SUMMARY

OBJECTIVE:

This retrospective study aimed to determine the predictive values of the C-reactive protein (CRP)/albumin ratio (CAR), fibrinogen/albumin ratio (FAR), and neutrophil/lymphocyte ratio (NLR) parameters, which reflect the systemic inflammatory status, for the severity of COVID-19.

METHODS:

A total of 188 patients diagnosed with COVID-19 were enrolled in this study. Among them, 118 were in the severe group, and 70 were in the non-severe group. Levels of albumin, CRP, D-dimer, procalcitonin, fibrinogen, and hemoglobin; leukocyte, neutrophil, lymphocyte, and monocyte counts; and the FAR, CAR, and NLR were compared between the two groups.

RESULTS:

The CAR, FAR, and NLR values were significantly higher in the severe group compared to the non-severe group. CAR, FAR, and NLR were positively correlated with leukocyte and neutrophil counts and CRP, procalcitonin, and fibrinogen levels. On the other hand, they were inversely correlated with monocyte (except for NLR) and lymphocyte counts. Receiver operator characteristic analysis showed that the area under the curve (AUC) for CAR, FAR, and NLR was 0.841, 0.737, and 0.802, respectively.

CONCLUSIONS:

Our investigation revealed that the CAR, FAR, and NLR indices can be used to predict the severity of COVID-19, among which CAR was the best predictor of severe COVID-19.

KEYWORDS:
COVID-19; C-reactive protein; Fibrinogen; Neutrophils

INTRODUCTION

The COVID-19 pandemic started in China in December 2019 and is still ongoing worldwide. This highly contagious disease, which is a priority public health problem in countries affected by the pandemic, is transmitted among humans via close contact and respiratory droplets. The patients present with a wide clinical spectrum ranging from asymptomatic infection to mild or severe viral pneumonia, or respiratory failure leading to death¹1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
https://doi.org/10.1016/S0140-6736(20)30... ^,22. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–20. https://doi.org/10.1056/NEJMoa2002032
https://doi.org/10.1056/NEJMoa2002032... . The course of the disease was reported to be more severe in frail patients, that is, elderly persons and patients with preexisting chronic illnesses³3. Du RH, Liang LR, Yang CQ, Wang W, Cao TZ, Li M, et al. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study. Eur Respir J. 2020;55(5):2000524. https://doi.org/10.1183/13993003.00524-2020
https://doi.org/10.1183/13993003.00524-2... ^,44. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229): 1054–62. https://doi.org/10.1016/S0140-6736(20)30566-3
https://doi.org/10.1016/S0140-6736(20)30... . Early diagnosis and discriminating the critical cases to administer timely therapy is very important to slow down or prevent the progression of the disease. Thus, for rapid clinical decision-making, easy-to-access, quick, and low-cost markers are needed. Among several laboratory parameters assessed in many studies, lymphocyte, platelet, albumin, C-reactive protein (CRP), fibrinogen, pro-calcitonin, D-dimer, interleukin-6, and their derived neutro-phil/lymphocyte ratio (NLR) and fibrinogen/albumin ratio (FAR) have been proposed as predictive markers for the severity of COVID-19⁵5. Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al. Diagnostic utility of clinical laboratory data determinations for patients with severe COVID-19. J Med Virol. 2020;92(7):791–6. https://doi.org/10.1002/jmv.25770
https://doi.org/10.1002/jmv.25770... ^–99. Aziz M, Fatima R, Lee-Smith W, Assaly R. The association of low serum albumin level with severe COVID-19: a systematic review and meta-analysis. Crit Care. 2020;24(1):255. https://doi.org/10.1186/s13054-020-02995-3
https://doi.org/10.1186/s13054-020-02995... . The CRP/albumin ratio (CAR) is a novel index calculated by dividing the CRP to albumin level, and many studies have shown that CAR can be used to predict the activity, severity, and prognosis of various conditions¹⁰10. Sayar S, Kurbuz K, Kahraman R, Caliskan Z, Atalay R, Ozturk O, et al. A practical marker to determining acute severe ulcerative colitis: CRP/albumin ratio. North Clin Istanb. 2019;7(1):49–55. https://doi.org/10.14744/nci.2018.78800
https://doi.org/10.14744/nci.2018.78800... ^,1111. Bozkurt E, Muhafiz E, Sengul D, Uçak T, Atum M. Can the CRP/albumin ratio be used as a new ındicator of activation in patients with uveitis? Ocul Immunol Inflamm. 2020;1–6. https://doi.org/10.1080/09273948.2020.1714061
https://doi.org/10.1080/09273948.2020.17... ^,1212. Yang WM, Zhang WH, Ying HQ, Xu YM, Zhang J, Min QH, et al. Two new inflammatory markers associated with disease activity score-28 in patients with rheumatoid arthritis: Albumin to fibrinogen ratio and C-reactive protein to albumin ratio. Int Immunopharmacol. 2018;62:293–8. https://doi.org/10.1016/j.intimp.2018.07.007
https://doi.org/10.1016/j.intimp.2018.07... ^,1313. Xu HJ, Ma Y, Deng F, Ju WB, Sun XY, Wang H. The prognostic value of C-reactive protein/albumin ratio in human malignancies: an updated meta-analysis. Onco Targets Ther. 2017;10:3059–70. https://doi.org/10.2147/OTT.S137002
https://doi.org/10.2147/OTT.S137002... . However, whether CAR is an efficient indicator in determining the severity of COVID-19 has not been investigated so far. Therefore, in this retrospective study, we aimed to determine the predictive values of the CAR, FAR, and NLR indices for the severity of COVID-19.

METHODS

Among the 188 included patients, 118 were in the severe group and 70 were in the non-severe group. Patients with connective tissue disorders, hematologic diseases, kidney or liver dysfunction, thyroid diseases, cancers, age less than 18 years, who were pregnant, and those receiving albumin transfusion before treatment were not included in the study. This retrospective study was approved by the Harran University Ethics Committee.

The age, gender, comorbidities, and laboratory results of the participants on admission were obtained from the database of the hospital information system. Complete blood count parameters (leukocyte, neutrophil, lymphocyte, monocyte, and hemoglobin) were determined using a Sysmex XN-1000 analyzer (Sysmex, Japan). Albumin, CRP, D-dimer, and procalcitonin levels were analyzed using the classical methods in a Cobas 8000 analyzer (Roche Diagnostics, Germany); the fibrinogen level was measured using a Sysmex CS-2000i analyzer (Sysmex, Japan). The FAR, CAR, and NLR values were calculated as follows: FAR=(fibrinogen/albumin ratio), CAR=(CRP/albumin ratio), and NLR=(neutrophil/lymphocyte ratio).

Statistical analysis

Data analysis was done using SPSS version 20 (IBM Corp, Armonk, NY) and a p<0.05 was considered significant. Demographic and laboratory data were compared between the severe and non-severe groups using the independent sample t-test, Mann-Whitney U-test, or χ². Correlations between CAR, FAR, and NLR and inflammatory markers in the COVID-19 patients were determined using the Spearman test. The predictive value of FAR, CAR and NLR in distinguishing severe from non-severe COVID-19 patients was determined by receiver operator characteristic (ROC) analysis.

RESULTS

A total of 188 patients with COVID-19 were included in this study. Of these patients, 112 were in the non-severe group while 70 were in the severe group. As shown in Table 1, the severe group had higher leukocyte and neutrophil counts; CRP, D-dimer, procalcitonin, and fibrinogen levels; and CAR, FAR, and NLR; and lower lymphocyte and monocyte counts and albumin levels than those in the non-severe group (p<0.05). The two groups did not differ in terms of age, male/female ratio, incidences of comorbidities, and hemoglobin level (p>0.05).

Correlations between CAR, FAR, and NLR and the inflammatory markers studied in COVID-19 patients are shown in Table 2. CAR and FAR were positively associated with leukocyte, neutrophil, CRP, procalcitonin, and fibrinogen levels and negatively associated with monocyte and lymphocyte counts. NLR was positively associated with leukocyte, neutrophil, CRP, procalcitonin, and fibrinogen levels and negatively associated with lymphocyte count.

ROC analysis results of the CAR, FAR, and NLR are shown in Table 3. The area under the ROC curve (AUC) was 0.841 (95%CI 0.784–0.899, p<0.001) for CAR, 0.737 (95%CI 0.663–0.811, p<0.001) for FAR, and 0.802 (95%CI 0.7350.869, p<0.001) for NLR (Figure 1).

Figure 1
Receiver operator characteristic curves of C-reactive protein/albumin ratio, fibrinogen/albumin ratio and neutrophil/lymphocyte ratio in predicting severe COVID-19 on admission.

DISCUSSION

In this study, we found that the severe COVID-19 group had higher CAR, FAR, and NLR compared to the non-severe COVID-19 group. In addition, the values of these 3 parameters were positively correlated with the leukocyte and neutrophil counts and CRP, procalcitonin, and fibrinogen levels and negatively correlated with monocyte (except for NLR) and lymphocyte counts. ROC analysis illustrated that CAR had the highest AUC value, thus demonstrating that it was more efficient than FAR and NLR in predicting the severity of COVID 19. To our knowledge, this is the first study that explores the predictive values of CAR for the COVID-19 severity.

COVID-19 infection has a wide clinical spectrum ranging from asymptomatic infection to severe/critical disease. Patients with severe COVID-19 can progress rapidly to develop worse clinical outcomes such as acute respiratory distress syndrome, multiple organ failure, and eventually death, while non-severe patients have a good prognosis¹⁵15. Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol. 2020;92(6):568–76. https://doi.org/10.1002/jmv.25748
https://doi.org/10.1002/jmv.25748... . Therefore, efficient indicators are needed to distinguish between severe and non-severe patients for timely treatment. In this context, the researchers focused on the predictive value of various laboratory parameters like lymphocyte count, NLR, CRP, albumin, and fibrinogen in severe COVID-19 disease⁵5. Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al. Diagnostic utility of clinical laboratory data determinations for patients with severe COVID-19. J Med Virol. 2020;92(7):791–6. https://doi.org/10.1002/jmv.25770
https://doi.org/10.1002/jmv.25770... ^–99. Aziz M, Fatima R, Lee-Smith W, Assaly R. The association of low serum albumin level with severe COVID-19: a systematic review and meta-analysis. Crit Care. 2020;24(1):255. https://doi.org/10.1186/s13054-020-02995-3
https://doi.org/10.1186/s13054-020-02995... .

Lymphopenia and neutrophilia are commonly observed hematological abnormalities in COVID-19 patients and have been proposed as effective indicators of disease severity and poor prognosis in COVID-19¹⁶16. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-ınfected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–9. https://doi.org/10.1001/jama.2020.1585
https://doi.org/10.1001/jama.2020.1585... ^,1717. Liu X, Zhang R, He G. Hematological findings in coronavirus disease 2019: indications of progression of disease. Ann Hematol. 2020;99(7):1421–8. https://doi.org/10.1007/s00277-020-04103-5
https://doi.org/10.1007/s00277-020-04103... ^,1818. Khartabil TA, Russcher H, van der Ven A, de Rijke YB. A summary of the diagnostic and prognostic value of hemocytometry markers in COVID-19 patients. Crit Rev Clin Lab Sci. 2020;57(6):415–31. https://doi.org/10.1080/10408363.2020.1774736
https://doi.org/10.1080/10408363.2020.17... . Recently, Nalbant et al.¹⁹19. Nalbant A, Kaya T, Varim C, Yaylaci S, Tamer A, Cinemre H. Can the neutrophil/lymphocyte ratio (NLR) have a role in the diagnosis of coronavirus 2019 disease (COVID-19)? Rev Assoc Med Bras (1992). 2020;66(6):746–51. https://doi.org/10.1590/1806-9282.66.6.746
https://doi.org/10.1590/1806-9282.66.6.7... found that the NLR index, which can be easily calculated by dividing the neutrophil count by the lymphocyte count, is an independent predictor for COVID-19 diagnosis. Moreover, some studies have reported that the NLR index is closely related to the progression of COVID-19²⁰20. Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol. 2020;84:106504. https://doi.org/10.1016/j.intimp.2020.106504
https://doi.org/10.1016/j.intimp.2020.10... ^,2121. Sun S, Cai X, Wang H, He G, Lin Y, Lu B, et al. Abnormalities of the peripheral blood system in patients with COVID-19 in Wenzhou, China. Clin Chim Acta. 2020;507:174–80. https://doi.org/10.1016/j.cca.2020.04.024
https://doi.org/10.1016/j.cca.2020.04.02... . Concordant with these studies, we observed that the NLR was higher in the severe than the non-severe COVID-19 patients and that it was positively associated with the inflammatory markers (leukocyte count, CRP, procalcitonin, and fibrinogen), suggesting that the NLR might be a potential predictor of severe COVID-19.

Albumin is a negative acute-phase reactant that tends to decrease in response to acute conditions such as inflammation, trauma, surgery, and burns²²22. Yap FHY, Joynt GM, Buckley TA, Wong ELY. Association of serum albumin concentration and mortality risk in critically ill patients. Anaesth Intensive Care. 2002;30(2):202–7. https://doi.org/10.1177/0310057X0203000213
https://doi.org/10.1177/0310057X02030002... . The albumin level was found to be lower in COVID-19 patients, and the hypoalbuminemia was more severe in critically ill patients⁹9. Aziz M, Fatima R, Lee-Smith W, Assaly R. The association of low serum albumin level with severe COVID-19: a systematic review and meta-analysis. Crit Care. 2020;24(1):255. https://doi.org/10.1186/s13054-020-02995-3
https://doi.org/10.1186/s13054-020-02995... ^,2323. Violi F, Cangemi R, Romiti GF, Ceccarelli G, Oliva A, Alessandri F, et al. Is albumin predictor of mortality in COVID-19? Antioxid Redox Signal. 2021;35(2):139–42. https://doi.org/10.1089/ars.2020.8142
https://doi.org/10.1089/ars.2020.8142... . On the other hand, fibrinogen is one of the positive acute phase response proteins that increase during inflammation²⁴24. Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol. 2012;34(1):43–62. https://doi.org/10.1007/s00281-011-0290-8
https://doi.org/10.1007/s00281-011-0290-... . Recent studies have shown that fibrinogen levels are significantly increased in severe COVID-19 patients compared to non-severe patients⁵5. Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al. Diagnostic utility of clinical laboratory data determinations for patients with severe COVID-19. J Med Virol. 2020;92(7):791–6. https://doi.org/10.1002/jmv.25770
https://doi.org/10.1002/jmv.25770... ^,66. Fu J, Kong J, Wang W, Wu M, Yao L, Wang Z, et al. The clinical implication of dynamic neutrophil to lymphocyte ratio and D-dimer in COVID-19: A retrospective study in Suzhou China. Thromb Res. 2020;192:3–8. https://doi.org/10.1016/j.thromres.2020.05.006
https://doi.org/10.1016/j.thromres.2020.... . In addition, Bi et al.⁷7. Bi X, Su Z, Yan H, Du J, Wang J, Chen L, et al. Prediction of severe illness due to COVID-19 based on an analysis of initial Fibrinogen to Albumin Ratio and Platelet count. Platelets. 2020;31(5):674–9. https://doi.org/10.1080/09537104.2020.1760230
https://doi.org/10.1080/09537104.2020.17... reported that FAR, simply calculated by the ratio of fibrinogen to albumin, could be a new marker for estimating the severity of COVID-19, which is consistent with our results.

CRP, another positive acute phase reactant, increases in response to infections, inflammation, and tissue damage²⁵25. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805–12. https://doi.org/10.1172/JCI18921
https://doi.org/10.1172/JCI18921... . It has been shown that in COVID-19 patients, CRP reaches high levels and the magnitude of the increase correlates with the severity of the illness⁸8. Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol. 2020;127:104370. https://doi.org/10.1016/j.jcv.2020.104370
https://doi.org/10.1016/j.jcv.2020.10437... . On the other hand, the role of the CAR index, the ratio of CRP to albumin, in predicting the severity of COVID-19 is unknown. Therefore, this study investigated the ability of CAR, as well as NLR and FAR, to differentiate between patients with and without severe COVID-19. We found that the CAR value was higher in severe patients compared to non-severe patients and that it was positively correlated with leukocyte, neutrophil, CRP, procalcitonin, and fibrinogen and negatively correlated with monocyte and lymphocyte counts. In addition, in our ROC curve analysis, the AUC value of CAR was greater than that of FAR and NLR. These results showed that CAR was more efficient than FAR and NLR in predicting the severity of COVID 19.

The main limitation of our study is its retrospective design and it was conducted at a single center. Another limitation was the lack of data on smoking, alcohol use, and body mass index affecting laboratory results.

CONCLUSIONS

In conclusion, we found that the CAR, FAR, and NLR indices could be used as new potential parameters to distinguish severe COVID-19 patients from non-severe patients. Of these, CAR was the best predictor of severe COVID-19.

REFERENCES

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