key: cord-0806475-jmf9qmc0 authors: Yu, Hai-Han; Qin, Chuan; Chen, Man; Wang, Wei; Tian, Dai-Shi title: D-dimer level is associated with the severity of COVID-19 date: 2020-07-27 journal: Thromb Res DOI: 10.1016/j.thromres.2020.07.047 sha: 13dd2197ca59643916cab9e1735bd29d511dc57f doc_id: 806475 cord_uid: jmf9qmc0 INTRODUCTION: Abnormal coagulation function has been demonstrated to be involved in the disease progression of COVID-19. However, the association between D-dimer levels and the severity of COVID-19 is not clear. The study was aimed to investigate the association between D-dimer levels and the severity of COVID-19 based on a cohort study and meta-analysis. MATERIALS AND METHODS: Demographic and clinical data of all confirmed cases with COVID-19 on admission to Tongji Hospital from January 27 to March 5, 2020, were collected and analyzed, and coagulation function parameters were described and compared between patients with severe infection and those with non-severe infection. Cohort studies reporting risk estimates for the D-dimer and severity of COVID-19 association were searched and included to perform a meta-analysis. RESULTS: In our cohort study, patients with severe disease were more likely to exhibit dysregulated coagulation function, and a significantly higher D-dimer level (median 1.8 μg/ml [interquartile range 0.9–4.6] vs 0.5 [0.3–1.1], p < 0.001) was found in severe cases than the mild ones, on admission. In the meta-analysis of 13 cohort studies (including the current study), patients with severe disease had an increase in mean D-dimer value by 0.91 (95% confidence interval, 0.51–1.31, p < 0.001) μg/ml compared to those with non-severe disease, and odds of severe infection was associated with D-dimer greater than 0.5 μg/ml (odds ratio = 5.78, 95% confidence interval, 2.16–15.44, p < 0.001) on admission. CONCLUSIONS: Patients with severe COVID-19 have a higher level of D-dimer than those with non-severe disease, and D-dimer greater than 0.5 μg/ml is associated with severe infection in patients with COVID-19. J o u r n a l P r e -p r o o f In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) and the disease it caused, now known as coronavirus disease 2019 , were initially reported in Wuhan, China and rapidly spread throughout the world. [1] As of June 25, 2020, more than 9 million laboratory-confirmed cases have been identified in 208 countries and areas, with more than 480,000 fatal cases, according to the data from World Health Organization (WHO) reports. [2] In recent studies documenting the clinical features of confirmed patients with COVID-19, it has been reported that most of them would present a type of mild infection of the COVID-19 disease. [3, 4] However, a number of patients were observed to present with severe infection on admission with high mortality. Therefore, it is crucial to discriminate accurately among subjects with COVID-19 who have a high risk of severe infection and guide the use of different therapies at an early stage. Abnormal coagulation function, including elevated D-dimer, has been demonstrated to be more common in deceased patients with COVID-19, and increasing odds of in-hospital death was associated with D-dimer greater than 1 µg/ml. [5, 6] However, the association between D-dimer and the severity of COVID-19 is not clear. In our cohort study, epidemiological, clinical characteristics, and coagulation function parameters of patients with confirmed COVID-19 on admission were collected and compared, between patients with severe infection and those with non-severe infection. Further, a meta-analysis including our cohort study was then conducted to evaluate the association between D-dimer levels and severe COVID-19. J o u r n a l P r e -p r o o f 5 Totally 1561 patients with COVID-19 were recruited retrospectively from January 27th to March 5th, 2020, at Tongji hospital, the largest comprehensive medical center in Wuhan and the specific hospital for the treatment of patients with severe COVID-19 in Wuhan designated by the Chinese government. Laboratory confirmation of COVID-19 was carried out by real-time reverse-transcriptasepolymerase-chain-reaction (RT-PCR) using method described previously. [4] This study was approved by Tongji Hospital Ethics Committee (IRB ID: TJ-C20200121). Written informed consent was waived by the Ethics Commission of Tongji hospital for emerging infectious diseases. Epidemiological characteristics, comorbidities, coagulation function markers on admission and disease severity, were obtained from patients' medical records. D-dimer were detected using a STA-R MAX coagulation analyzer and original reagents (Diagnostica Stago, Saint-Denis, France). The severity of COVID-19 was defined according to WHO clinical management guidance of COVID-19. [7] Severe type was defined as followed: Fever or suspected respiratory infection, plus one of respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 <90% on room air. J o u r n a l P r e -p r o o f 6 hospital) were excluded. Two of the authors scanned and selected the studies independently, and any controversies were resolved by discussion, with a kappa of 0.78 for inter-rater agreement. The identified name of the study (first author, year of publication), sample size, the value of D-dimer, the number of patients with abnormal D-dimer (≥0.5µg/ml), were retrieved from the articles directly or by calculation. Two of the authors extracted the corresponding data independently, and any controversies were resolved by discussion. The mean and standard deviation (SD) were imputed when a study only provided median and interquartile ranges, as described in other studies. [8, 9] Differences of mean value of D-dimer between patients with severe disease and patients with non-severe disease, and odds of severe COVID-19 associated with D-dimer greater than 0.5ug/ml, on admission, were defined as the outcome of the meta-analysis. For our cohort study, continuous variables were described as medians (IQR), and For meta-analysis, weighted mean difference (WMD) with 95% confidence interval (95% CI) and odds ratio (OR) with 95% CI, were pooled for differences of D-dimer value and odds of severe COVID-19, respectively. The heterogeneity was evaluated using I 2 and P value based on Chi-square test. I 2 ≤ 50% or P ≥ 0.1 demonstrated no significant heterogeneity, and a fixed-effects model was used. I 2 > 50% or P < 0.1 indicated a significant heterogeneity, and a random-effects model was applied. Comparison of characteristics between patients with severe disease and mild cases in our cohort study is shown in Table 1 Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia COVID-19) Situation Report -51, the World Health Organization (WHO) Clinical Characteristics of Coronavirus Disease 2019 in China Dysregulation of immune response in patients with COVID-19 in Wuhan Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Estimating the mean and variance from the median, range, and the size of a sample Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: a meta-analysis Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing，China A descriptive study of the impact of diseases control and prevention on the epidemics dynamics and clinical features of SARS-CoV-2 outbreak in Shanghai, lessons learned for metropolis epidemics prevention Epidemiologic and Clinical Characteristics of 91 Hospitalized Patients with COVID-19 in Zhejiang, China: A retrospective, multi-centre case series Pneumonia Compared to Controls in Chinese Han Population Clinical features and outcomes of 221 patients with COVID-19 in Clinical characteristics of 140 patients infected with SARS-CoV-2 in Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Plasma d-dimer levels correlate with outcomes in patients with community-acquired pneumonia D-dimer levels in assessing severity and clinical outcome in patients with community-acquired pneumonia. A secondary analysis of a randomised clinical trial Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury Clinical features of patients infected with