key: cord-0728813-s7mj1pb5
authors: Ullah, Waqas; Thalambedu, Nishanth; Haq, Shujaul; Saeed, Rehan; Khanal, Shristi; Tariq, Shafaq; Roomi, Sohaib; Madara, John; Boigon, Margot; Haas, Donald C.; Fischman, David L.
title: Predictability of CRP and D-Dimer levels for in-hospital outcomes and mortality of COVID-19
date: 2020-09-03
journal: Journal of community hospital internal medicine perspectives
DOI: 10.1080/20009666.2020.1798141
sha: d502e555eccfb7870454a9ad917975d5e1bd048c
doc_id: 728813
cord_uid: s7mj1pb5

BACKGROUND: Systemic inflammation elicited by a cytokine storm is considered a hallmark of coronavirus disease 2019 (COVID-19). This study aims to assess the clinical utility of the C-reactive protein (CRP) and D-Dimer levels for predicting in-hospital outcomes in COVID-19. METHODS: A retrospective cohort study was performed to determine the association of CRP and D-Dimer with the need for invasive mechanical ventilation (IMV), dialysis, upgrade to an intensive care unit (ICU) and mortality. Independent t-test and multivariate logistic regression analysis were performed to calculate mean differences and adjusted odds ratios (aOR) with its 95% confidence interval (CI), respectively. RESULTS: A total of 176 patients with confirmed COVID-19 diagnosis were included. On presentation, the unadjusted odds for the need of IMV (OR 2.5, 95% CI 1.3–4.8, p = 0.012) and upgrade to ICU (OR 3.2, 95% CI 1.6–6.5, p = 0.002) were significantly higher for patients with CRP (>101 mg/dl). Similarly, the unadjusted odds of in-hospital mortality were significantly higher in patients with high CRP (>101 mg/dl) and high D-Dimer (>501 ng/ml), compared to corresponding low CRP (<100 mg/dl) and low D-Dimer (<500 ng/ml) groups on day-7 (OR 3.5, 95% CI 1.2–10.5, p = 0.03 and OR 10.0, 95% CI 1.2–77.9, p = 0.02), respectively. Both high D-Dimer (>501 ng/ml) and high CRP (>101 mg/dl) were associated with increased need for upgrade to the ICU and higher requirement for IMV on day-7 of hospitalization. A multivariate regression model mirrored the overall unadjusted trends except that adjusted odds for IMV were high in the high CRP group on day 7 (aOR 2.5, 95% CI 1.05–6.0, p = 0.04). CONCLUSION: CRP value greater than 100 mg/dL and D-dimer levels higher than 500 ng/ml during hospitalization might predict higher odds of in-hospital mortality. Higher levels at presentation might indicate impending clinical deterioration and the need for IMV.

Currently, the novel coronavirus disease 2019 (COVID-19) has become one of the deadliest pandemics that has ravaged the world and carries a high mortality rate. In the USA (US), as of May 2020, over 100,000 deaths have been reported. A large group of these patients present with a sepsis syndrome and hypoxia, eventually requiring a higher level of care and invasive mechanical ventilation (IMV). Due to a higher volume of patients, it is imperative to look for predictors that can guide us in allocating resources for these patients and be prepared in advance as presently our health systems have been stretched to their limits. In the multitude of blood tests and imaging conducted on these patients, CRP and D-Dimer levels are measured in many health-care settings.

CRP is a protein discovered in the 1930s by Tillett and Francis and is an acute phase reactant. It is a pentameric protein which is synthesized by the liver under the action of cytokine interleukin 6 (IL-6). A very high level of CRP >50 mg/dL is mostly associated with bacterial infections but elevated levels are also seen in injuries, cardiovascular processes and other inflammatory states. Elevated CRP levels not only suggest a pro-inflammatory state but also can be used as a prognostic marker for the underlying disease processes [1] . D-dimers are multiple peptide fragments produced as a result of degradation of crosslinked fibrin, mediated by plasmin [2] . The presence of D-dimers indicates the production and degradation of crosslinked fibrin, reflecting the coagulation and fibrinolysis processes occurring concomitantly. In healthy subjects, it is measurable in small amounts, because 2-3% of fibrinogen is converted to fibrin and enters the fibrinolytic pathway under normal physiological conditions [3] . Any processes that involve production and breakdown of fibrin cause an elevation in D-dimer levels. These include acute venous thromboembolism (VTE), cancer, pregnancy, acute or chronic inflammatory states, acute infections and surgery. As it lacks specificity its role in the current scenario is mainly limited to rule out acute VTE. D-dimer levels vary among patients with confirmed VTE depending on clot burden, timing of measurement, and initiation of treatment [4] .

In our study, we aim to see if C-reactive protein and D-Dimer values can be potential predictors of adverse outcomes in the hospital.

This is a retrospective study in a single communitybased academic hospital designed to look at the relationship between different acute phase reactants/ inflammatory markers in patients admitted with COVID 19. All patients had a confirmed diagnosis of COVID-19 between 1 March 2020, and 30 May 2020. The study was approved by the Institutional Review Board (IRB) and the requirement for informed consent was waived by the Research Ethics Committee (REC).

Patients were divided into two groups for each comparison. High D-Dimer (>501 ng/ml) and low D-Dimer (<500 ng/ml) groups were compared both on day-1 and day-7 of hospitalization. Similarly, high CRP (>101 mg/dl) and low CRP (<100 mg/ dl) were compared for in-hospital outcomes assessment. Clinical, demographic, laboratory, treatment, and outcome data were extracted from electronic medical records (Sunrise) using a standardized data collection form. Most authors contributed in data retrieval and an independent author adjudicated any difference in interpretation between the data extractors. Laboratory procedures, methods for laboratory confirmation of SARS-CoV-2 infection were standardized. Briefly, SARS-CoV-2 detection in respiratory specimens (throat swabs) by nextgeneration sequencing or real-time qualitative polymerase chain reaction (RT-qPCR) methods at the Thomas Jefferson University Hospitals, USA was used for all included populations. The criteria for discharge were absence of fever, freedom from symptoms for at least 1 day, substantial clinical or radiological improvement. Routine blood work included coagulation profile, complete blood count, serum biochemical tests (renal function, liver function) lactate dehydrogenase (LDH), myocardial enzymes (troponin T TnT) and serum ferritin.

Continuous variables were presented as mean and standard deviations (SD), categorical variables were reported in percentages and proportions. A chisquare (χ2) test was used for comparison of categorical data, Fisher exact test was only adopted if the expected count in more than 20% cells was less than 5. To quantify the association between the dichotomous categorical variables, an unadjusted odds ratio (OR) was obtained using a Cochran-Mantel-Haenszel method. To explore the risk factors and gauge the impact of potential effect modifiers (covariates) on our endpoints (in-hospital death, need for an upgrade, ventilators and dialysis) binomial and multinomial logistic regression models were applied. The differences in the baseline comorbidities (DM, HTN, CAD, CKD) and medication use (HCQ, tocilizumab, ramdisivir, anticoagulation and steroids) were accounted for to obtain an adjusted odds ratio (aOR) for all outcomes. For normally and abnormally distributed continuous data, an independent sample t-test and Mann-Whitney U test were used, respectively. A one-way analysis of variance (ANOVA) was used to compare differences in the mean of continuous variables for multiple inhospital complications. A two-sided α of less than 0.05 was considered statistically significant corroborating inference from a 95% confidence interval (CI). Statistical analyses were performed using the SPSS software (version 25).

A total of 176 patients with a confirmed diagnosis of COVID-19 were included in our study. Patients were divided into two comparison groups [low D-Dimer (<500 ng/ml) vs. high D-Dimer (>501 ng/ml)] and [low CRP (<100 mg/dl) and high CRP (>100)]. The mean age for CRP patients was (63.6 vs. 61.6) and for D-Dimer groups it was (62.6 vs. 63.7) years, respectively. The baseline comorbidities across all groups were comparable except that higher CRP group (>101 mg/dl) had female predominance. The proportions of underlying comorbidities between low and high CRP groups included DM (83.9% vs. 16.1%), HTN (86.9% vs 13.1%), CAD (93.1% vs 6.1%), CKD (87.1% vs 12.9%), and COPD (91.7% vs 8.3%) respectively. These percentages for low and high D-Dimer groups were; DM (21.1% vs 78.9%), HTN (23.0% vs 80.0%), CAD (19.4% vs 80.6%), CKD (25% vs 75%), and COPD (16.7% vs 83.3%) respectively. Patients in both CRP and D-Dimer groups had similar proportions of medication use (HCQ, tocilizumab, AC, steroids) across both groups (p-value ≤0.05). (Table 1) 

The mean difference in the levels of CRP and D-Dimers between patients on definitive COVID-19 therapy compared to those not receiving therapy were mostly identical across its respective groups with few exceptions. 

The mean differences in CRP and D-Dimer for hard clinical outcomes such as in-hospital mortality and resources allocation were also calculated. The mean CRP differences on day-1 of admission were significantly higher for patients requiring an upgrade (164. 

In terms of in-hospital complications, patients with deep venous thrombosis and pulmonary embolism had significantly higher mean D-Dimer levels (69,000 and 16.907, p = <0.001), respectively. There was no significant difference in the mean CRP and D-Dimer levels for other in-hospital complications as shown in supplementary tables. Figure 2 ). By contrast, on presentation, the unadjusted odds ratio for in-hospital mortality (OR 2.4, 95% CI 0.89-6.68, p = 0.13), need for upgrade to ICU (OR 1.42, 95% CI 0.7-2.7, p = 0.38), requirement for IMV (OR 2.30, 95% CI 1.2-4.4, p = 0.15) and dialysis (OR 2.3, 95% CI 0.57-9.2, p = 2.5) were not significantly different between patients with a higher D-Dimer (>501 ng/ml) as compared to a low D-Dimer (<500 ng/ml). However, on day-7 of hospitalization, a high D-Dimer (>501 ng/ml) was associated with higher odds of in-hospital mortality (OR 10.0, 95% CI 1.2-77.9, p = 0.02), increased need for upgrade to the ICU (OR 7.8, 95% CI 2.8-21.6, p = <0.001) and higher requirement for IMV (OR 8.2, 95% CI 3.1-21.6, p = <0.001). (Table 3 , Figure 3 ) A multivariate regression model was used to adjust the observed odds ratios for baseline comorbidities and medications including DM, HTN, CKD, CAD, use of AC at home, HCQ, tocilizumab, steroids and therapeutic anticoagulation during hospital stay. The adjusted odds values were mostly consistent with unadjusted odds ratios indicating no influence of covariates with one exception. In contrast to unadjusted OR, the adjusted odds ratio for the need of IMV with a high CRP (>101 mg/dl) on day 7 was significant (aOR 2.5, 95% CI 1.05-6.0, p = 0.04).

Our study reveals that higher D-Dimer levels (>501 ng/ml) on admission might indicate a higher need for invasive mechanical ventilation (IMV). Compared to D-Dimers, a high C-reactive protein (CRP) (>101 mg/dl) on admission predicts not only a greater need for IMV but also for an upgrade to a higher level of care. After completion of therapy for COVID-19, both a high CRP (>101 mg/dl) and elevated D-Dimer levels (>501 ng/ml) were associated with higher odds of in-hospital mortality, need for IMV and upgrade to ICU. When adjusted for baseline comorbidities and medications, patients with CRP level (>101 mg/dl) on presentation have twofold higher odds of requiring IMV and 3 times higher odds to be upgraded to the intensive care units (ICU). During hospitalization with a consistently higher CRP (>101 mg/dl) on day-7, the odds of requiring IMV and upgrade to ICU increases to 3 and 4 fold compared to patients having lower CRP (<100 mg/ dl). Similarly, high CRP (>101 mg/dl) levels were found to confer a 4 times higher rate of in-hospital all-cause mortality when controlled for major confounders. Compared to CRP, elevated D-Dimer levels (>501 ng/ml) during hospitalization can serve as a more sensitive marker for the severity of COVID-19 infection. Our study showed that patients on the seventh day of admission with D-dimer levels more than 500 ng/mL are 10 times more likely to die than patients with D-dimer levels less than 500 ng/mL. By contrast, the odds of mortality in the higher CRP (>101 mg/dl) were 3 times compared to patients with lower CRP (<100 mg/dl). Even at presentation, elevated D-Dimer (>501 ng/ml) and raised CRP levels (>101 mg/dl) were associated with higher odds of mortality; however, these values did not reach the level of statistical significance. These results contrast the recent findings of a study from Wuhan, China reporting a four-fold increase in inhospital mortality with a higher D-Dimer level [5] . Previous studies have shown that in medically ill patients, D-dimer levels twice the upper limit of normal were found to have a high risk of developing VTE [6] [7] [8] [9] [10] . Our findings also showed a significantly higher mean d-dimer levels for patients developing pulmonary embolism and deep VTE.

Our data on CRP are also in line with literature seen on ICU admissions and mortality pertaining to sepsis syndromes, where a higher CRP was associated with longer length of stays and worse prognosis in terms of mortality [11, 12] . To our best knowledge, this is the first study looking at CRP levels and its impact on the need for a higher level of care along with the need for IMV in COVID-19 patients. We believe that CRP at presentation could serve as a reliable early predictor for in-hospital complications in terms of both the need for IMV and upgrade to ICU, while elevated D-Dimer (>501 ng/ml) could predict only the need for IMV. Nonetheless, both high CRP and raised D-Dimer are useful prognostic markers for overall in-hospital mortality risk, need for IMV and upgrade to ICU. This indicates that both elevated CRP (>101 mg/dl) and D-dimer levels serve as a marker of disease severity at any point during the hospital stay. This is consistent with a smaller retrospective study from Suzhou, China which showed elevated D-Dimer levels in severe COVID-19 patients on day 1, 7 and 14 of hospitalization when compared to mild/ moderate COVID-19 patients during the same time period [13] .

Previous studies have also shown that patients being admitted to the hospital for COVID 19 can suffer from acute kidney injury and proteinuria that is associated with a higher mortality [14] .

Our study, however, demonstrated no significant association of CRP and D-Dimer levels with the inhospital need for hemodialysis (HD) despite the fact that patients on HD had a higher mean CRP at admission on day-7 of admission.

Briefly, our study advocates for the use of CRP and D-Dimer levels at admission and during hospitalization as the severity and prognostic markers. Patients with rising levels of the markers might need higher levels of care and more vigilant monitoring. Our study highlights the higher risk of adverse outcomes in this patient population allowing physicians to not only anticipate and prognosticate these unfortunate outcomes but also to inform decisions about resource allocation.

The findings of our study should be interpreted in light of its limitations. Due to the retrospective nonrandomized nature of the study, a causal relationship could not be ascertained. Although the overall findings were adjusted for covariates, including baseline comorbidities and medications, the impact of unmeasured confounders such as initiation of several complementary therapies at the treating physician's discretion, could not be determined. Based on our clinical experience, the average duration of any therapy for COVID-19 was less than seven days; therefore, we chose to use day-1 and day-7 laboratory values. However, given the variable frequency of laboratory specimen collection, it is not possible for us to ascertain if these truly represented pre-and post-treatment values accurately in all cases. Moreover, by excluding patients still in the hospital, the case fatality ratio in our study cannot reflect the true mortality of COVID-19. Lastly, the interpretation of our findings might be limited by the sample size. However, by adjusting the adult patients with confirmed disease, we believe our population is the best representative of the real-world cohort.

A high CRP (>101 mg/dl) at presentation appears to predict an increased need for IMV and intensive care. A high CRP (>101 mg/dl) and elevated D-Dimer (>501 ng/ml), after COVID-19 therapy, predict higher odds of mortality; however, large scale and longer-term studies are needed to validate our findings.

No potential conflict of interest was reported by the authors. 

Role of C-reactive protein at sites of inflammation and infection. Front Immunol

D-Dimer antigen: current concepts and future prospects

D-Dimer testing: laboratory aspects and current issues

Review of D-dimer testing: good, Bad, and Ugly

D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19

New paradigms in venous thromboprophylaxis of medically ill patients

D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial

Measurement of D-Dimer as aid in risk evaluation of VTE in elderly patients hospitalized for acute illness: a prospective, multicenter study in China

Extended thromboprophylaxis with betrixaban in acutely ill medical patients

The IMPROVEDD VTE risk score: incorporation of D-Dimer into the IMPROVE score to improve venous thromboembolism risk stratification. TH Open

C-reactive protein as a prognostic factor in intensive care admissions for sepsis: A Swedish multicenter study

Elevated C-reactive protein levels at ICU discharge as a predictor of ICU outcome: a retrospective cohort study. Ann Intensive Care

The clinical implication of dynamic neutrophil to lymphocyte ratio and D-Dimer in COVID-19: A retrospective study in Suzhou China

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study