Role of D-Dimer in assessing severity, monitoring, and predicating outcome in COVID-19 pneumonia: A single center study

INTRODUCTION

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), originally emerged from China, has documented 274,628,461 confirmed cases and 5,358,978 deaths globally, and 34,752,164 confirmed cases 478,007 deaths in India.^[1] The International Federation of Clinical Chemistry and Laboratory Medicine Task Force on COVID-19 has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management.^[2,3]

COVID-19, the pandemic disease caused by infection with the novel virus, SARS-CoV-2 can now be added to the already extensive list of conditions that may be associated with elevated D-dimer. The discovery that D-dimer may be elevated in COVID-19 was first reported by physicians in Wuhan, China where the epidemic started. A study of 191 patients with COVID-19, who were hospitalized in Wuhan during January 2020 at the outset of the pandemic, revealed that D-dimer was elevated in many of these patients and the magnitude of the elevation was greatest in those who did not survive.^[4,5]

Fibrin degradation products are a highly heterogeneous group of soluble fragments that appear in the circulation as a result of two simultaneous physiological processes: (1) Coagulation, resulting in the conversion of soluble fibrinogen into insoluble stabilized fibrin by the enzymes thrombin and factor XIIIa, (2) Fibrinolysis, resulting in the dissolution of the fibrin clot by the enzyme plasmin. The D-dimer fragment is the terminal product of this process.^[5] A number of subsequent studies conducted around the world have confirmed that D-dimer is elevated in those with severe COVID-19 and highest in those who are most critically ill and those who do not survive. Much COVID-19 research over the past months has been directed at understanding the significance of D-dimer elevation and the COVID-19 related coagulopathy that is presumed responsible for the elevation.^[4,5]

D-dimer has been extensively investigated for the diagnosis, monitoring, and treatment of venous thromboembolism for which it is used routinely.^[5,6] D-dimer levels are also elevated in conditions of chronic inflammation, such as active malignancy, rheumatoid arthritis, sickle cell disease, and asthma.^[7] In the setting of COVID-19, D-dimer has been reported to be higher in subjects who are critically ill or those who expire.^[4,8-11]

MATERIAL AND METHODS

All study cases were undergone following assessment before enrolling in study

COVID-19 RT-PCR test was performed on nasopharyngeal samples collected with all standard institutional infection control policies, if first test results were negative and radiological features clearly documenting pneumonia, we have repeated RT-PCR test and enrolled all cases with positive COVID-19 RT-PCR test. HRCT Thorax to assess severity of lung involvement as per COVID-19 Reporting and Data System,^[12] and categorized as mild if score <7, moderated if score 8–15 and severe if score >15 or 15–25. Clinical assessment and routine biochemistry and hematological workup with viral inflammatory markers as C-reactive protein (CRP), Ferritin, lactate dehydrogenase, interleukin 6 (IL-6) titers, and D-Dimer in all cases. Entry point D-Dimer titer was utilized as an assessment tool of severity of illness with clinical parameters. If D-dimer analysis was normal at entry point, then D-Dimer titer was repeated on day of discharge from hospital or done during hospitalization if clinical course deteriorates. If D-dimer analysis was abnormal at entry point, we repeated it every 72 h as follow-up to assess severity, progression of illness and also titer utilized to assess response to medical treatment. Follow-up HRCT thorax was done after 12 weeks of discharge from hospital for analysis of post-COVID lung fibrosis in selected cases with abnormal D-Dimer titer at discharge and required BIPAP/NIV during hospitalization and cases required oxygen supplementation at home [Figure 1].

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Figure 1:

Flow of the study.

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RESULTS: COVARIATES

In the present study, 2000 COVID-19 pneumonia cases confirmed by COVID-19 RT-PCR, males were 1300/2000 and females were 700/2000, age >50 were 1200 cases, and age <50 were 800 cases. Significant association in D-Dimer and COVID-19 pneumonia has been documented with variables such as age, gender, diabetes mellitus, ischemic heart disease (IHD), hypertension, chronic obstructive pulmonary disease (COPD), and obesity (P < 0.00001) [Table 1].

DISCUSSION

In the present study, CT severity score at entry point with D-Dimer titer has significant correlation in COVID-19 pneumonia cases, score <8, 8–15, and >15 documented normal and abnormal D-Dimer (P < 0.00001). We observed that CT severity is best visual assessment and indirect marker of inflammation which can be collaborated with D-dimer, and as CT severity score increases, D-Dimer titer also increases, which is a marker of coagulation abnormality. Numerous studies^[13-19] have documented similar observation.

In the present study, D-Dimer titer has significant association with DOI in COVID-19 pneumonia cases, DOI <7 days, 8–15 days, and >15 days of onset of symptoms documented ormal and abnormal D-Dimer levels (P < 0.00001). As DOI in COVID-19 pneumonia increases, ongoing inflammation increases and having abnormal D-Dimer titer due to abnormal coagulation cascade stimulation. Studies by various author^[14-20] have documented similar observation. We have also documented that; entry point abnormal D-Dimer with other inflammatory markers such as CRP and IL-6 with DOI more than a week or 7 days is predictor of prolonged hospital stay with requirement of ventilatory requirement in intensive care unit. Similar observation has been documented in various studies.^[20-24]

In the present study, BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with D-Dimer level (P < 0.00001).

We have documented positive correlation with hypoxia and resulting in need of ventilatory support during hospitalization with abnormal D-Dimer level. Similarly, various authors^[14,20-25] have observed that abnormal or high D-dimer is predictor of poor outcome and these patients require aggressive interventions such as BIPAP/NIV, mechanical ventilation, or ECMO in due course and persistent high level denotes higher chances of mortality.

In the present study, D-Dimer titer has significant association with oxygen saturation in COVID-19 pneumonia cases (P < 0.00001). We have documented positive correlation with hypoxia at entry point during hospitalization and abnormal D-Dimer titer which is similar to studies by various authors.^[14,25] Low oxygen saturation or hypoxia is independent predictor of poor outcome in COVID-19 pneumonia, as hypoxia is trigger for deranged coagulation secondary to increase in hypoxia-inducible transcription factor which will increase D-Dimer level, numerous studies^[20-24] have documented similar observation.

In the present study, timing of BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with D-Dimer titer (P<0.00001) We have documented positive correlation with hypoxia and resulting in need of ventilatory support during hospitalization with abnormal D-Dimer level. Cases with high D-dimer would have required BIPAP/NIV early as compared with normal to slightly raised D-Dimer level, which is in correlation with studies^[14,25] documented similar observation.

In the present study, follow-up D-Dimer titer during hospitalization during hospitalization as compared to entry point abnormal D-Dimer has significant association in post-COVID lung fibrosis (P < 0.00001). Follow-up D-Dimer titer during hospitalization as compared to entry point abnormal D-Dimer has significant association in presence of deep vein thrombosis (P < 0.00001). We have observed that ongoing inflammation is the key for rise of D-Dimer titer irrespective of CT severity score as mild cases were also having significant rise in D-Dimer titer as compared to advanced CT severity, thus it will help in predicting progression of disease in due course during hospitalization and aggressive steps to be taken during management of these cases. Numerous studies^[25-31] have documented similar risk of poor outcome and adverse lung outcome as increased D-Dimer is an indication of severe inflammatory response and resulted in lung fibrosis in follow-up of survivors of COVID-19pneumonia.

In the present study, follow-up D-Dimer titer during hospitalization as compared to entry point normal D-Dimer has significant association in post-COVID lung fibrosis (P < 0.00001). In this study, a small fraction of non-severe patients developed into severe cases in the first 2 weeks after symptom onset. Therefore, health care institutions should also pay close attention to the mild patients, identify progressor early, and provide appropriate treatment to reduce mortality. Follow-up D-Dimer titer during hospitalization as compared to entry point normal D-Dimer has significant association with pulmonary thromboembolism (P < 0.00001). Authors in various studies^{[14-17,20-25]} have documented similar observation.

In the present study, age of patient, that is., <50 years and >50 years has significant association in COVID-19 cases with normal and abnormal D-Dimer titer (P < 0.00001). We have also documented that the gender of included cases has significant association with normal and abnormal D-Dimer titer in COVID-19 cases (P < 0.010). Studies by various authors^{[14-19,25-32]} have documented similar observation.

In the present study, comorbidities as Diabetes mellitus, COPD, hypertension, IHD, and obesity have documented significant association in COVID-19 cases with normal and abnormal D-Dimer titer at entry point (P<0.00001). Numerous studies^{[14-19,25-32]} have documented similar observation.

CONCLUSION

D-Dimer has documented very crucial role in COVID-19 pneumonia in predicting severity of illness, ventilatory support requirement and course in critical care setting. D-Dimer follow-up titer can help in predicting progression of COVID-19 pneumonia, and assessing risk of post-COVID lung fibrosis. D-Dimer serial titers have documented significant role in step-up or step-down interventions in critical care setting.

D-Dimer titer has significant associations with predicting progression of pneumonia, as proportionate number of pneumonia cases with mild variety on CT thorax and normal initial D-Dimer has progressed to critical course and we have documented follow-up titers has played crucial role with other inflammatory markers.

Correlating D-dimer with variables such as DOI, oxygenation status, and timing of BIPAP/NIV at entry point is important to have satisfactory treatment outcome. D-Dimer follow-up titer has documented role in predicting lung fibrosis and deep vein thrombosis and pulmonary embolism.