Has “D-Dimeritis” Worsened during the Coronavirus Disease 2019 Pandemic?

Coronavirus disease 2019 (COVID-19) is a novel infectious disease that was originally identified in November 2019 and has since spread all over the world, as one of the worst pandemics recorded throughout human history.[1] The clinical phenotype of this pathology, sustained by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly variable, ranging from an almost completely asymptomatic infection to a systemic disease that may often lead to death.[2]

An increased risk of developing acute thrombotic events, both venous and arterial, is a hallmark of severe/critical COVID-19 cases, as comprehensively described elsewhere.[3] [4] [5] Thus, D-dimer values are very frequently elevated in patients with acute SARS-CoV-2 infection, correlate with the clinical phenotype, and predict the risk of developing thrombosis and multiple organ failure.[6] [7] It is therefore not surprising that the number of D-dimer test requests may have undergone a paramount increase throughout the COVID-19 pandemic, whereby the value of this biomarker may provide a valuable, almost unreplaceable contribution to the diagnostic approach, clinical decision-making, risk stratification, and managed care of patients with COVID-19. To this end, the purpose of this report is to provide some reliable figures on how D-dimer testing may have been inflated by the ongoing COVID-19 pandemic.

Two independent analyses were conducted for this report. The first encompassed a digital search in Medline (through the PubMed interface), using the keyword “D-dimer” (in all fields), restricted to the past 40 years (i.e., between 1992–2022), with no language restriction (last access date, December 29, 2022). The output of this search, available in “csv” format, was transcribed into a Microsoft Excel worksheet (Microsoft, Redmond, WA), where it was graphically plotted and statistically analyzed. The second analysis was instead based on data provided by the management control unit of the University Hospital of Verona (encompassing two separate hospital facilities, averaging nearly 1,500 beds and representing the COVID-19 referral centers for the province of Verona), concerning the number of D-dimer tests requested (overall, and for specific hospital units) in the full years 2019 (i.e., “pre-COVID-19”), 2021 and 2022 (i.e., during “COVID-19”). The year 2020 was purposely omitted from this analysis since the first COVID-19 case in Verona was diagnosed in March 2020 so that the statistics of the entire year 2020 would not appropriately reflect COVID-19-related trends. Notably, at the beginning of the pandemic (i.e., March 2020), D-dimer has been included within a minimal laboratory testing panel made available to all hospital units, as thoughtfully described elsewhere.[8] The output of this search was imported within a Microsoft Excel worksheet, where it was graphically plotted and statistically analyzed. The statistical analysis was performed with Microsoft Excel, encompassing linear and polynomial regression analysis (with relative correlation coefficients), as well as the calculation of the relative “fold-increase” over the reference year 2019 (i.e., pre-COVID-19). The study was conducted in accordance with the Declaration of Helsinki, under the terms of all relevant local legislations.

The results of these analyses are summarized in [Figs. 1] and [2]. As concerns the number of PubMed documents containing the word “D-dimer,” the overall volume increased by 3.0-folds in 2020, 3.9-fold in 2021, and 3.1-fold in 2022 compared with the year 2019. During the past 3 years, 59% (year 2020), 64% (year 2021), and 56% (year 2022) of all PubMed documents concerning D-dimer contained also the words “COVID-19” or “SARS-CoV-2.” The trend throughout the observational period is summarized in [Fig. 1]. Between 1992 and 2019 (i.e., pre-COVID-19), the increase was almost perfectly linear (r = 0.989), while the linear fit was dramatically impaired after the inclusion of the past 3 years (i.e., 2020–2022). Specifically, the correlation between time and number of PubMed documents fell to 0.739 between the years 1992 and 2022 and was no longer adequately fitted bylinear regression, as clearly shown in [Fig. 1]. Applying a polynomial equation during the same entire observational period (i.e., between the years 1992–2022), the correlation could be improved to 0.941 ([Fig. 1]).

Fig. 1 Number of PubMed documents containing the word “D-dimer” between 1992 and 2022.

Fig. 2 Fold-increase in the number of D-dimer requests placed at the University Hospital of Verona (Italy) in the year 2019, 2021, and 2022.

As concerns D-dimer test requests placed at the local institutions, the overall volume increased from 1,885 in 2019, to 10,449 in 2021 and 5,803 in 2022, thus displaying a 5.5- (p = 0.011) and 3.1-fold (p = 0.027) growth in 2021 and 2022 compared with 2019, respectively. The complete trend (fold-increase from 2019) is summarized in [Fig. 2]. Regarding the hospital units, the largest increase in the volume of D-dimer test requests over the year 2019 was seen for COVID-19-specific units (i.e., pneumology and infectious diseases units; 34.5- and 13.8-fold increase in 2021 and 2022, respectively), followed by intensive care units (ICUs; 23.1- and 12.9-fold increase in 2021 and 2022, respectively), and emergency medicine departments (6.9-fold increase in 2021, no difference in 2022). The trend in the remaining hospital units was also reflective of a very modest increase in 2021 (i.e., 1.3-fold), followed by normalization in 2022. A subanalysis with the calculation of statistical significance was unfeasible for specific hospital units, due to their insufficient sample size.

The results of these two separate analyses provide independent evidence that both the scientific and clinical interests for D-dimer have been magnified by the COVID-19 pandemic. These figures not necessarily reflect a questionable trend of over- or misuse of laboratory diagnostics, whereby the essential contribution that D-dimer provides in COVID-19 has already been extensively addressed in the preamble of this article. Nonetheless, these data provide important evidence to policymakers, health care administrators, clinicians, laboratory professionals, and even manufacturers (shortage of reagents is a tangible risk that must be prevented) that the volume of requests placed for some analytes (D-dimer, in such case) may undergo paramount fluctuations depending on—more or less—predictable events.

The almost exponential increase in the number of PubMed articles seen during the past 3 years confirms that D-dimer has received renewed interest as an object of clinical research, with over 50% of such articles containing the words COVID-19 or SARS-CoV-2 but as many as 36–44% of them possibly unrelated to COVID-19. The second important evidence that emerged from this analysis is that scientific interest has been translated into clinical practice, whereby the volume of D-dimer test requests placed in the local hospital facilities has increased between 3.1- to 5.5-folds compared with the pre-COVID period during the past 2 years which overlap with the ongoing COVID-19 pandemic. The relative decrease of D-dimer test requests seen in 2022 compared with 2021 seems to reflect the lower clinical burden of COVID-19 that has been recorded worldwide after the emergence of the Omicron variants.[9] Nonetheless, these changes can be compared with another recent report from Australia, which showed increases in D-dimer testing of up to ninefold according to a timeline of COVID-19 “waves,” with similar increases across all metropolitan hospital sites, where the burden of COVID-19 patients would be highest, compared with rural/regional sites.[10]

In conclusion, the combination of these two almost independent findings is seemingly suggesting that clinicians have clear in mind that D-dimer is a key biomarker in COVID-19 but also that D-dimeritis (intended as often unscrupulous ordering of D-dimer test)[7] may still be among us.

Publication History

Article published online:
24 January 2023

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