Association of Plasma Calprotectin Levels with Disease Severity in COVID-19 Patients

Abstract

Objectives

Inflammation plays an important role in the pathogenesis of COVID-19. Calprotectin, a protein released by inflammatory cells, is associated with this inflammatory response.

Materials and Methods

A prospective study was conducted on 30 patients with mild to moderate COVID-19, 30 patients with severe COVID-19, and 30 healthy controls. Calprotectin levels were analyzed with a commercially purchased Cloud Cloning Kit.

Results

Plasma calprotectin levels in COVID-19 patients (12.5 ± 8.8 ng/mL) were significantly greater than those in the controls (8.23 ± 2.99 ng/mL; p = 0.012). The calprotectin level in the mild to moderate COVID-19 group (9.85 ± 6.94 ng/mL) was significantly lower than that in the severe COVID-19 group (15.19 ± 9.87 ng/mL; p = 0.019). The recommended cutoff value for the calprotectin level was 7.45 ng/mL with 63.3% sensitivity and 53.3% specificity. Seventeen (28.3%) of the COVID-19 patients died due to COVID-19-related causes. The calprotectin level in the exiting patients (16.33 ± 7.65 ng/mL) was significantly greater than the calprotectin level in the living cases (11.01 ± 8.95 ng/mL; p = 0.035).

Conclusion

Calprotectin levels were greater in COVID-19 patients than in healthy controls and in more severe patients than in mild to moderate cases. Calprotectin levels may be used as a biomarker to predict severe COVID-19 cases.

Keywords

COVID-19 - calprotectin - prognosis - biomarker - severity

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is a virus that causes COVID-19 infection in humans. The clinical course of COVID-19 varies significantly across individuals. While some patients experience mild symptoms such as fever, fatigue, diarrhea, and joint and muscle pain, others may develop more severe manifestations, including pneumonia, respiratory failure, cytokine release syndrome, and thromboembolic complications.[1] [2] As the spectrum of disease severity can be wide, early identification of patients at risk of severe outcomes is crucial for improving clinical management and outcomes.

Although the precise pathophysiology of COVID-19 remains unclear, a major contributor to disease severity is the body's inflammatory response.[3] It has been reported that the virus infects respiratory tract epithelial cells, leading to the release of proinflammatory cytokines and an exacerbated inflammatory response, particularly in patients with severe respiratory failure.[4] Neutrophils and macrophages play important roles in the inflammatory response. The cytokines interleukin-6 (IL-6) and IL-1β, released by these cells, are considered negative prognostic markers.[5] [6] Several laboratory parameters, including thrombocytopenia, lymphocytopenia, anemia, elevated C-reactive protein (CRP), increased procalcitonin, increased D-dimer, and increased lactate dehydrogenase (LDH) are used to assess the severity of COVID-19. However, it remains unclear which markers can reliably predict the clinical course of the disease, and the search for new biomarkers continues.

Calprotectin, a member of the calcium-binding S100 family, is secreted by neutrophils, monocytes, macrophages, epithelial cells, and platelets.[7] Its levels rise in response to infections, autoimmune diseases, and other inflammatory conditions.[8] [9] Calprotectin functions as an inflammatory mediator, interacting with receptors like toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), which in turn stimulates the production of proinflammatory cytokines.[10] As such, calprotectin is a critical regulator of inflammation, promoting neutrophil migration and the release of cytokines such as IL-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α).[7] Elevated calprotectin levels have been associated with a heightened inflammatory response, and it is increasingly being considered a potential biomarker for disease activity and prognosis in various inflammatory diseases.[11]

Despite the growing body of research, the role of calprotectin as a biomarker in COVID-19 remains underexplored.[12] [13] [14] [15] Therefore, we conducted this study to understand the role of calprotectin in COVID-19 and to evaluate its potential in predicting disease severity. By addressing the gap in existing research, we aim to provide a clearer perspective on how this biomarker can be utilized in the management of COVID-19 patients.

Materials and Methods

This study was designed to evaluate the association between plasma calprotectin levels and the severity of COVID-19, so participants were selected based on their disease severity. In our study, 30 patients with mild to moderate COVID-19 and 30 patients with severe COVID-19 who were followed up at Atatürk University Faculty of Medicine Hospital were evaluated. COVID-19 was diagnosed in the cases in which the SARS-CoV-2 virus was detected in nasopharyngeal and/or oropharyngeal swabs by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In addition, 30 healthy individuals were included in the control group. The control group consisted of patients who were asymptomatic for COVID-19 but were negative for SARS-CoV-2 by RT-PCR for other reasons. Participants with mild to moderate and severe COVID-19 were specifically selected to capture a broad spectrum of disease severity, as this range is most relevant for understanding how calprotectin levels might correlate with disease progression and prognosis. Pregnant women, patients with malignancy, patients receiving immunosuppressive therapy, and individuals with autoimmune, infectious, or inflammatory diseases were excluded from the study. Additionally, patients with preexisting comorbid conditions, such as diabetes or other systemic diseases, were not included to minimize the impact of underlying health issues on COVID-19 outcomes. Only patients whose symptoms had started within the last week were included, ensuring consistent timing of presentation across participants. This allowed for a clearer assessment of the relationship between symptom onset and disease severity. Finally, vaccinated individuals were excluded to focus on unvaccinated COVID-19 patients and avoid the confounding effects of vaccination on immune responses and calprotectin levels.

Patients with a respiratory rate of less than 30/min, oxygen saturation ≥94% in room air, and mild to moderate pneumonia findings (<50%) on chest radiography or CT scan were considered to have mild to moderate COVID-19. Patients with a respiratory rate ≥30/min, oxygen saturation less than 94% in room air, and severe pneumonia findings (>50%) on chest radiography or tomography, and those requiring mechanical ventilation or intensive care unit follow-up were considered patients with severe COVID-19. The severity-based selection of participants directly influenced the design and outcomes of the study by ensuring that we could draw meaningful comparisons between different stages of disease and evaluate calprotectin's potential as a predictive biomarker for severe disease.

Ten milliliter of blood was collected from all patients and centrifuged at 3,000 rpm for approximately 5 minutes. The plasma portion was collected and stored at −80°C until analysis. After the serum samples were thawed under appropriate conditions for analysis, all analyses were performed in the Medical Biochemistry Laboratory of Atatürk University Health Research and Application Center Directorate.

Calprotectin levels were analyzed with a commercially purchased Cloud Cloning Kit (CALPRO) according to the manufacturer's standard protocol. Routine laboratory tests including complete blood count, sedimentation rate, LDH, CRP, procalcitonin, ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatine, albumin, fibrinogen, D-dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalization ratio (INR) values were obtained from the hospital database.

The data were analyzed using SPSS 20.0 (SPSS, Chicago, IL, United States). Descriptive data are expressed as the mean ± standard deviation (SD), and categorical data are expressed as proportions. The compatibility of the parameters with a normal distribution was evaluated by the Kolmogorov–Smirnov test. Independent sample t-tests were used for comparisons of two groups with a normal distribution and Mann–Whitney U tests were used for comparisons of two groups without a normal distribution. The Kruskal–Wallis test and Dunn–Bonferroni correction were used for comparisons of quantitative variables that did not show a normal distribution between more than two groups. Correlations between quantitative variables were evaluated with Pearson's and Spearman's correlation analyses. Receiver operating characteristic (ROC) analysis was used to determine the risk of severe COVID-19. Survival analyses were performed with the Kaplan–Meier method and univariate and multivariate Cox regression analyses, and hazard ratios (HRs) and 95% confidence intervals (95% CIs) were evaluated for different parameters. A p-value of less than 0.05 was considered to indicate statistical significance.

Results

Thirty-five (58.3%) COVID-19 patients were females and 25 (41.7%) were males, aged 61.85 ± 12.54 years. In the control group, 18 (60%) patients were females and 12 (40%) patients were males, with an average age of 57.5 ± 4.7 years. The COVID-19 and control groups were similar in terms of gender distribution and age (p = 0.07 and 0.06, respectively).

Of the patients with COVID-19 included in the study, 30 (50%) had mild to moderate COVID-19 and 30 (50%) had severe COVID-19. The demographic and laboratory characteristics of these two groups are shown in [Tables 1] and [2].

Table 1 Demographic characteristics of COVID-19 cases

	Mild to moderate COVID-19	Severe COVID-19	p-value
Age (y)	54.12 ± 14.34	64.21 ± 8.12	0.03
Gender (female/male), n (%)	18 (60%)/12 (40%)	13 (43.3%)/17 (56.7%)	0.3
Diabetes mellitus, n (%)	8 (26.7%)	13 (43.3%)	0.27
Hypertension, n (%)	7 (23.3%)	13 (43.3%)	0.17
Coronary artery disease, n (%)	3 (10%)	10 (33.3%)	0.05
Chronic obstructive pulmonary disease, n (%)	4 (13.3%)	12 (40%)	0.03
Chronic renal failure, n (%)	0	4 (13.3%)	0.02
Obesity, n (%)	8 (26.7%)	13 (43.3%)	0.27

Table 2 Laboratory findings of COVID-19 cases

Parameter	Mild to moderate COVID-19	Severe COVID-19	p-value
Leukocytes (µL)	7803,3 ± 4133,8	11606,7 ± 5967.9	0.08
Monocytes (µL)	533.3 ± 351.8	387.4 ± 238.9	0.06
Lymphocytes (µL)	1664.2 ± 1904.2	928.2 ± 1233.6	0.07
Neutrophils (µL)	5522.6 ± 3824.1	10259.6 ± 5586.6	<0.01
Hemoglobin (g/dL	14.16 ± 1.63	11.84 ± 2.4	<0.01
Hematocrit (%)	43.6 ± 4.7	37.2 ± 7.8	<0.01
Platelets (µL)	238266.6 ± 92425.1	215000 ± 115654.4	0.9
Sedimentation (mm/h)	38.6 ± 32.4	44.5 ± 30.3	0.6
Procalcitonin (ng/mL)	0.7 ± 1	4.3 ± 9.8	0.08
Ferritin (ng/mL)	487.6 ± 463.6	1313.3 ± 2091.7	0.03
Fibrinogen	541.5 ± 146.5	475.6 ± 201.2	0. 16
D-dimer (ng/mL)	1242.1 ± 1444.6	5494.5 ± 10103.5	0.02
Prothrombin time (sec)	13.6 ± 1.5	17.1 ± 4.8	<0.01
Activated partial thromboplastin time (s)	29.4 ± 3.1	34.3 ± 14.2	0.06
International normalization rate	1.01 ± 0.1	1.2 ± 0.3	<0.01
Aspartate amino transferase (U/L)	65.6 ± 145.7	154.8 ± 381.6	0.23
Alanine aminotransferase (U/L)	46.7 ± 76	145.2 ± 297.3	0.08
Alkaline phosphatase (U/L)	78.5 ± 60.3	136.2 ± 177.3	0.019
Gamma glutamyltransferase (U/L)	48.7 ± 47.4	133.5 ± 88.9	<0.01
Lactate dehydrogenase (U/L)	333.9 ± 148.4	581.5 ± 290.8	<0.01
Blood urea nitrogen (mg/dL)	24.2 ± 18.4	36.4 ± 22.8	0.02
Creatine (mg/dL	1.03 ± 0.6	2 ± 4.4	0.23
Albumin (g/L)	41 ± 4.4	35.6 ± 20.3	0.16
C-reactive protein (mg/dL)	165 ± 57.8	176.8 ± 99.9	0.23

The calprotectin level in the COVID-19 group (12.5 ± 8.8 ng/mL) was significantly greater than the calprotectin level in the control group (8.23 ± 2.99 ng/mL; p = 0.012). This finding highlights the role of calprotectin as a marker of inflammation in COVID-19. In addition, the calprotectin level in the mild to moderate COVID-19 group (9.85 ± 6.94 ng/mL) was significantly lower than that in the severe COVID-19 group (15.19 ± 9.87 ng/mL; p = 0.019). The p-value of 0.019 indicates that this difference is statistically significant, suggesting that calprotectin levels are higher in severe cases of COVID-19. Clinically, this difference may reflect the intensity of the inflammatory response in severe cases. The relationships between calprotectin levels and the symptoms and clinical course of the patients are shown in [Table 3].

Table 3 The relationship between calprotectin level and admission symptoms and clinical course

Parameter		Calprotectin level (ng/mL)	p-value
Cough	Present (n = 24)	14.48 ± 9.5	0.017
	None (n = 36)	9.17 ± 5.35
Loss of taste	Present (n = 22)	16.11 ± 9.43	0.008
	None (n = 38)	10.18 ± 7.21
Loss of smell	Present (n = 18)	15.79 ± 10	0.04
	None (n = 42)	10.88 ± 7.42
Diarrhea	Present (n = 15)	18.36 ± 12.07	0.009
	None (n = 45)	11.01 ± 6.98
Myalgia	Present (n = 42)	11.06 ± 6.2	0.001
	None (n = 18)	6.39 ± 3.68
Sore throat	Present (n = 44)	13.6 ± 7.37	0.72
	None (n = 16)	12.32 ± 8.58
Runny nose	Present (n = 38)	15.8 ± 11.87	0.57
	None (n = 22)	12.33 ± 8.4
The need for a high-frequency oscillator or continuous positive airway pressure	Present (n = 22)	13.49 ± 8.95	0.04
	None (n = 38)	7.84 ± 2.24
Cytokine release syndrome	Present (n = 15)	19.05 ± 8.98	0.006
	None (n = 45)	11.14 ± 7.73

There was a negative correlation between the plasma calprotectin level and platelet count (r = 0.27, p = 0.03). This finding indicates a weak but statistically significant relationship between lower platelet counts and higher calprotectin levels. This correlation might suggest that higher calprotectin levels could be associated with more severe systemic inflammation, which could contribute to thrombocytopenia, a known complication of severe COVID-19. There was no correlation between calprotectin levels and leukocyte, lymphocyte, monocyte, neutrophil, hemoglobin, sedimentation, CRP, procalcitonin, fibrinogen, D-dimer, PT, aPTT, INR, AST, ALT, ALP, GGT, LDH, BUN, creatine, and albumin levels 442 / 5.000 (r = 0.23, p = 0.07; r = 0.18, p = 0.15; r = 0.07, p = 0.59; r = 0.19, p = 0.14; r = 0.008, p = 0.94; r = 0.07, p = 0.58; r = 0.048, p = 0.59; r = 0.13, p = 0.29; r = 0.08, p = 0.5; r = 0.03, p = 0.76; r = 0.04, p = 0.76; r = 0.17, p = 0.18; r = 0.01, p = 0.88; r = 0.02, p = 0.87; r = 0.05, p = 0.7; r = 0.21, p = 0.1; r = 0.23, p = 0.07; r = 0.15, p = 0.25; r = 0.1, p = 0.41; r = 0.09, p = 0.48; r = 0.4, p = 0.09). This lack of correlation may suggest that calprotectin operates through a distinct inflammatory pathway compared with these more commonly used biomarkers.

In terms of the need for mechanical ventilation, the area under the ROC curve (AUC) for the calprotectin level was 0.666 (95% CI: 0.529–0.803, p = 0.027). The AUC value of 0.666 suggests that calprotectin has moderate predictive power for identifying patients who may require mechanical ventilation. The recommended cutoff value for calprotectin was 7.45 ng/mL, with 63.3% sensitivity and 53.3% specificity ([Fig. 1])

Fig. 1 Receiver operating characteristic (ROC) analysis of the ability of calprotectin to predict the need for mechanical ventilation.

During the follow-up period, 17 (28.3%) of the patients with COVID-19 had excitus due to COVID-19-related causes. The calprotectin level (16.33 ± 7.65 ng/mL) in deceased patients was significantly greater than the calprotectin level (11.01 ± 8.95 ng/mL) in living patients (p = 0.035). This p-value indicates that the difference in calprotectin levels between patients who died and those who survived is statistically significant. Higher calprotectin levels in deceased patients suggest that these patients had a more intense inflammatory response, which might have contributed to their fatal outcome. This highlights the potential role of calprotectin as a prognostic marker for mortality in COVID-19. The parameters found to be associated with patient survival are shown in [Table 4].

Table 4 The effect of demographic findings and laboratory tests on survival

Parameters	Hazard ratio (95.0% Cl)	p-value
Univariate analysis
Age	0.71 (0.28–1.75)	0.03
Gender	0.44 (0.37–1.36)	0.04
Diabetes mellitus	1.13 (0.29–1.26)	0.02
Coronary artery disease	1.09 (0.47–1.73)	0.03
Obesity	0.81 (0.41–1.96)	0.03
Leukopenia	1.07 (0.26–1.31)	0.02
Lymphocytopenia	1.03 (0.86–1.64)	0.03
Anemia	1.34 (0.34–2.14)	0.04
Thrombocytopenia	0.31 (0.23–1.97)	0.02
Increased C-reactive protein	1.19 (0.64–1.93)	0.02
D-dimer height	1.24 (0.11–1.75)	0.03
Hypoalbuminemia	0.44 (0.31–1.91)	0.04
High calprotectin value	0.91 (0.72–1.8)	0.03
Multivariate analysis
Age	1.23 (0.49–1.27)	0.02
Coronary artery disease	0.64 (0.21–2.1)	0.03
Lymphocytopenia	1.19 (0.42–1.31)	0.03
Thrombocytopenia	1.29 (0.54–2.1)	0.02
D-dimer	1.12 (0.12–1.45)	0.04
High calprotectin level	0.58 (0.19–2.8)	0.03

Abbreviation: CI, confidence interval.

Discussion

In our study, we found that plasma calprotectin levels were higher in COVID-19 patients than in healthy individuals, in patients with severe COVID-19 than in patients with mild to moderate COVID-19, and in patients with intensive care needs than in patients without intensive care needs. These findings suggest that the plasma calprotectin level may be a biomarker that can be used to predict disease severity and intensive care needs in COVID-19 patients.

The clinical course of COVID-19 can range from mild symptoms such as runny nose, muscle and joint pain, weakness, and fatigue to severe symptoms such as thromboembolic complications and severe respiratory failure. Predicting the clinical course of cases is very important, as early detection of severe cases can guide important clinical decisions and reduce mortality rates. Some parameters can be used to predict mild/moderate or severe COVID-19 patients at the time of diagnosis.[16] [17] [18] Increased neutrophil count, ferritin, CRP, IL-1β, and IL-6 are among these parameters.[5] [6] [19] [20] [21] [22] One of the most important causes of inflammation and respiratory failure is increased neutrophil counts. Calprotectin is a protein secreted mainly from neutrophils and macrophages and its prognostic importance in COVID-19 cases has been investigated in various studies.[14] [15] [23] [24] [25] [26] Our study supports previous research indicating that calprotectin levels are elevated in COVID-19 patients. However, we extend this finding by showing that calprotectin levels are significantly higher in severe cases compared with mild to moderate cases. This finding is consistent with the literature, but our study emphasizes the potential of calprotectin as a predictor of disease severity and the need for intensive care.

In COVID-19 cases, serum or plasma calprotectin levels as well as fecal calprotectin levels can be evaluated. This is because SARS-CoV-2 binds to intestinal epithelial cells via specific receptors and triggers acute inflammation characterized by neutrophil and macrophage infiltration.[27] Shokri-Afra et al reported that plasma and fecal calprotectin levels were higher in COVID-19 patients than in controls, but there was no difference between patients with and without gastrointestinal symptoms.[26] Ojetti et al reported a significant correlation between high fecal calprotectin levels and COVID-19 pneumonia and the severity of the disease.[28] Our study complements these findings by also identifying that plasma calprotectin levels were higher in COVID-19 patients with gastrointestinal symptoms such as diarrhea. This finding strengthens the understanding that calprotectin levels could be a marker of not just respiratory but also gastrointestinal involvement in COVID-19, adding a layer of insight to existing research.

The severity of inflammation in COVID-19 cases is the most important factor in determining disease severity.[3] The level of calprotectin is also increased in cases of inflammation. In our study, we detected higher calprotectin levels in patients with severe COVID-19 than in mild to moderate cases, consistent with this finding. Therefore, we believe that the plasma calprotectin level is a biomarker that can be used to predict the prognosis of patients with COVID-19.

De Guadiana et al. showed that serum calprotectin levels were positively correlated with ferritin, CRP and D-dimer levels.[15] In our study, we found no correlation between calprotectin levels and acute phase reactants such as sedimentation, CRP and ferritin. This discrepancy may be due to differences in patient populations or disease stages. While calprotectin is a well-established marker of neutrophil-driven inflammation, it is possible that the inflammatory cascade in COVID-19 involves a complex interplay between different immune cells and pathways, which may explain why calprotectin does not correlate with these more traditional biomarkers.

Ojetti et al. reported a significant association between increased fecal calprotectin and the severity of COVID-19.[28] In our study, we detected increased higher plasma calprotectin levels in patients who needed mechanical ventilation. This finding underscores the potential of calprotectin as a predictive marker not only for disease severity but also for the need for mechanical ventilation, further confirming its clinical relevance in COVID-19 management.

Increased acute phase reactants such as CRP, ferritin and D-dimer are indicators of decreased survival in COVID-19 patients.[29] De Guadiana Romualdo et al reported that calprotectin has a predictive capacity similar to that of D-dimer and CRP, but much better than that of ferritin in terms of determining the risk of death.[15] There are also some recent studies showing that high serum calprotectin levels are strongly associated with the risk of death in patients with COVID-19, usually due to thrombotic problems.[14] [30] In our study, we determined that calprotectin level was one of the factors affecting mortality. Our study reinforces these findings by demonstrating that elevated calprotectin levels are associated with an increased risk of mortality in COVID-19 patients, thus contributing valuable insights into the role of calprotectin in predicting patient outcomes.

Conclusion

Calprotectin testing is an inexpensive test that can be performed in many centers. It is a biomarker that can predict the clinical course, need for intensive care, and mortality risk in COVID-19 cases. Our findings suggest that calprotectin could be integrated into routine clinical practice to help identify high-risk patients early, guiding treatment and resource allocation. Further research is needed to validate these results and explore the use of calprotectin in other inflammatory diseases. Future studies should investigate its role in disease progression and treatment response, with multicenter trials to assess its broader applications. We recommend that clinicians and researchers consider incorporating calprotectin testing into clinical decision-making for better management of COVID-19 and similar conditions.

Conflict of Interest

None declared.

Authors' Contributions

All the authors contributed to collecting the data, writing the article, reviewing, and approving the final article.

Compliance with Ethical Principles

Approval for this study was obtained from the Atatürk University Faculty of Medicine Clinical Research Ethics Committee (Date: April 28, 2022, Decision no: 38).

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Publication History

Article published online:
08 May 2025