key: cord-0813996-wqo9nt2n
authors: Tuncer, G.; Surme, S.; Bayramlar, O. F.; Karanalbant, H. K.; Copur, B.; Yazla, M.; Zerdali, E.; Yilmaz-Nakir, I.; Kurt-Cinar, A. R.; Buyukyazgan, A.; Balli, H.; Kurekci, Y.; Simsek-Yavuz, S.; Sonmez, M. M.; Sengoz, G.; Pehlivanoglu, F.
title: NEWS2 and laboratory predictors correlated with clinical deterioration in hospitalised patients with COVID-19
date: 2021-01-20
journal: nan
DOI: 10.1101/2021.01.17.21249878
sha: 93877c2a924b1a8a528f09dc35c2272408b67145
doc_id: 813996
cord_uid: wqo9nt2n

Background: We aimed to determine prognostic values of NEWS2 and laboratory parameters during the first week of COVID-19. Methods: All adult patients who were hospitalized for a confirmed COVID-19 between the 11th of March and the 11th of May 2020 were retrospectively included. To evaluate the factors in prognosis which are admission to intensive care unit (ICU) and in-hospital death, univariate logistic regression analysis was performed at admission (D0), at day-3 (D3), day-5 (D5), and day-7 (D7). Additionally, receiver operating characteristic (ROC) analyses were performed. Results: Overall, 611 patients were included. Clinical deterioration was observed in 79 (12.9%) patients during hospitalisation, 36 (5.9%) during the first three days, 54 (8.8%) during the first five days, and 62 (10.1%) during the first week of hospitalisation. Our results showed that NEWS2, procalcitonin, neutrophil/lymphocyte ratio (NLR), and albumin were the best predictors for clinical deterioration at D0, D3, D5, and D7. Procalcitonin had the highest odds ratio for clinical deterioration on all days in univariate analysis. ROC analyses showed that NEWS2 at D7, procalcitonin at D5, albumin at D7, and NLR at D5 had highest AUC values. Additionally, we detected a strong correlation between NEWS2 and laboratory parameters including neutrophil, lymphocyte, NLR, platelet/lymphocyte ratio, CRP, procalcitonin, ferritin, and urea on all days. Conclusion: This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for ICU admission or in-hospital death during the clinical course of COVID-19. Dynamic monitoring of NEWS2 and laboratory parameters is vital for improving clinical outcomes.

The COVID-19 pandemic due to the SARS-CoV-2 virus causes high rates of mortality, morbidity, longer duration of hospitalization and increased need for intensive care unit (ICU) admission (1) . Improving critical care patient flow is crucial for high quality care to severe cases. Therefore, we need to predict clinical deterioration in patients with COVID-19, in order to hospitalize the patients and admit to ICU, when necessary. The National Institute for Health and Care Excellence recommend The National Early Warning Score 2 (NEWS2) to predict the risk for clinical deterioration in patients with COVID-19 (2, 3) . NEWS2 is a simple scoring system including physiological parameters and vital signs (respiratory rate, oxygen saturation, systolic blood pressure, heart rate, level of consciousness, temperature and supplemental oxygen dependency) used to predict the risk for acute deterioration including sepsis (4, 5) . An increasing number of studies have assessed the parameters in NEWS2 score for severe COVID-19 illness (6) . However there is a lack of knowledge about the predictive value of NEWS2, despite some studies focus on NEWS2 and related scores (3) .

In this study, we aimed to determine prognostic value of NEWS2 and laboratory parameters in COVID-19 patients. Additionally, the correlation between NEWS2 and laboratory parameters at admission, D3, D5, and D7 during the clinical course of COVID-19 were evaluated.

In this retrospective and single-center study, all adult patients (≥18 years old) who were hospitalized for a laboratory confirmed COVID-19 between the 9th of March and the 8th of May 2020 were included. SARS-CoV-2 testing was performed by real-time reverse transcriptionpolymerase chain reaction (RT-PCR) of samples collected by nasopharyngeal and/or oropharyngeal swabs.

Patients with COVID-19 requiring hospitalisation were included in the study. Outpatients and asymptomatic patientswere excluded. Also, we excluded patients if oropharyngeal or nasopharyngeal swab samples were repeatedly negative for SARS-CoV-2 by RT-PCR. Our primary outcome was the occurence of clinical deterioration defined as a composite of ICU admission during hospitalisation or in-hospital death.

Epidemiological and demographic characteristics, clinical, laboratory, radiological findings, and outcomes were collected from medical records. Vital signs including respiratory rate, peripheral capillary oxygen saturation, heart rate, blood pressure, body temperature, and consciousness (Glasgow Coma Scale) were recorded. Laboratory parameters including albumin, C-reactive protein (CRP), procalcitonin, haemoglobin, hematocrit, neutrophil count, lymphocyte count,, platelet count, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), urea, ferritin, albumin, fibrinogen, d-dimer, aspartate aminotransferase (AST), and alanin aminotransferase (ALT) were included. The NEWS2 score was calculated.

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The parameters associated with admission ICU and in-hospital death at D0, D3, D5, and D7 were NEWS2, lymphocyte count, neutrophil count, platelet count, NLR, PLR, CRP, procalcitonin, ddimer, troponin, AST, urea, LDH, and albumin. The median and IQR values of the laboratory parameters and are available in Table- 1. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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In univariate analysis, among parameters associated with ICU admission or in-hospital death at D0, D3, D5, and D7, best predictors were NEWS2, procalcitonin, NLR, and albumin.

Additionally, d-dimer (at D0, D3, and D7) and haemoglobin (at D3 and D5) were valuable predictors in univariate analysis (Table-2 ). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Laboratory parameters correlated with NEWS2 at D0, D3, D5, and D7 were lymphocyte count, neutrophil count, NLR, PLR, CRP, procalcitonin, ferritin and urea (Suppl. Fig. 1 . and Suppl. Fig. 

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The copyright holder for this preprint this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.17.21249878 doi: medRxiv preprint Supp. Figure 1 . Correlation between NEWS2 and lymphocyte count, neutrophil count, NLR, PLR, CRP, procalcitonin, ferritin and urea at D0 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 20, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 20, 2021. ; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 20, 2021. Figure 2 . Receiver Operating Characteristic (ROC) curve and performance value for the best cut off for: A: procalcitonin at admission using clinical deterioration. B: procalcitonin at D3 using clinical deterioration. C: procalcitonin at D5 using clinical deterioration. D: procalcitonin at D7 using clinical deterioration.

ProCa-D7

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The copyright holder for this preprint this version posted January 20, 2021. ; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 20, 2021. ; Figure 4 . Receiver Operating Characteristic (ROC) curve and performance value for the best cut off for: A: neutrophil/lymphocyte ratio (NLR) at admission using clinical deterioration B: NLR at D3 using clinical deterioration C: NLR at D5 using clinical deterioration D: NLR at D7 using clinical deterioration

In this study, we presented a detailed analysis of the NEWS2 score and laboratory parameters in hospitalized patients with COVID-19. Our results showed that NEWS2, procalcitonin, NLR, and albumin were the best predictors for clinical deterioration (ICU admission or in-hospital death) at D0, D3, D5, and D7. Procalcitonin had the highest odds ratio for clinical deterioration at D0, D3, D5, and D7 in univariate analysis. ROC analyses showed that NEWS2 at D7, procalcitonin at D5, albumin at D7, and NLR at D5 had highest AUC values. Additionally, we detected a strong correlation between NEWS2 and laboratory parameters including lymphocyte count, neutrophil count, NLR, PLR, CRP, procalcitonin, ferritin, and urea at D0, D3, D5, and D7.

Early and accurate discrimination of need for ICU improves the clinical course of COVID-19 and reduce unnecessary use of ICU beds. To date limited data exists on the NEWS2 and laboratory parameters in patients with COVID-19. There are several published studies on the use of NEWS2 in COVID-19 patients (2) (3) (4) (7) (8) (9) (10) (11) (12) . However, most studies evaluate NEWS2 at admission only (10) (11) (12) (13) . In the study of Sze et al., they suggested that NEWS2 score was not a valuable tool to predict clinical deterioration in elderly patients with COVID-19 (14) . However, they reported the results of only 17 elderly patients. Kim Similarly, Sixt et al. showed that AUROC values of NEWS2 was 0.74 at D0, with a best cut-off of 6 and was 0.98 at D7, with a best cut-off of 7. They reported high sensitivity and specificity at D7 (%92 and %97, respectively) (8).

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The copyright holder for this preprint this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01. 17.21249878 doi: medRxiv preprint Due to the physiopathological changes, deterioration in different laboratory parameters occurs while the disease progresses. Therefore, laboratory parameters are commonly used for assessing disease severity. Lagadinou et al. found an association between COVID-19 severity and the following laboratory parameters NLR, LDH, d-dimers, CRP, fibrinogen, and ferritin (15) . In the study of Xu et al., procalcitonin, CRP, and NLR were valuable predictors for COVID-19 mortality. They showed that the AUC from highest to lowest was combined effect> CRP > procalcitonin > NLR, respectively (16) . Liao et al. reported that NLR, thrombocytopenia, prothrombin time, and D-dimer were associated with death. They showed that increased NLR (≥9·13) was associated with 5-fold increased mortality risk (17) . Similarly, in our study, increased NLR was associated with OR = 1.286-fold at D0, OR = 1.754-fold at D3, OR = Additionally, procalcitonin (≥ 0.10 ng/mL) and CRP (≥ 52.14 mg/L) but not NLR exhibited independent increasing risks of mortality, with HRs of 52.68 (95% CI: 1.77-1571.66) and 5.47 (95% CI: 1.04-28.72), respectively (16) .

In the study of Shang et al., Spearman's rank correlation analysis revealed that leukocyte, neutrophil, CRP, procalcitonin, and LDH were positively correlated and albumin was negatively correlated with mortality in patients with receiving maintenance hemodialysis. Additionally, they showed that CRP had the highest AUROC value (0.895), and the values of AUROC of neutrophil count, LDH, leukocyte, albumin, and procalcitonin were 0.813, 0.758, 0.757, 0.743, and 0.728, respectively (20) . In contrast, we found that procalcitonin was the best predictor for clinical deterioration our study. The optimal cut-off value of procalcitonin at D0, D3, D5, and D7 were 0.065 ng/mL, 0.125 ng/mL, 0.155 ng/mL, and 0.120 ng/mL, and the sensitivity and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 20, 2021. Procalcitonin is not well studied for COVID-19 cases. However, some studies suggested that increased procalsitonin levels were found to be associated with the disease severity in patients with COVID-19. A meta-analysis showed that severe patients with COVID-19 had increased procalcitonin levels (18, 19) . Similarly, we found that procalcitonin was the best prognostic parameter for the clinical deterioration in our study. Elevated procalcitonin levels could be associated with acute secondary bacterial pnemonia or systemic secondary bacterial infection in patients with COVID-19 due to the production and release into the circulation from procalcitonin producing extrathyroidal tissues. (21) In our study, despite elevated procalcitonin levels, this elevation was limited. In a previous study by Xu et al., they suggested that a limited increase in procalcitonin levels could be associated with increased interferon-gamma (16) .

Low serum albumin in studies with COVID-19 patients levels are suggested to be associated with an increased risk of mortality (22) (23) (24) (25) In consistent with other studies, our results confirm that albumin is a valuable predictor for ICU admission or in-hospital death. Albumin is a negative acute phase reactant produced in the liver and causes down-regulation of the expression of ACE-2 receptors which play a role in the cell entry mechanism of SARS-CoV-2. Liu et al.

reported that albumin was associated with clinical deteroration and significantly higher in patients with the improvement/stabilization than in those with disease progression (36.62 ± 6.60 vs. 41.27 ± 4.55 g/L, p=0.006) (24) . In the study of Aziz et al., mean albumin at D0 was 3.50 g/dL (CI 3.26-3.74 g/dL) in severe group and 4.05 g/dL (CI 3.82-4.27 g/dL) in non-severe group (p < 0.001). They reported that hypoalbuminemia was associated with 12.6-fold increased risk of mortality (25) .

An increase in neutrophils and a decrease in lymphocytes have been found in various studies.

Some studies have shown that NLR may be an important indicator for the severity of COVID -19 patients. Yan et al. showed that NLR was significantly correlated with all-cause in-hospital mortality (OR 44.351; 95% CI 4.627-425.088) (26) . The NLR reflects the balance between the innate and adaptive immune systems (30) and increased NLR levels were found to be associated with clinical deterioration in COVID-19 (16) .

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The copyright holder for this preprint this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01. 17.21249878 doi: medRxiv preprint This study has also several limitations. First, it was retrospectively conducted in a single-center. Second, this study had a small sample size and a control group was not included. The generalizability of our results may be limited. Thus, we need new large scale studies providing important information to better understand COVID-19 pandemic. Our study has also several strengths. First, we were able to admit all critically ill patients requiring intensive care to the ICU during the first months of pandemic. This prevent a selection bias. Second, longitudinally evaluation of the association between clinical deterioration and the dynamic changes of laboratory parameters was performed, since we regularly monitored laboratory parameters during the clinical course.

This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for ICU admission or in-hospital death during the clinical course of COVID-19.

NEWS2, procalcitonin, NLR, and albumin have a high accuracy to predict clinical outcomes/disease progression in hospitalized patients and should be considered in the clinical decision of ICU admission. In conclusion, dynamic monitoring of NEWS2 and laboratory parameters is vital for improving clinical outcomes.

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The authors acknowledge all healthcare professionals who contribute to the care of our patients.

This research did not receive any specific grant. No funding was used.

The authors declare that they have no competing interests.

GT proposed the concept, designed the study, wrote the protocol, and managed the study. GT,