Inflammatory responses play a crucial role in progression of COVID-19 [11, 12, 13]. Rapid viral replication of the SARS-CoV-2 virus involves recruitment of macrophages and monocytes, release of cytokines and chemokines, thus triggering inflammatory responses[14]. CRP (C-Reactive protein) has been reported in dengue patients[15]. Dengue virus and SARS-CoV-2 are RNA virus, share similarity in the course of infection[15]. CRP is rapidly synthesized in response to a variety of eukaryotic and prokaryotic pathogens, by hepatocytes when stimulated by inflammation, facilitating complement activation through classical pathway[16], indicating immune activation, lymphocyte infiltration, immune molecules consumption and inflammation outbreak. It is also inferred that increased CRP levels could be early indicators of nosocomial infections in COVID-19 patients who were slow to recover [10]. Higher levels of CRP, a potential inflammatory biomarker has been reported to be significantly associated with disease severity in COVID-19 infections[10, 17, 18]. CRP levels have also been reported to be increased in elderly or old age individuals [17, 18].
A total of 228 patients with a confirmed diagnosis of COVID-19 were included in our study. [Supplementary Tables 1 and 2].Based on disease severity, patients were divided into two comparison groups (Cabin/Ward and ICU patients).We found significantly strong correlation between D-dimer and CRP levels with age and severity in the combined dataset of ICU and non-ICU COVID-19 patients [Fig. 1 and Table 1].Increased age and D-dimer values were found to be significantly associated with the patients admitted to ICU. Significant correlation of CRP levels with Age (Correlation coefficient = 0.250, P-value < 0.05), and Severity (Correlation Coefficient = 0.445, P- value < 0.001) was found in non-ICU patients [Supplementary Table 3]. In patients admitted to ICU, we found strong correlation of D-dimer with age (Correlation Coefficient = 0.304, P-value < 0.01) and Severity (Correlation Coefficient = 0.465, P-value < 0.001);correlation of CRP levels with severity (Correlation Coefficient = 0.292 P-value < 0.01) and D-dimer (Correlation coefficient = 0.193, P-value < 0.05) [Supplementary Table 4].Both Higher D-dimer (odds ratio = 1.723, 95% confidence interval: 1.420–2.089, p < 0.001) and CRP-values (odds ratio = 1.011, 95% confidence interval: 1.004–1.019, p = 0.001) were associated with increased severity in patients (Table 2).
Table 1
Correlations between Age, Gender, D-dimer value, CRP value, Hospital ward and Severity for the combined dataset of ICU and non-ICU COVID-19 patients
| Age | D-dimer Value (mg/L) | CRP value (mg/L | Hospital ward | Severity | Gender |
Age | Pearson Correlation | 1 | .382** | .148* | .391** | .210** | 0.109 |
Sig. (2-tailed) | | < 0.001 | 0.029 | < 0.001 | 0.002 | 0.103 |
N | 223 | 223 | 220 | 223 | 222 | 223 |
D-dimer Value (mg/L) | Pearson Correlation | .382** | 1 | 0.147* | .658** | .504** | -0.016 |
Sig. (2-tailed) | < 0.001 | | 0.027 | < 0.001 | < 0.001 | 0.809 |
N | 223 | 228 | 225 | 228 | 227 | 228 |
CRP value (mg/L | Pearson Correlation | .148* | .147* | 1 | 0.012 | .313** | -0.016 |
Sig. (2-tailed) | 0.029 | 0.027 | | 0.853 | < 0.001 | 0.816 |
N | 220 | 225 | 252 | 225 | 224 | 225 |
Hospital ward | Pearson Correlation | .391** | .658** | 0.012 | 1 | .269** | -0.018 |
Sig. (2-tailed) | < 0.001 | < 0.001 | 0.853 | | < 0.001 | 0.788 |
N | 223 | 228 | 225 | 228 | 227 | 228 |
Severity | Pearson Correlation | .210** | .504** | .313** | 0.269** | 1 | 0.028 |
Sig. (2-tailed) | 0.002 | 0 | 0 | 0 | | 0.679 |
N | 222 | 227 | 224 | 227 | 227 | 227 |
Gender | Pearson Correlation | 0.109 | -0.016 | -0.016 | -0.018 | 0.028 | 1 |
Sig. (2-tailed) | 0.103 | 0.809 | 0.816 | 0.788 | 0.679 | |
N | 223 | 228 | 225 | 228 | 227 | 228 |
**. Correlation is significant at the 0.01 level (2-tailed). |
*. Correlation is significant at the 0.05 level (2-tailed). |
Table 2
Logistic regression analysis predictive of severity in COVID-19 patients.
Variable | OR (95%CI) | P-value |
CRP (mg/l) | 1.011 (1.004–1.019) | 0.001 |
D-dimer (µg/ml) | 1.723 (1.420–2.089) | < 0.001 |
Supplementary Table 1. Values of D-dimer and CRP in ICU patients admitted to Hospital. |
Supplementary Table 2. Values of D-dimer and CRP in non-ICU patients admitted to Hospital. |
Supplementary Table 3. Correlations between Age, Gender, D-dimer value, CRP value, Hospital ward and Severity for non-ICU COVID-19 patients. |
Supplementary Table 4. Correlations between Age, Gender, D-dimer value, CRP value, Hospital ward and Severity for ICU COVID-19 patients. |
It is interesting to note that D-dimer is commonly high in patients with COVID-19. D-dimer levels indicate disease severity and are reliable prognostic test to rule out the presence of a serious blood clot in patients who were admitted for COVID-19 treatment. While higher levels of C reactive protein (CRP) may be a predictive marker in determining systemic inflammation and can predict which patients with mild COVID-19 will progress to a severe case.
Processes that involve production and breakdown of fibrin cause an elevation in D-dimer levels [2, 19]. Increased D dimer levels are reported to develop acute respiratory distress in COVID-19, with the more chances of micro pulmonary embolism especially in severe forms of COVID-19 [22]. D-dimer levels have been reported to vary among patients with confirmed venous thromboembolism (VTE) depending on clot burden, timing of measurement, and initiation of treatment [23]. D-dimer has also been shown to increase with age, which can cause more false positive tests in older patients [24]. Also, several potential risk factors during hospitalization like, disseminated intra vascular coagulation, infection, dehydration, prolonged immobilization, mechanical ventilation, and central venous catheter use may further increase D-dimer concentrations [23, 24].
In conclusion, we confirm the association of two main, inflammatory and biochemical covariates with COVID-19 severity for the first time in Bangladeshi patients. The study can help in detail understanding of the complications caused and predict the progression of the disease with much more confidence.