Thromboembolism in Patients With COVID-19 in Japan　- From the CLOT-COVID Study.

Background: To date, there are no large-scale data on the association between D-dimer levels at admission and the occurrence of venous thromboembolism (VTE) in Japanese patients with coronavirus disease 2019 (COVID-19). Methods and Results: The CLOT-COVID study was a retrospective, multicenter cohort study enrolling consecutive hospitalized patients with COVID-19 across 16 centers in Japan from April 2021 to September 2021. Among 2,894 enrolled patients, 2,771 (96%) had D-dimer levels measured at admission. Patients were divided into 3 groups based on tertiles of D-dimer levels at admission (1st tertile, D-dimer ≤0.5 µg/mL, n=949; 2nd tertile, D-dimer 0.51-1.09 µg/mL, n=894; 3rd tertile, D-dimer ≥1.1 µg/mL, n=928). The higher the tertile group, the more severe the COVID-19 status at admission. The incidence of VTE during hospitalization was highest in the 3rd tertile group (1st tertile, 0.3%; 2nd tertile, 0.3%; 3rd tertile, 3.6%; P<0.001). Even after adjusting for confounders in the multivariable logistic regression model, the higher D-dimer levels in the 3rd tertile (≥1.1 µg/mL) were independently associated with a higher risk of VTE during hospitalization (adjusted odds ratio 4.83 [95% confidence interval 1.93-12.11; P<0.001]; reference=1st tertile). Conclusions: Higher D-dimer levels at admission were associated with a higher risk of VTE events during hospitalization in Japanese patients with COVID-19. This could be helpful in determining patient-specific anticoagulation management strategies for COVID-19 in Japan.

Association Between the Development of Thrombosis and Worsening of Disease Severity in Patients With Moderate COVID-19 on Admission　- From the CLOT-COVID Study.

BACKGROUND: The worsening of coronavirus disease 2019 (COVID-19) severity is a critical issue in current clinical settings and may be associated with the development of thrombosis.Methods and Results: This study used patient data obtained in the CLOT-COVID study, a retrospective multicenter cohort study. The demographics of patients with moderate COVID-19 on admission with and without worsened severity during hospitalization were compared and predictors were identified. Of 927 patients with moderate COVID-19 on admission, 182 (19.6%) had worsened severity during hospitalization. Patients with worsening of severity were older, more likely to have hypertension, diabetes, heart disease, and active cancer, and more likely to use pharmacological thromboprophylaxis. Patients with worsening of severity had higher D-dimer levels on admission and were more likely to develop thrombosis and major bleeding during hospitalization than those without worsening. Increased age (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.03, P=0.005), diabetes (OR: 1.63, 95% CI: 1.11-2.33, P=0.012), D-dimer levels >1.0 µg/mL on admission (OR: 2.10, 95% CI: 1.45-3.03, P<0.001), and thrombosis (OR: 6.28, 95% CI: 2.72-14.53, P<0.001) were independently associated with worsening of COVID-19 severity. CONCLUSIONS: Approximately 20% of patients with moderate COVID-19 had worsened severity during hospitalization. Increased age, diabetes, D-dimer levels >1.0 µg/mL on admission, and the development of thrombosis during hospitalization were significantly associated with worsened COVID-19 severity.

Therapeutic-Dose vs. Prophylactic-Dose Anticoagulation Therapy for Critically Ill Patients With COVID-19 in a Practice-Based Observational Study.

BACKGROUND: The potential benefit of therapeutic-dose anticoagulation for critically ill patients with coronavirus disease 2019 (COVID-19) is still controversial.Methods and Results: In the CLOT-COVID study, 225 patients with severe COVID-19 on admission requiring mechanical ventilation or extracorporeal membrane oxygenation were divided into patients with therapeutic-dose anticoagulation (N=110) and those with prophylactic-dose anticoagulation (N=115). There was no significant difference in the incidence of thrombosis between the groups (9.1% vs. 7.8%, P=0.73). CONCLUSIONS: Among a cohort of critically ill patients with COVID-19, approximately half received therapeutic-dose anticoagulation, although it did not show a potential benefit compared with prophylactic-dose anticoagulation.

Outcome of early-stage combination treatment with favipiravir and methylprednisolone for severe COVID-19 pneumonia: A report of 11 cases.

Although the use of corticosteroids is not recommended in the World Health Organization statement for the treatment of coronavirus disease 2019 (COVID-19), steroid therapy may be indicated for critical cases in specific situations. Here, we report the successful treatment of 11 cases of severe COVID-19 pneumonia with favipiravir and methylprednisolone. All cases were severe and patients required oxygen administration or had a blood oxygen saturation ≤93% on room air. All were treated with favipiravir and methylprednisolone, and 10 of 11 patients responded well and required no further oxygen supplementation or ventilator management. This study shows the importance of the early-stage use of a combination of favipiravir and methylprednisolone in severe cases to achieve a favorable clinical outcome.