key: cord-337705-snwktcz5
authors: Bansal, Agam; Singh, Achintya D.; Jain, Vardhmaan; Aggarwal, Manik; Gupta, Samiksha; Padappayil, Rana Prathap; Nadeem, Mahum; Joshi, Sonya; Mian, Agrima; Greathouse, Tyler; Wells, David; Gupta, Mohak; Khan, Muhammad Zarrar
title: The Association of D-dimers with Mortality, Intensive Care Unit admission or Acute Respiratory Distress Syndrome in Patients Hospitalized with Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-analysis
date: 2020-09-18
journal: Heart Lung
DOI: 10.1016/j.hrtlng.2020.08.024
sha: 
doc_id: 337705
cord_uid: snwktcz5

AIM: To determine if D-dimers are elevated in individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who have adverse clinical outcomes including all-cause mortality, intensive care unit (ICU) admission or acute respiratory distress syndrome (ARDS). METHODS: We conducted a systematic review and meta-analysis of the published literature in PubMed, Embase and Cochrane databases through April 9, 2020 for studies evaluating D-dimer levels in SARS-COV-2 infected patients with and without a composite clinical endpoint, defined as the presence of all-cause of mortality, Intensive care unit (ICU) admission or acute respiratory distress syndrome (ARDS). A total of six studies were included in the meta-analysis. RESULTS: D-dimers were significantly increased in patients with the composite clinical end point than in those without (SMD, 1.67 ug/ml (95% CI, 0.72-2.62 ug/ml). The SMD of the studies (Tang et al, Zhou et al, Chen et al), which used only mortality as an outcome measure was 2.5 ug/mL (95% CI, 0.62-4.41 ug/ml). CONCLUSION: We conclude that SARS-CoV-2 infected patients with elevated D-dimers have worse clinical outcomes (all-cause mortality, ICU admission or ARDS) and thus measurement of D-dimers can guide in clinical decision making.

1. D-dimer levels can discriminate between COVID 19 patients with and without worse clinical outcomes (all-cause mortality, ICU admission or ARDS) 2. Elevated D-dimer levels are associated with increased risk of adverse clinical outcomes in patients hospitalized with COVID 19 infection 3. Patients who died had higher D-dimer levels than patients who survived 4. A substantial elevation in D-dimers may be an indicator of progressive disease 

We carried out an electronic search in Medline (PubMed), Embase, and Cochrane database using the keywords "D-dimer" AND "Coronavirus 2019" OR "COVID 19" OR "SARS-CoV-2" OR "severe acute respiratory syndrome coronavirus 2" OR "2019-nCoV" between 2019 and current date (9 th April, 2020). Only the articles published in peer-reviewed journals were included in the analysis. Articles were limited to English language publications.

We applied the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) to the methods for this study (5) (Figure 1 ). After duplications were removed, the title and abstracts were independently screened by two reviewers (AB and VJ). The studies reporting the mean or the median D-dimer values in COVID 19 patients with and without a composite end point defined as all-cause mortality, ICU admission or ARDS were included in the study. Allcause mortality was analyzed as a separate outcome in addition to the composite end-point. We excluded case reports, studies involving pediatric patient population and those not reporting the above-mentioned composite end points. We cross-referenced the research papers to identify additional studies meeting the inclusion criteria. Full texts of the included studies were then reviewed by two independent reviewers (AB and VJ) and data was extracted. Any conflicts were settled by a third author (ADS).

The following data variables were collected: author name, year published, country where the study was performed, type of study, number of patients, composite end point definition, and mean D-dimer values in patients with and without outcome of interest (all-cause mortality, ICU admission and ARDS).

Two authors (AB and VJ) independently assessed the risk of bias in the included studies using the validated Newcastle-Ottawa Scale.

The meta-analysis was conducted with the calculation of standardized mean difference (SMD) and 95% confidence interval (95% CI) of D-dimers in coronavirus 2019 patients with and without a composite clinical end point. D-dimers were entered as a continuous variable. The mean and the standard deviation were extrapolated from the sample size, median and interquartile range (Q1-Q3) as per Hozo et al (6) . I 2 statistic was used to assess the heterogeneity between studies with values 0-30%, more than 30-60%, and more than 60% corresponding to low, moderate, and high degree of heterogeneity, respectively. DerSimonian and Laird random effects model was used for pooling the studies. The statistical analysis was performed using Stata 12 software (Stata Corp, College Station, Texas).

Our systematic electronic search resulted in 21 publications after the initial screening of titles and abstracts. Subsequently, 16 studies were excluded, yielding 5 studies that met the inclusion criteria for systematic review. Cross-referencing of full-text articles resulted in 1 additional study. Therefore, 6 studies were included in the final meta-analysis for association of mean/median D-dimer values with all-cause mortality, ICU admission or ARDS. Table 1 elucidates the baseline characteristics and outcomes of the included studies.

There were a total of 1329 patients with 434 (32.65%) patients having a composite clinical end point. The composite end point was defined as defined as mortality in 3 studies (4, 9, 11) , ICU admission in 2 studies (8, 12) and onset of ARDS in another study (10) . Zhou et al (4) (11)), which used only mortality as an outcome measure was 2.5 ug/mL (95% CI, 0.62-4.41). The heterogeneity of the studies was found to be relatively high (i.e. I 2 statistic 98%).

There were two additional studies which reported higher d-dimer levels in patients with worse outcomes. However, they were not included in our meta-analysis as they did not report the median/mean D-dimer levels. Zhang et al (13) described the characteristics of 95 patients and found that out of the 25 patients having an outcome (ICU admission, mechanical ventilation or death), 23 (92%) had D-dimer values > 1 ug/ml. Similarly, another study (14) showed around 70% of the patients with worse outcome (death, mechanical ventilation or ICU admission) having D-dimers > 0.5 ug/ml.

We performed a systematic review and meta-analysis of studies to assess whether the D-dimer In severe cases of SARS-CoV-2 infection, there is an uncontrolled release of pro-inflammatory cytokines (IL-2, IL-6, IL-8, IL-17, and TNF-a) which lead to upregulation of tissue factor expression on the endothelial cells, resulting in an increased pro-coagulant state. There is increasing evidence that SARS-CoV-2 infection is associated with increased risk of venous thromboembolism (VTE) and in-situ microvascular thrombosis which has been linked to worse clinical outcomes (19) .

The major limitation of the studies included was lack of information on the timing of the Ddimer measurements relative to admission. In addition, there was a significant heterogeneity in the reported results. This was likely due to differences in study size, selection bias, and different stages at which the D-dimer values were measured. Also, since all the studies included have been performed in China, the external validity is lacking.

The results of this concise meta-analysis suggest that D-dimer is significantly increased in patients having a worse clinical outcome (all-cause mortality, ICU admission or ARDS). Further studies are required to assess if the serial measurement of D-dimer plays any role in predicting evolution towards a more critical form of disease. Finding a threshold D-dimer level, above which SARS-CoV-2 infected patients are at an increased risk of having worse clinical outcomes can assist in following a proactive approach and aid in clinical decision making. Also, it will be imperative to know if anticoagulation therapies are of use in patients with severe SARS-CoV-2 infection.

There were NO conflicts of interest 

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