Original Article

The Relationship Between Inflammatory Indicators and the Severity of the Disease in Coronavirus Disease

10.4274/meandros.galenos.2021.65477

  • Recai Aci
  • Mukadder Erdem
  • Göksenin Ünlügüzel Üstün
  • Utku Duran
  • Adem Keskin
  • Melek Bilgin

Received Date: 10.11.2020 Accepted Date: 09.11.2021 Meandros Med Dent J 2022;23(2):208-213

Objective:

The complete blood count parameters and biochemical biomarkers important for the follow-up of patients in the inflammatory process of coronavirus disease 2019 (COVID-19) inpatients in the ward, and intensive care were analysed retrospectively.

Materials and Methods:

One hundred thirty inpatients in the intensive care and 147 inpatients in the COVID-19 ward were included in this study. Additionally, 47 healthy people were added as a control group. Whole blood parameters [white blood cell (WBC), lymphocyte, monocytes, platelet, neutrophil, monocyte/lymphocyte (MLR), neutrophil/lymphocyte (NLR)], ferritin, C-reactive protein (CRP), procalcitonin, erythrocyte sedimentation ratio (ESR) and albumin values of these patients and individuals were analyzed retrospectively. Obtained laboratory values were compared.

Results:

The procalcitonin, CRP, ESR, WBC, neutrophil, NLR, MLR, ferritin and procalcitonin values of the patients the intensive care patients were higher than the other two groups (p<0.001). However, the albumin and lymphocyte levels of the patients in the intensive care unit were lower (p<0.001). Additionally, the CRP and ESR values of the inpatients in the ward were higher than those in the control group (p<0.001).

Conclusion:

Hematological findings such as lymphocytes, NLR, WBC and inflammatory findings such as procalcitonin, ESR, CRP, and ferritin are associated with disease severity. Additionally, increased NLR levels may indicate aggravation of the inflammatory process and the possibility of intensive care admission. Therefore, monitoring of inflammatory findings, and NLR, can help predict and treat the prognosis of COVID-19.

Keywords: Coronavirus disease, C-reactive protein, ferritin, procalcitonin, neutrophil-lymphocyte ratio, inflammation

Introduction

Coronavirus disease-2019 (COVID-19) outbreak, which arose in China in the last months of 2019, quickly caused a pandemic. Although measures were taken to prevent spread, the number of people caught with COVID-19 reached approximately 37 million worldwide as of October, while the number of people who died of this disease exceeded 1 million (1). COVID-19 can cause respiratory failure, severe pneumonia, high fever, joint pain and even death (2). Studies conducted to date on inflammation markers in viral respiratory infections have played an major role in the rapid progress of our knowledge about the prognosis of COVID-19 (3).

C-reactive protein (CRP) is a biomarker of acute phase-response in inflammation, infection and tissue damage that can be used as a marker of inflammation (4). Procalcitonin levels have a more important role than CRP and white blood cell (WBC) count in separating one bacterial infection from other inflammatory process. In studies conducted on COVID-19 disease, a significant increase has been found in procalcitonin levels of groups whose disease had a severe course (5). Erythrocyte sedimentation rate (ESR) is not specific for any disease; however, it is used in combination with other tests to find out the presence of increased inflammatory activity. ESR has been long been used as a “disease indicator” due to its repeatability and low cost (6). Ferritin is an acute phase protein as demonstrated in both infectious and non-infectious diseases. High serum ferritin is a useful marker for a possible disease progression towards the critical development of COVID-19 (7).

A large number of studies have shown an increase in neutrophils with the decrease in lymphocyte in patients with COVID-19 (8-10). The neutrophil/lymphocyte ratio (NLR), obtained by the ratio of rising neutrophils to falling lymphocytes in infection, is a very strong indicator of the systemic inflammatory state (11).

The aim of our study is to evaluate the relationship between the hematological and inflammatory biomarkers and the severity of the disease that are important in the course of the COVID-19 disease. This evaluation was made as a result of comparing the whole blood and inflammatory parameters of inpatients with COVID-19 followed in the intensive care and ward with each other and with healthy individuals. As a result, whole blood and inflammatory biomarkers that come to the forefront in the hospitalization process of inpatients with COVID-19 both in the intensive care and ward are determined.


Materials and Methods

Our study was carried out after obtaining 2020/13 session numbered and 2020.13.6 decision numbered University of Health Sciences Turkey, Samsun Training and Research Hospital Non-Invasive Clinical Research Ethics Committee (date: 09.09.2020). Three groups were formed in the study.

Criteria of Groups

First of all, patients with positive COVID-19 real-time polymerase chain reaction test were included in the study. Patients with COVID-19 diagnosed with radiological or clinical findings but negative polymerase chain reaction test were not included in the study. Patients with COVID-19 were divided into two groups according to the unit they were hospitalized in. Inpatients in the ward were determined as a group, and inpatients in the intensive care as a group. In addition, a control group consisting of healthy individuals was added to the study.

Biochemical Process

After the ethics committee approval, with the authorization from Hospital Information Management system, the inpatients followed in COVID-19 ward and intensive care with a suspicion of coronavirus in May, June and July months of 2020 were found and their complete blood count parameters [WBC, lymphocyte, monocyte, neutrophil, platelet, monocyte/lymphocyte ratio (MLR), NLR] and CRP, procalcitonin, ferritin, ESR and albumin values, which are important biomarkers in the inflammatory process in terms of the prognosis of the disease, were examined retrospectively. Complete blood count parameters had been studied in Beckman Coulter DXH800 device, procalcitonin and ferritin were studied in Roche Cobas E411 device, CRP was studied in Beckman Coulter AU5800 device by using suitable kits and materials.

Statistical Analyses

SPSS 22.0 Windows Program was used for statistical analysis. It was determined that the data were not normally distributed. For this reason, non-parametric analyzes were used. Mann-Whitney U test was used for pairwise comparison of the groups.


Results

One hundred thirty inpatients diagnosed with COVID-19 from the intensive care and 147 inpatients from the ward were included in this study. In addition, 47 healthy individuals were added as a control. Of the inpatients in the intensive care, 46 (35.38%) were female and 84 (64.62%) were male. Of the inpatients in the ward, 74 (50.34%) were female and 73 (49.66%) were male. Twenty (42.55%) of the control group were female and 27 (57.45%) were male. While the average age of the inpatients in the intensive care was 68.28±14.22, the average age of the inpatients in the ward was 54.96±16.66, and the average age of the control group is 46.72±10.82. While the average day of hospital stay of the inpatients in the intensive care was 19.85, the average day hospital stay of the inpatients in the ward was 7.56. While 77 of the inpatients in the intensive care died, the others were discharged. Whole blood and inflammatory parameter mean ± standard deviations of the groups are given in Table 1.

In the comparison of the whole blood parameter values of the groups, the values of WBC, neutrophil, NLR and MLR of the inpatients in the intensive care was found to be higher than the values of the inpatients in the ward and the control group (p<0.001) (Figure 1). Additionally, the values of lymphocytes of the inpatients in the intensive care was found to be lower than the values of the inpatients in the ward and the control group (p<0.001) (Figure 1).

In the comparison of the inflammatory parameter levels of the groups, the values of CRP, ESR, ferritin and procalcitonin of the inpatients in the intensive care was found to be significantly higher than the values of the inpatients in the ward and the control group (p<0.001) (Figure 2). Additionally, the values of albumin of the inpatients in the intensive care was found to be lower than the values of the inpatients in the ward and the control group (p<0.001) (Figure 2). In addition, the values of CRP and ESR of the inpatients in the ward were found to be higher than the control group (p<0.001) (Figure 2).


Discussion

Haematological parameters which are used to classify COVID-19 inpatients include WBC, neutrophil, lymphocyte, monocyte, thrombocyte, eosinophil, MLR, NLR and haemoglobin. In addition to being very important component in the immune of the body, lymphocytes are also the main executers of all immune functions and at the same time a cellular component on the forefront to fight external infections. Lymphopenia has an important prognostic value in COVID-19 disease. While lymphopenia has been reported in 80% of the critical inpatients (12), this rate has been reported as 25% in mild inpatients (13). In a meta-analysis which included 758 COVID-19 positive cases that had severe disease and 1688 COVID-19 positive cases that had mild disease, a significant increase was found in the neutrophil count in cases with severe disease. It was also stated that an increase in WBC values of patients with COVID-19 (14). In our study, the values of WBC, neutrophil of the inpatients in the intensive care was found to be higher than the values of the inpatients in the ward and the control group.

In a study of 1141 patients with COVID-19, severe patients had a higher NLR than non-severe patients. NLR has been described as a prognostic value bio-marker for inpatients with sepsis (15). Our study, the values of NLR of the inpatients in the intensive care was found to be higher than the values of the inpatients in the ward and the control group.

In a study on coagulation and platelet parameters of patients with suspected COVID-19, platelet values of polymerase chain reaction (PCR)-negative participants were found to be higher than those of PCR-positive patients (16). In our study, there was no significant difference between the mean platelet levels of the groups.

Increase in CRP alone or with another marker can cause infections. CRP values are increased in patients with COVID-19 before compudet tomography findings and in the early stages of infection. More importantly, CRP has been associated with disease development (17). In a study including 663 patients, CRP value was found to be higher in patients with COVID-19 positive when compared with patients with COVID-19 negative (18). In our study, the values of CRP of the inpatients in the intensive care was found to be higher than the values of the inpatients in the ward and the control group. In addition, the values of CRP of the inpatients in the ward were found to be significantly higher than the control group.

Procalcitonin, a glycoprotein, is calcitonin precursor. Procalcitonin levels can be used to distinguish between viral and bacterial infections (19). In a study conducted in Wuhan with the inclusion of 191 positive patients, it was found that procalcitonin level increased in association with the severity of the disease (7). In another meta-analysis including 1099 patients, almost four times higher procalcitonin value was found in the severe group (20). It has been found that procalcitonin can make a significant distinction between severe cases and non-severe and fatal cases and thus can function as a possible predictic biomarker in individual studies (21). In our study, the values of procalcitonin of the inpatients in the intensive care was found to be higher than the values of the inpatients in the ward and the control group.

Serum ferritin levels can increase significantly as a response to inflammation and various diseases. ferritin synthesis regulation is under the control of cytokine (22). Due to the cytokine storm observed in fatal and critical COVID-19 cases, an increase occurs in serum ferritin levels in these cases. It has been reported that ferritin levels ranging from 400 μg/L to >2000 μg/L are seen in COVID-19 patients and that the highest ferritin levels are seen in serious cases and in those who did not survive (7,13). In a previous study including 653 COVID-19 positive patients, it was found that mean ferritin level was 408.28 ng/mL and this value was correlated with disease severity and the increase in ferritin level could be used as prognostic marker of imminent death (23). In our study, the values of ferritin of the inpatients in the intensive care was found to be higher than the mean values of the inpatients in the ward and the control group.

There are very few data on ESR in patients with COVID-19. In a study conducted on 113 patients, it was reported that fatal cases had higher ESR tendency than the cases that recovered, without reporting the significance of the difference observed between positive and negative patients (13). In another study with 80 patients, it was found that ESR was associated with CRP and haemoglobin and patients with severe disease had higher ESR levels (24). In a study conducted with patients with COVID-19 with diabetes comorbidity, inflammatory parameters (ESR, procalcitonin, ferritin and CRP) were found to be higher (25). In our study, the values of ESR of the inpatients in the intensive care was found to be higher than the values of the inpatients in the ward and the control group. In addition, the values of ESR of the inpatients in the ward were found to be higher than the control group.


Conclusion

In summary, it has been concluded that haematological findings such as lymphocyte, WBC, MLR, NLR and inflammatory findings such as procalcitonin, CRP, ferritin, ESR are associated with the disease severity and that they could be used as very important risk factors for the progress of the disease. In addition, increased NLR levels reflecting an increased inflammatory process can show possibility of hospitalization in intensive care. For this reason, the surveillance of inflammatory findings, and NLR, can help in the diagnosis, early screening of COVID-19 and in the treatment of severe diseases.

Ethics

Ethics Committee Approval: Our study was carried out after obtaining 2020/13 session numbered and 2020.13.6 decision numbered Health Sciences University of Health Sciences Turkey, Samsun Training and Research Hospital Non-Invasive Clinical Research Ethics Committee (date: 09.09.2020).

Informed Consent: Retrospective study.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: R.A., G.Ü.Ü., A.K., Concept: M.E., U.D., Design: M.E., G.Ü.Ü., U.D., Data Collection or Processing: R.A., U.D., A.K., M.B., Analysis or Interpretation: R.A., G.Ü.Ü., A.K., M.B., Literature Search: R.A., M.E., G.Ü.Ü., U.D., A.K., M.B., Writing: R.A., A.K.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.


Images

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